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Preparation method of ozanimod and intermediate thereof

A compound, the technology of tert-butyldimethylsilane, which is applied in the field of preparation of Ozamod and its intermediates, can solve the problems of unfavorable industrial production, increase of production cost, high risk, etc., and achieve the benefit of large-scale Industrialized production, reduced production cost, and short reaction time

Active Publication Date: 2020-12-11
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] After that, there have been literatures to improve this route. For example, the patent application WO2011060392 discloses three reaction routes for the synthesis of Ozamod, one of which is based on WO2009151529, using chiral Ru reagents such as RuCl(p-isopropyltoluene)[(R,R)-Ts-DPEN] replaces sodium borohydride for chiral reduction, and others are basically consistent with the route of WO2009151529; this method uses expensive transition metal catalysts, which is not conducive to industrial production
Among them, the other route is to use 4-bromo-1-indan-one as raw material, after substitution, and then use the chirality of sulfinamide to induce control, hydrolyze and remove the sulfinyl protecting group to obtain chiral amine group, and then replace the protective group with the reaction, and then undergo addition reaction, ring formation reaction, deprotection group, and then replace to obtain Ozamod; the reaction route has many steps, the product cycle is long, and the production cost is increased. The first step The highly toxic reagent zinc cyanide is also used, which is very harmful to the human body
Another method is to use dangerous sodium hydride as a protective group on the chiral amine group, which is prone to explosion during industrial scale-up and is difficult to replace with other alkaline reagents, which limits the possibility of large-scale production
The method disclosed in WO2018215807 uses sulfenamide as a chiral inducing reagent to obtain Ozamod through substitution reaction, addition, ring formation, and deprotection; the first step reaction also uses dangerous sodium hydride, and there is the same Factors that are not conducive to industrial production

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  • Preparation method of ozanimod and intermediate thereof
  • Preparation method of ozanimod and intermediate thereof
  • Preparation method of ozanimod and intermediate thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0066] The preparation of embodiment 1 compound (B)

[0067] To the compound (A) that is (S)-N-((S)-4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinic acid Add 26 mg of sodium tungstate dihydrate and 2 mL of DMF to the reaction flask of amide (55 mg), stir at room temperature, and after 30 min, add 95 mg of 30% H 2 o 2 Solution, 2min dripping. After the drop, the temperature was raised to 45°C, and the stirring was continued for 5 h, and the reaction was completed; then, 5 mL of ethyl acetate and 10 mL of water were added to the reaction system, and the mixture was stirred and extracted at room temperature. After 25 minutes, let it stand still, separate the liquid, and collect the organic phase. The aqueous phase was extracted twice with ethyl acetate (6 mL / time), the organic phases were collected and combined, and the organic phases were concentrated under reduced pressure at 45-50 ° C to obtain compound (B), namely (S)-N-(4-cyano -2,3-dihydro-1H-inden-1-yl)-2-...

Embodiment 2

[0068] The preparation of embodiment 2 compound (B)

[0069]Add compound (A) in a single-necked bottle, that is, (S)-N-((S)-4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2- Sulfinamide (11g), 4.15g sodium tungstate dihydrate, 55mL DMF, add 30% H 2 o 2 (19.0g) solution, heated to 50 ℃ and stirred, the reaction ended; then add Na in the reaction system 2 SO 3 (21.12g, 4eq) in water (100mL) solution to quench the reaction, add 150mL ethyl acetate and 100mL water, stir for 30min, separate the liquid, collect the organic phase, combine the organic phase layers and distill under reduced pressure at 45°C to obtain the compound (B) namely (S)-N-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfonamide, 11.2 g.

Embodiment 3

[0070] The preparation of embodiment 3 compound (C)

[0071] The compound (B) obtained in Example 1 is equipped with (S)-N-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2- Add 147mg CS to the reaction vial of sulfonamide 2 CO 3 and 2mL DMF, stirred at room temperature, after 25min, added 108mg (2-bromoethoxy)-tert-butyldimethylsilane, reacted at room temperature for 15h, and the reaction ended; added 10mL water to the reaction system, stirred at room temperature, turbid , Stir for about 1h, observe that the turbid system is not a solid, similar to an emulsion, then add 5mL of dichloromethane to the turbid system, stir and extract at room temperature, stir for 25min, let stand, and find emulsification, add 2mL saturated saline, the layering is obvious, The organic phase was collected, the aqueous phase was extracted twice with dichloromethane (6 mL / time), the organic phase was collected, combined, and the organic phase was concentrated under reduced pressure at 30-40° C...

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Abstract

The invention relates to a preparation method of ozanimod and an intermediate thereof, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: oxidizinga sulfonamide substrate to obtain a sulfamide compound, and carrying out substitution and other reactions to obtain ozanimod. The method disclosed by the invention does not need to use a sodium-hydrogen reagent with high risk, has the advantages of high yield, high purity of the obtained ozanimod intermediate, convenience in operation and good safety, and is suitable for industrial amplification.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of Ozamod and its intermediate. Background technique [0002] Ozamod, English name: Ozanimod, also known as 5-[3-[(1S)-2,3-dihydro-1-[(2-hydroxyethyl)amino]-1H-indene-4- Base]-1,2,4-oxadiazol-5-yl]-2-(1-methylethoxy)-benzonitrile), its structure is shown in formula (I), Ozamod is A novel oral, selective sphingosine 1 phosphate receptor (S1P1R) modulator developed by the Scripps Research Institute for the treatment of autoimmune diseases such as multiple sclerosis (MS ), Crohn's disease (CD), etc. [0003] [0004] Patent application WO2009151529 discloses the steps of using 4-cyano-1-indan-one as a raw material, adding hydroxylamine after hydroboration reduction, further ring-forming reaction with carboxylic acid, and then substituting reaction with 2-hydroxyethylamine. Obtain the method of Ozamod afterward; Its method is the route of achiral synthesi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/10C07D271/06C07C311/07
CPCC07F7/10C07D271/06C07C311/07C07C2602/08Y02P20/55
Inventor 许国彬胡燕青王仲清廖守主罗忠华黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD