CN112062785A - Preparation method of ozapimod and intermediate thereof - Google Patents

Preparation method of ozapimod and intermediate thereof Download PDF

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CN112062785A
CN112062785A CN201910501725.1A CN201910501725A CN112062785A CN 112062785 A CN112062785 A CN 112062785A CN 201910501725 A CN201910501725 A CN 201910501725A CN 112062785 A CN112062785 A CN 112062785A
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compound
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formula
tert
butyldimethylsilane
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CN112062785B (en
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许国彬
胡燕青
王仲清
廖守主
罗忠华
黄芳芳
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Guangdong HEC Pharmaceutical
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention relates to a preparation method of ozapimod and an intermediate thereof, belonging to the field of pharmaceutical chemistry. The preparation method comprises the following steps: oxidizing a sulfenamide substrate to obtain a sulfonamide compound, and then carrying out substitution and other reactions to obtain the ozapimod. The method provided by the invention does not need a sodium-hydrogen reagent with high risk, has high yield, and the obtained intermediate of the ozagrimod has high purity, is convenient to operate, has good safety, and is suitable for industrial amplification.

Description

Preparation method of ozapimod and intermediate thereof
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a preparation method of ozapimod and an intermediate thereof.
Background
Ozatimod, english name: ozanimod, also known as 5- [3- [ (1S) -2, 3-dihydro-1- [ (2-hydroxyethyl) amino ] -1H-inden-4-yl ] -1,2, 4-oxadiazol-5-yl ] -2- (1-methylethoxy) -benzonitrile, has the structure shown in formula (I), and Ozanimod is a novel oral, selective sphingosine 1 phosphate receptor (S1P1R) modulator developed by the schripps Research Institute for the treatment of autoimmune diseases, such as Multiple Sclerosis (MS), crohn' S disease (CD), etc.
Figure BDA0002090457600000011
Patent application WO2009151529 discloses a method for obtaining ozagrimod by using 4-nitrile-1-indene-ketone as a raw material, performing hydroboration reduction, then performing addition reaction with hydroxylamine, further performing cyclization reaction with carboxylic acid, performing substitution reaction with 2-hydroxyethylamine, and the like; the method is a non-chiral synthetic route, the obtained intermediate or product is a racemic compound, and further chiral resolution is needed so as to obtain the ozagrimod.
After that, documents are continuously available to improve the route, for example, patent application WO2011060392 discloses three reaction routes for synthesizing ozagrimod, wherein one route is based on WO2009151529, chiral Ru reagent such as RuCl (p-cymene) [ (R, R) -Ts-DPEN ] is adopted to replace sodium borohydride for chiral reduction during reduction reaction, and the others are basically consistent with the route of WO 2009151529; the method uses an expensive transition metal catalyst, and is not favorable for industrial production. Wherein, the other route is to take 4-bromo-1-indene-ketone as a raw material, substitute, then utilize chirality of sulfenamide to carry out induction control, hydrolyze and remove sulfinyl protecting group to obtain chiral amino, then carry out protecting group on substitution reaction, then carry out addition reaction, cyclization reaction, remove protecting group, and obtain ozaimod after substitution; the reaction route has multiple steps, the product period is long, the production cost is improved, and a highly toxic reagent zinc cyanide is also used in the first step, so that the harm to human bodies is great. In another method, the protective group on the chiral amine group uses sodium hydride with high danger, explosion easily occurs during industrial scale-up, and the substitution with other alkaline reagents is difficult, which limits the possibility of large-scale production. According to the method disclosed by WO2018215807, sulfinamide is used as a chiral induction reagent, and ozapimod is obtained through substitution reaction, addition, cyclization and deprotection; the first reaction step also uses dangerous sodium hydride, and the same factors are unfavorable for industrial production.
Therefore, research on the preparation method of ozapimod is still needed to obtain a method which is safe and simple to operate, easy to implement, low in cost, high in yield, high in purity and environment-friendly.
Disclosure of Invention
The invention aims to solve the problems and provides a preparation method of ozagrimod and an intermediate thereof, which has low production cost and good safety and is suitable for industrial production.
