Patent Description:
The present disclosure belongs to the field of organic chemical synthesis of pharmaceutical intermediates, and specifically relates to a new method for the synthesis and industrialization of (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate using an in-house designed and innovative intermediate.

(<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate belongs to a class of chiral small molecules that are difficult to synthesize. This chiral fragment is widely used in the manufacture of an influenza virus RNA polymerase inhibitors, the most representative of which is Pimodivir developed by Vertex, which has entered the clinical phase III study. The novel target of this class of drugs is a milestone in addressing influenza virus drug resistance.

Three main routes have been reported for the synthesis of this structural fragment of (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate as follows.

Route I is shown as the following chart "Route I reported in a patent". This route starts with cyclohexadiene, undergoes Diels-Alder reaction with maleic anhydride, further selective alcoholysis in the presence of quinidine to obtain cis-carboxylic acid esters, flips the ester group conformation under strong base conditions, and finally performs Curtius rearrangement with diphenyl azide phosphate, and finally obtain the target product by removal of benzoxy carbonyl. Although the starting material is relatively cheap, the main shortcomings of this route include:.

Route II is shown as the following chart "Route II reported in a patent". This route takes cyclohexadiene as the starting material, undergoes the Diels-Alder reaction with ethyl propargylate, and after further hydrogenation for selective reduction of the double bond, undergoes Michael addition reaction with chiral amine anion at low temperature, and finally removes the two protecting groups to obtain the target compound.

This route also has many shortcomings. Firstly, the starting materials are expensive and costly; secondly, special metal catalysts are used in the selective reduction of double bonds and harsh conditions such as ultra-low temperatures are used in the subsequent addition reactions, which are not conducive to scale-up production; the overall production cost is also high.

Route III is shown as the following chart "Route III reported in a patent". This route starts with ethyl glyoxylate, which undergoes the Henry reaction with nitromethane under alkaline conditions to obtain ethyl nitroacrylate by elimination reaction, which is further hydrogenated with cyclohexadiene by the Diels-Alder reaction catalyzed by chiral auxiliaries to obtain the target product.

Although this route is short, the raw materials are expensive and chemically unstable, while the use of nitromethane and nitro-containing intermediates poses a greater safety risk to the production.

In summary, the reported synthetic routes for (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate are characterized by high production risks and high costs, which make it difficult to meet the demand for this class of pharmaceutical intermediates in the pharmaceutical industry. <CIT> discloses the preparation of a compound of formula I via reaction of a compound of formula (C) with diphenylphosphoryl azide and benzyl alcohol to form a compound of formula (D) which is then hydrogenated to obtain the expected product.

To address the shortcomings of the prior art and to solve the problems of high preparation cost, low material safety and difficulty in production scale-up of (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate, the present invention provides a method for the preparation of (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate through two independently designed and innovative intermediates. The method utilizes a chiral reductive amination strategy and achieves excellent results.

The present disclosure provides a method for preparing (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate, the method comprises: using <NUM>-carbonyl-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate as raw material, carring out reductive amination, flip of ester group conformation and removal of protecting group to obtain the (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate, and reaction process is shown below,
<CHM>
wherein the method comprises:.

According to an embodiment of the present invention, the X is preferably phenyl, the Y is preferably methyl and the R is preferably ethyl considering the availability of the materials.

According to an embodiment of the present invention, in the S <NUM>, the metal catalyst for hydrogenation reduction comprises one of platinum carbon, platinum dioxide and ruthenium metal catalyst; the reduction reagent comprises one of sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride and sodium trifluoroacetoxy borohydride.

According to an embodiment of the present invention, in the S2, the metal-catalyzed hydrogenation is carried out using a metal catalyst, the metal catalyst comprising at least one selected from the group consisting of platinum carbon, platinum dioxide and ruthenium metal catalyst; the reducing agent comprising at least one selected from the group consisting of sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride and sodium trifluoroacetoxy borohydride; preferably, to further improve the selectivity of the reaction, the metal catalyst is platinum dioxide; the reducing agent is sodium triacetoxy borohydride.

According to an embodiment of the present invention, in the S3, the strong base comprises at least one selected from the group consisting of sodium tert-butoxide, sodium tert-amylate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide; preferably, considering price and availability of materials, the strong base is sodium tert-butoxide.

According to an embodiment of the present invention, in the S <NUM>, the acid is organic acid or inorganic acid; preferably, the acid is strong organic acid; further preferably, the acid comprises p-toluenesulfonic acid or trifluoroacetic acid.