In one aspect, the present invention provides an intermediate compound (B), which has a structure represented by formula (B):
Figure BDA0002090457600000021
in another aspect, the present invention also provides a method for preparing compound (B), comprising: adding oxidant and catalyst into reaction solvent, oxidizing at certain reaction temperature, post-treating to obtain compound B
Figure BDA0002090457600000022
The reaction for producing the compound (B) in the present invention may be carried out in one reaction solvent or a mixed solvent of a plurality of reaction solvents. In some embodiments, the reaction solvent is selected from at least one of DMF, DMA, DMSO, NMP, and THF. In some embodiments, the reaction solvent is DMF, which facilitates reaction performance and operation, and facilitates control of impurities.
In some embodiments, the oxidation reaction is carried out at a reaction temperature of from 40 ℃ to 60 ℃. In some embodiments, the oxidation reaction is carried out at a reaction temperature of 45 ℃ to 50 ℃.
The oxidant is at least one of hydrogen peroxide, TEMPO and IBX. In some embodiments, the oxidizing agent is hydrogen peroxide.
The catalyst is selected from at least one of sodium tungstate dihydrate and potassium tungstate. In some embodiments, the catalyst is sodium tungstate dihydrate.
In some embodiments, the molar ratio of compound (a) to oxidant is 1:3.0 to 1: 5.0; or the molar ratio is 1:3.5-1: 4.5.
In some embodiments, the molar ratio of compound (a) to catalyst is from 1:0.2 to 1: 0.4.
In some embodiments, the oxidation reaction has a reaction time of 3h to 7 h; or the oxidation reaction time is 4h-6 h.
The post-treatment comprises the following steps: stopping the reaction, adding ethyl acetate and water into the reaction system, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (B); the compound (B) is optionally purified, etc.
In some embodiments, a method for preparing an otimod intermediate compound (B) comprises: in a reaction solvent, the compound (A) reacts at 40-60 ℃ in the presence of an oxidant and a catalyst, and after the reaction is finished, the compound (B) is prepared by post-treatment.
In some embodiments, a method for preparing an otimod intermediate compound (B) comprises: in the reaction solvent, the compound (a) and the catalyst are stirred at room temperature; then carrying out reaction at 40-60 ℃ in the presence of an oxidant; after the reaction is finished, the compound (B) is prepared by post-treatment.
In some embodiments, a method for preparing an otimod intermediate compound (B) comprises: in a reaction solvent, reacting a compound (A) at 40-60 ℃ in the presence of an oxidant and a catalyst, adding ethyl acetate and water after the reaction is finished, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (B).
In some embodiments, a method for preparing an otimod intermediate compound (B) comprises: in the reaction solvent, the compound (a) and the catalyst are stirred at room temperature; then carrying out reaction at 40-60 ℃ in the presence of an oxidant; after the reaction is finished, adding ethyl acetate and water, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (B).
In some embodiments, a method for preparing an intermediate compound (B) of ozatimodThe method comprises the following steps: in DMF, compound (A) is stirred with sodium tungstate dihydrate at room temperature, and then H is added2O2Reacting at 40-60 ℃, and after the reaction is finished, carrying out post-treatment to obtain the compound (B).
In some embodiments, a method for preparing an otimod intermediate compound (B) comprises: in DMF, compound (A) is stirred with sodium tungstate dihydrate at room temperature, and then H is added2O2Reacting at 40-60 ℃, adding ethyl acetate and water after the reaction is finished, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain the compound (B).
In some embodiments, a method for preparing an otimod intermediate compound (B) comprises: in DMF, compound (A) and sodium tungstate dihydrate were stirred at room temperature, and then H was added dropwise2O2Reacting at 40-60 ℃, adding ethyl acetate and water after the reaction is finished, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (B); wherein, the compound (A) and H2O2The molar ratio of the compound (A) to the sodium tungstate dihydrate is 1:3.0-1:5.0, and the molar ratio of the compound (A) to the sodium tungstate dihydrate is 1:0.2-1: 0.4.
In the above reaction, the end point of the reaction can be monitored by High Performance Liquid Chromatography (HPLC), and the reaction is considered to be completed when the HPLC purity of the compound A is 0.5% or less, and the reaction time is usually 10 hours or less.
In the reaction, after the compound (A), namely (S) -N- ((S) -4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfinamide, is oxidized, the compound (B), namely (S) -N- ((S) -4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfonamide, is obtained, the reaction condition is mild and easy to operate, the yield is nearly 100 percent, and the compound (B) is more stable than the compound (A), is very suitable to be used as a reaction intermediate and is convenient to control the quality.
In another aspect, the present invention also provides a method for producing the compound (C), which comprises: reacting a compound (B) with (2-halogenated ethoxy) -tert-butyl dimethyl silane shown as a formula (01) in a reaction solvent in the presence of an alkaline reagent at a certain temperature, and carrying out aftertreatment to obtain a compound (C), wherein the reaction is shown as the following formula, X is halogen selected from chlorine, bromine and iodine,
Figure BDA0002090457600000041
in the process for producing the above-mentioned compound (C) of the present invention, the reaction may be carried out in one reaction solvent or a mixed solvent of a plurality of reaction solvents. In some embodiments, the reaction solvent is selected from at least one of DMF, DMA, DMSO, NMP, and THF. In some embodiments, the reaction solvent is DMF, which facilitates reaction performance and operation, and facilitates control of impurities.
In some embodiments, in the above method for preparing compound (C), the reaction temperature of the reaction is 20 ℃ to 40 ℃.
The alkaline reagent is at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide and NaHMDS. In some embodiments, the alkaline reagent is cesium carbonate, which facilitates the reaction and the production of high quality products.
The (2-halogenated ethoxy) -tert-butyldimethylsilane is at least one selected from (2-chloroethoxy) -tert-butyldimethylsilane, (2-bromoethoxy) -tert-butyldimethylsilane and (2-iodoethoxy) -tert-butyldimethylsilane.
In some embodiments, the molar ratio of compound (B) to (2-haloethoxy) -tert-butyldimethylsilane is from 1:1 to 1: 3; or the molar ratio is 1:1.5-1: 2.5.
In some embodiments, the molar ratio of compound (B) to basic agent may be from 1:2.0 to 1: 4.0. In some embodiments, the molar ratio of compound (B) to basic agent is 1:2.5 to 1:3.5, which facilitates the reaction.
In some embodiments, the reaction is for a reaction time of 10h to 20 h; or the reaction time is 12h-18 h.
In some embodiments, in the method of preparing compound (C), the post-treatment comprises: the reaction was stopped, methylene chloride and saturated brine were added to the reaction system, followed by extraction, and the organic phase was collected and concentrated under reduced pressure to obtain compound (C).
In some embodiments, in the method of preparing compound (C), the post-treatment comprises: the reaction was stopped, ethyl acetate and water were added, extraction was carried out, the organic phase was collected, and the organic phase was concentrated under reduced pressure to obtain compound (C).
In some embodiments, a method for preparing an otimod intermediate compound (C) comprises: reacting compound (B) with (2-haloethoxy) -tert-butyldimethylsilane in the presence of a basic agent in a reaction solvent at 20 ℃ to 40 ℃; after the reaction is finished, adding ethyl acetate and water, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (C).
In some embodiments, a method for preparing an otimod intermediate compound (C) comprises: reacting compound (B) with (2-haloethoxy) -tert-butyldimethylsilane in the presence of a basic agent in a reaction solvent at 20 ℃ to 40 ℃; after the reaction, dichloromethane and saturated brine are added for extraction, an organic phase is collected, and the organic phase is concentrated under reduced pressure to obtain a compound (C).
In some embodiments, a method for preparing an otimod intermediate compound (C) comprises: compound (B) in cesium carbonate (C) in DMFS2CO3) Reacting with (2-bromoethoxy) -tert-butyldimethylsilane at 20-40 ℃ in the presence of a catalyst; after the reaction, dichloromethane and saturated brine are added for extraction, an organic phase is collected, and the organic phase is concentrated under reduced pressure to obtain a compound (C).