The present disclosure provides a compound shown in formula V below, wherein, the R is methyl, ethyl, propyl, butyl, phenyl or benzyl, preferably ethyl; the X is methyl, ethyl, phenyl or <NUM>-naphthyl, and the Y is methyl, ethyl, phenyl or <NUM>-naphthyl, and the X and the Y are not identical and the X is larger than the Y, preferably, the X is phenyl, the Y is methyl,
<CHM>.

The present disclosure provides use of the compound V for preparation of (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate.

The present disclosure provides a compound shown in formula VI below, wherein, the R is methyl, ethyl, propyl, butyl, phenyl or benzyl, preferably ethyl; the X is methyl, ethyl, phenyl or <NUM>-naphthyl, and the Y is methyl, ethyl, phenyl or <NUM>-naphthyl, and the X and the Y are not identical and the X is larger than the Y, preferably, the X is phenyl, the Y is methyl,
<CHM>.

The present disclosure provides use of the compound VI for preparation of (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate.

Compared with the prior art, the present invention has the following advantages.

The following is a detailed description of preferred embodiments of the present invention to make the advantages and features of the present invention more easily understood by those skilled in the art, so that the scope of protection of the present invention can be more clearly defined.

To the reactor was added <NUM> toluene, <NUM> ethyl <NUM>-carbonyl-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate, <NUM> p-toluenesulfonic acid, <NUM> S-<NUM>-phenylethylamine, and the reaction was refluxed under nitrogen protection for <NUM> to obtain the enamine intermediate ethyl (S) -<NUM>-(<NUM>-phenylethylamino)-bicyclo[<NUM>. <NUM>]octene-<NUM>-carboxylate, which was used in the next reaction step.

The above enamine intermediate (S)ethyl-<NUM>-(<NUM>-phenylethylamino)-bicyclo[<NUM>. <NUM>]octene-<NUM>-carboxylate solution was desolvated, then <NUM> of tetrahydrofuran and <NUM> of acetic acid was added, then <NUM> of sodium triacetoxyborohydride was added after cooling. Bring to room temperature and reacted for <NUM>. 3N sodium hydroxide solution was added dropwise to adjust to alkaline, extracting with ethyl acetate (<NUM> Lx <NUM>), the combined organic phases were washed with saturated salt water and concentrated to give <NUM> of ethyl (2R,<NUM>)-<NUM>-((S)-<NUM>-phenylethylamino)-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate (corresponding to compound IV in the synthetic route of the present invention) as a pale yellow oil, in yield <NUM>%. <NUM>HNMR (<NUM>, CDCl<NUM>) <NUM>-<NUM> (m, <NUM>), δ4. <NUM> (q, <NUM>), δ3. <NUM> (q, <NUM>), δ2. <NUM>-<NUM> (m, <NUM>), δ1. <NUM> (m, <NUM>) , δ1. <NUM>-<NUM> (m, <NUM>) , δ1. <NUM> (t, <NUM>) ; ESI-MS: m/z <NUM> [M+<NUM>].

To the reactor was added <NUM> tetrahydrofuran, <NUM> tert-butanol, <NUM> sodium tert-butoxide, and cooled to <NUM>-<NUM> under nitrogen protection. Add tetrahydrofuran solution of ethyl (2R,<NUM>)-<NUM>-((S)-<NUM>-phenylethylamino)-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate (<NUM> dissolved in <NUM> tetrahydrofuran) dropwise. After dropwise addition, the reaction was held for <NUM>. The reaction solution was transferred to <NUM> saturated ammonium chloride solution for quenching. After extraction with ethyl acetate (<NUM> x <NUM>), the combined organic phases were washed with saturated brine and concentrated to give <NUM> of ethyl (<NUM>,<NUM>)-<NUM>-((S)-<NUM>-phenylethylamino)-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate (corresponding to compound V in the synthetic route of the present invention) as pale yellow oily form with <NUM>% yield and diastereomeric purity <NUM>%. <NUM>HNMR (<NUM>, CDCl<NUM>) δ7. <NUM>-<NUM> (m, <NUM>), δ4. <NUM> (q, <NUM>), δ3. <NUM> (q, <NUM>), δ3. <NUM> (d, <NUM>) , δ2. <NUM> (d, <NUM>) , δ1. <NUM> (d, <NUM>) ,δ1. <NUM>-<NUM> (m, <NUM>), δ1. <NUM>-<NUM> (m, <NUM>) ; ESI-MS: m/z <NUM> [M+<NUM>].