In some embodiments, a method for preparing an otimod intermediate compound (C) comprises: compound (B) in cesium carbonate (C) in DMFS2CO3) Reacting with (2-bromoethoxy) -tert-butyldimethylsilane at 20-40 ℃ in the presence of a catalyst; after the reaction is finished, adding ethyl acetate and water, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (C); wherein the compound (B) is reacted with cesium carbonate (C)S2CO3) In a molar ratio of 1:2.0-1:4.0, compound (B) and (2-bromoethoxy) -tert-butylThe molar ratio of the dimethylsilane is 1:1 to 1:3.
In the process for producing the compound (C), the post-treatment comprises: adding water into the reaction system, and extracting by taking dichloromethane, ethyl acetate or toluene as an organic phase; optionally adding a proper amount of saturated salt water according to the separation condition to ensure that the separation is more obvious, and collecting an organic phase; the organic phase was concentrated under reduced pressure to give compound (C).
In the above-mentioned process for producing the compound (C) of the present invention, the end of the reaction can be monitored by High Performance Liquid Chromatography (HPLC), and the reaction is considered to be completed when the HPLC purity of the compound (B) is 0.5% or less, and the reaction time is usually 20 hours or less.
In the preparation method of the compound (C), the compound (B), namely (S) -N- ((S) -4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfonamide, is subjected to substitution reaction with (2-halogenated ethoxy) -tert-butyldimethylsilane in the presence of a basic reagent to obtain the compound (C), namely (S) -N- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -N- (4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfonamide, compared with the published literature, the oxidized compound (B), the sulfonamide protecting group is more stable, so that the substitution reaction is further carried out, a sodium-hydrogen reagent with high risk is not needed, and only an alkaline reagent such as cesium carbonate is needed, so that the compound (C) can be obtained with high yield and high purity.
The present invention also provides a process for producing the compound (F), which comprises: adding the compound (C) and hydroxylamine hydrochloride to obtain a compound (D); cyclizing the compound (D) and 3-cyano-4-isopropoxybenzoic acid to obtain a compound (E); hydrolyzing the compound (E) under an acidic condition to remove a protecting group to obtain the ozapimod; the reaction route is as follows:
Figure BDA0002090457600000061
in some embodiments, a method of making compound (F) comprises: in a reaction solvent, in the presence of an alkaline reagent and under a certain temperature condition, reacting a compound (B) with (2-halogenated ethoxy) -tert-butyl dimethyl silane shown as a formula (01), and carrying out aftertreatment to obtain a compound (C); adding the compound (C) and hydroxylamine hydrochloride to obtain a compound (D); cyclizing the compound (D) and 3-cyano-4-isopropoxybenzoic acid to obtain a compound (E); hydrolyzing the compound (E) under an acidic condition to remove a protecting group to obtain the ozapimod; the reaction route is as follows:
Figure BDA0002090457600000071
in some embodiments, a method of making compound (F) comprises: in a reaction solvent, in the presence of an alkaline reagent and under a certain temperature condition, reacting a compound (B) with (2-halogenated ethoxy) -tert-butyl dimethyl silane shown as a formula (01), and carrying out aftertreatment to obtain a compound (C); adding the compound (C) and hydroxylamine hydrochloride under the condition of adding alkali such as triethylamine to obtain a compound (D); cyclizing the compound (D) and 3-cyano-4-isopropoxybenzoic acid under the condition of adding HOBT and EDCI.HCl to obtain a compound (E); and (3) hydrolyzing the compound (E) under the action of hydrochloric acid to remove the protecting group to obtain the ozapimod.
In the above-mentioned process for producing the compound (F), the compound (B) can be produced by the above-mentioned process for producing the compound (B).
In some embodiments, a method of preparing compound (F) comprises: in DMF, cesium carbonate (C)S2CO3) In the presence of the compound (B), reacting the compound (B) with (2-halogenated ethoxy) -tert-butyldimethylsilane shown as a formula (01) at the temperature of between 20 and 40 ℃, and performing aftertreatment to obtain a compound (C); adding the compound (C) and hydroxylamine hydrochloride under the condition of adding alkali such as triethylamine to obtain a compound (D); cyclizing the compound (D) and 3-cyano-4-isopropoxybenzoic acid under the condition of adding HOBT and EDCI.HCl to obtain a compound (E); and (3) hydrolyzing the compound (E) under the action of hydrochloric acid to remove the protecting group to obtain the ozapimod.
In some embodiments, a method of preparing compound (F) comprises: in DMF, the compound (A) and sodium tungstate dihydrate are stirred at room temperature,then H is added2O2Reacting at 40-60 ℃, and after the reaction is finished, performing post-treatment to obtain a compound (B); in DMF, cesium carbonate (C)S2CO3) In the presence of the compound (B), reacting the compound (B) with (2-halogenated ethoxy) -tert-butyldimethylsilane shown as a formula (01) at the temperature of between 20 and 40 ℃, and performing aftertreatment to obtain a compound (C); adding the compound (C) and hydroxylamine hydrochloride under the condition of adding triethylamine to obtain a compound (D); cyclizing the compound (D) and 3-cyano-4-isopropoxybenzoic acid under the condition of adding HOBT and EDCI.HCl to obtain a compound (E); and (3) hydrolyzing the compound (E) under the action of hydrochloric acid to remove the protecting group to obtain the ozapimod.
The intermediate compound (B) obtained by the intermediate and the preparation method thereof provided by the invention has the advantages that the sulfonamide protecting group is more stable, the substitution reaction is further carried out, a sodium-hydrogen reagent with high risk is not required, the adopted conditions are mild, the obtained intermediate is more stable, the operation is convenient, the safety is good, the reaction time is short, the energy consumption is low, the control is convenient, the production cost is reduced, and the large-scale industrial production is facilitated.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound a" and "compound represented by formula a" means the same compound.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means hour, g means g, and ml means ml.
In the present invention, DMF represents N, N-dimethylformamide, DMA represents N, N-dimethylacetamide, DMSO represents dimethyl sulfoxide, NMP represents N-methylpyrrolidone, THF represents tetrahydrofuran, and DCM represents dichloromethane.
In the present invention, TEMPO represents 2,2,6, 6-tetramethylpiperidine-nitroxide, and IBX represents 2-iodoxybenzoic acid.
In the present invention, NaHMDS represents sodium bis (trimethylsilyl) amide.
In the present invention, room temperature means ambient temperature, and is generally 20 ℃ to 40 ℃ or 20 ℃ to 30 ℃.
In the present invention, TEA represents triethylamine, HOBT represents 1-hydroxybenzotriazole, and EDCI.HCl represents carbodiimide hydrochloride.
EXAMPLE 1 preparation of Compound (B)
To a reaction flask containing compound (A), i.e. (S) -N- ((S) -4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfinamide (55mg), 26mg of sodium tungstate dihydrate and 2mL of DMF were added, and the mixture was stirred at room temperature for 30min, and 95mg of 30% H was added dropwise to the reaction flask2O2The solution was dropped over 2 min. After the dripping is finished, heating to 45 ℃, continuing stirring for 5 hours, and finishing the reaction; then, 5mL of ethyl acetate and 10mL of water were added to the reaction system, and the mixture was extracted with stirring at room temperature. After 25min, standing, separating liquid and collecting an organic phase. Extracting the water phase with ethyl acetate twice (6 mL/time), collecting organic phases, mixing, and concentrating the organic phases at 45-50 deg.C under reduced pressure to obtain compound (B) (S) -N- (4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfonamide, 64 mg; the yield is 100%, and the detection is as follows: purity 91%, LC-MS M/z (ESI) 279.3(M + H) +.
EXAMPLE 2 preparation of Compound (B)
A single-neck flask was charged with compound (A) (S) -N- ((S) -4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfinamide (11g), sodium tungstate dihydrate 4.15g, 55mL of DMF and 30% H was added dropwise2O2(19.0g) heating the solution to 50 ℃ and stirring to finish the reaction; then adding Na into the reaction system2SO3(21.12g, 4eq) in water (100mL) to quench the reaction, 150mL ethyl acetate and 100mL water were added, stirred for 30min, separated, the organic phases collected, the organic phase layers combined and distilled at 45 ℃ under reduced pressure to give compound (B) (S) -N- (4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfonamide, 11.2 g.
EXAMPLE 3 preparation of Compound (C)
To a reaction flask containing the compound (B) obtained in example 1, i.e. (S) -N- (4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfonamide, 147mg of CS2CO3And 2mL of DMF, stirring at room temperature, adding 108mg of (2-bromoethoxy) -tert-butyldimethylsilane after 25min, and reacting at room temperature for 15h to finish the reaction; adding 10mL of water into the reaction system, stirring at room temperature to precipitate turbidity, stirring for about 1h, observing to find that the turbidity system is not solid and is similar to emulsion, then adding 5mL of dichloromethane into the turbidity system, stirring and extracting at room temperature, stirring for 25min, standing, finding emulsification, adding 2mL of saturated saline solution, obviously layering, collecting an organic phase, adding dichloromethane into an aqueous phase for extracting twice (6 mL/time), collecting the organic phases, combining, and concentrating the organic phase at 30-40 ℃ under reduced pressure to obtain a compound (C) of 99 mg; the yield is 100%, and the detection is as follows: the purity is 89%.
EXAMPLE 4 preparation of Compound (C)
The compound (B) obtained in example 2, i.e. (S) -N- (4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfonamide (1.8g) was added to a single-neck flask, 10mL of DMF and cesium carbonate (6.32g) were added, stirring was started, and the reaction was carried out at room temperature until the reaction was completed; adding 50mL of water, extracting with ethyl acetate three times (30 mL/time), combining ethyl acetate layers, and concentrating under reduced pressure to obtain compound (C), 2.8 g; the yield is 99 percent, and the detection: purity 91%, LC-MS: M/z (ESI):475.3(M + K) +;
1H NMR(400MHz,DMSO)7.76(d,J＝7.6Hz,1H),7.66(d,J＝7.6Hz,1H),7.48(t,J＝7.6Hz,1H),3.88(t,J＝5.7Hz,1H),3.74(t,J＝6.1Hz,6H),3.46(s,2H),1.39(s,9H),0.76(s,9H),-0.13(s,6H)。
example 5 preparation of azamod hydrochloride
Adding hydroxylamine hydrochloride (8.38g, 3eq), TEA (12.2g, 3eq) and absolute ethanol (100mL) into a flask, stirring at 40 ℃ for clarification, adding the compound (C) (17.55g, 1eq) under stirring, and continuing stirring for reaction for 4 hours to finish the reaction; cooling the system to room temperature, concentrating under reduced pressure at 45 ℃ to remove ethanol, adding 100mL of water, extracting twice with ethyl acetate (150 mL. times.2), collecting the organic phase, concentrating under reduced pressure to obtain 7.0g of compound (D), and detecting: the purity is 95%.
3-cyano-4-isopropoxybenzoic acid (1.51g), HOBT (1.29g), EDCI.HCl (1.83g), DMA (12mL), TEA (1.6mL) were added to the flask, and the mixture was stirred at 25 ℃ for 30min, then a DMA (8mL) solution of Compound (D) (3.49g) was added to the reaction mixture, and after stirring, the mixture was warmed to 80 ℃ and allowed to react for 24h, whereupon the reaction was terminated; cooling to 30 ℃, adding 60mL of water, extracting twice with DCM (50mL × 2), separating the liquids to collect the organic phase, washing the organic phase with aqueous solution (40mL) of sodium bicarbonate (0.6g), collecting the organic phase, removing the solvent under reduced pressure to obtain a total of 6.0g of compound (E), detecting: the purity was 70%.
Adding the compound (E) (2.0g) and DCM (10mL) into a flask, adding hydrochloric acid into the flask while stirring at 25 ℃ and stirring for 16h, finishing the reaction, recrystallizing and purifying the mixture by using 10mL of ethanol to obtain 0.4g of the compound (F), namely the ozatimod hydrochloride, and detecting: the purity is 95%.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.

Claims (10)

1. A method for preparing a compound (C) comprises the steps of reacting a compound (B) with (2-halogenated ethoxy) -tert-butyldimethylsilane shown as a formula (01) in a reaction solvent in the presence of an alkaline reagent at a certain temperature, and carrying out aftertreatment to obtain the compound (C), wherein the reaction formula is shown as the following formula:
Figure FDA0002090457590000011
wherein the content of the first and second substances,
the alkaline reagent is selected from at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide and sodium bis (trimethylsilyl) amide;
the (2-halogenated ethoxy) -tert-butyldimethylsilane is at least one selected from (2-chloroethoxy) -tert-butyldimethylsilane, (2-bromoethoxy) -tert-butyldimethylsilane and (2-iodoethoxy) -tert-butyldimethylsilane.
2. The process according to claim 1, wherein the molar ratio of compound (B) to (2-haloethoxy) -tert-butyldimethylsilane is from 1:1 to 1:3, or the molar ratio of compound (B) to basic agent is from 1:2.0 to 1: 4.0.
3. The method of claim 1, wherein the reaction solvent is selected from at least one of DMF, DMA, DMSO, NMP, and THF.
4. The method of claim 1, wherein the temperature is 20 ℃ to 40 ℃.
5. A process for producing a compound (F), which comprises adding a compound (C) produced by the process according to claim 1 to hydroxylamine hydrochloride to obtain a compound (D); cyclizing the compound (D) and 3-cyano-4-isopropoxybenzoic acid to obtain a compound (E); hydrolyzing the compound (E) under an acidic condition to obtain a compound (F); the reaction formula is shown as the following formula:
Figure FDA0002090457590000021
6. the method of claim 1 or 2, further comprising the steps of adding an oxidant and a catalyst into the reaction solvent to perform an oxidation reaction at a certain reaction temperature, and performing post-treatment to obtain the compound (B), wherein the reaction formula is shown as the following formula:
Figure FDA0002090457590000022
wherein the content of the first and second substances,
the oxidant is at least one of hydrogen peroxide, 2,6, 6-tetramethyl piperidine-nitrogen oxide or 2-iodoxybenzoic acid;
the catalyst is selected from at least one of sodium tungstate dihydrate or potassium tungstate.
7. The process of claim 6, wherein the molar ratio of compound (A) to oxidant is from 1:3.0 to 1:5.0, or the molar ratio of compound (A) to catalyst is from 1:0.2 to 1: 0.4.
8. The process of claim 6, wherein the reaction temperature is from 40 ℃ to 60 ℃.
9. The method of claim 6, wherein the oxidation reaction is carried out for a reaction time of 3h to 7 h.
10. A compound having the structure of formula (B), formula (C), formula (D), or formula (E):
Figure FDA0002090457590000031
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009151529A1 (en) * 2008-05-14 2009-12-17 The Scripps Research Institute Novel modulators of sphingosine phosphate receptors
WO2011060392A1 (en) * 2009-11-13 2011-05-19 Receptos, Inc. Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
US20150299150A1 (en) * 2009-11-13 2015-10-22 Receptos, Inc. Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
CN105130922A (en) * 2009-11-13 2015-12-09 瑞塞普托斯公司 Selective heterocyclic sphingosine 1 phosphate receptor modulators
WO2018215807A1 (en) * 2017-05-22 2018-11-29 Egis Gyógyszergyár Zrt. Process for the production of ozanimod

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009151529A1 (en) * 2008-05-14 2009-12-17 The Scripps Research Institute Novel modulators of sphingosine phosphate receptors
WO2011060392A1 (en) * 2009-11-13 2011-05-19 Receptos, Inc. Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
US20150299150A1 (en) * 2009-11-13 2015-10-22 Receptos, Inc. Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
CN105130922A (en) * 2009-11-13 2015-12-09 瑞塞普托斯公司 Selective heterocyclic sphingosine 1 phosphate receptor modulators
WO2018215807A1 (en) * 2017-05-22 2018-11-29 Egis Gyógyszergyár Zrt. Process for the production of ozanimod

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