<NUM> of ethanol, <NUM> of ethyl (<NUM>,<NUM>)-<NUM>-((S)-<NUM>-phenylethylamino)-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate, and <NUM> of <NUM>% palladium carbon were added to a <NUM> stainless steel autoclave. The reactor was evacuated and full filled with nitrogen, then exchanged to hydrogen and pressurized to to <NUM> MPa. The reaction mixture was heated to <NUM> and kept for <NUM> hours. The palladium carbon was removed by filtration and the filtrate was concentrated to give <NUM> of ethyl (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate (corresponding to compound I in the synthetic route of the present invention) as a pale yellow oil in <NUM>% yield and <NUM>% chiral purity. <NUM>HNMR (<NUM>, CDCl<NUM>) δ4. <NUM> (q, <NUM>), δ3. <NUM>-<NUM> (m, <NUM>), δ2. <NUM>-<NUM> (m, <NUM>), δ1. <NUM>-<NUM> (m, <NUM>) , δ1. <NUM>-<NUM> (m, <NUM>) , δ1. <NUM>-<NUM> (m, <NUM>) ,δ1. <NUM> (t, <NUM>) ; ESI-MS: m/z <NUM> [M+<NUM>].

<NUM> of toluene, <NUM> of ethyl <NUM>-carbonyl-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate, <NUM> of trifluoroacetic acid, <NUM> of S-<NUM>-naphthyl ethylamine were added to the reactor and reacted under nitrogen protection at reflux for <NUM> hours. Cooled to room temperature, washed with <NUM> saturated sodium bicarbonate solution, the organic layer was concentrated to <NUM>, <NUM> n-heptane was added and stirred for <NUM> at room temperature, filtered, washed with a small amount of n-heptane and dried under vacuum to give <NUM> ethyl (S)-<NUM>-(<NUM>-naphthylethylamino)-bicyclo[<NUM>. <NUM>]octene-<NUM>-carboxylate as a white solid in <NUM>% yield.

<NUM> of ethanol, <NUM> of ethyl acetate, <NUM> of ethyl (S)-<NUM>-(<NUM>-naphthylethylamino)-bicyclo[<NUM>. <NUM>]octene-<NUM>-carboxylate, <NUM> of <NUM>% platinum carbon to <NUM> were added to stainless steel autoclave, degassing with nitrogen and then ventilating with hydrogen to <NUM> MPa, then the mixture was raised to <NUM> and kept for <NUM> hours. Filtered to remove the platinum carbon and the filtrate was concentrated to obtain <NUM> ethyl (2R,<NUM>)-<NUM>-((S)-<NUM>-naphthylethylamino)-bicyclo[<NUM>. <NUM>] octane-<NUM>-carboxylate as an off-white solid in <NUM>% yield.

<NUM> tetrahydrofuran, <NUM> tert-butanol, <NUM> sodium tert-butoxide were added to the reactor, cooled down to <NUM>-<NUM> under nitrogen protection, and added dropwise a tetrahydrofuran solution of ethyl (2R,<NUM>)-<NUM>-((S)-<NUM>-naphthylethylamino)-bicyclo[<NUM>. <NUM>] octane-<NUM>-carboxylate (<NUM> dissolved in <NUM> tetrahydrofuran). After dropwise addition, the reaction was held for <NUM>. The reaction solution was quenched by pouring into <NUM> saturated ammonium chloride solution, then extracted with ethyl acetate (<NUM> x <NUM>). The combined organic phases were washed with saturated brine and concentrated to give <NUM> of ethyl (<NUM>,<NUM>)-<NUM>-((S)-<NUM>-naphthylethylamino)-bicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate as a pale yellow solid in <NUM>% yield and <NUM>% diastereomeric purity.

Claim 1:
A method for preparing a (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>.<NUM>]octane-<NUM>-carboxylate, wherein, the method comprises: using a <NUM>-carbonyl-bicyclo[<NUM>.<NUM>]octane-<NUM>-carboxylate of formular II as a raw material, carring out reductive amination, epimerization and removal of protecting group to obtain the (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>.<NUM>]octane-<NUM>-carboxylate of formular I, and the reaction process is shown below,
<CHM>
wherein,
the R is methyl, ethyl, propyl, butyl, phenyl or benzyl, the X is methyl, ethyl, phenyl or <NUM>-naphthyl, the Y is methyl, ethyl, phenyl or <NUM>-naphthyl, and the X and the Y are not identical, the X group is larger than the Y group;
the method comprises:
S1, reacting the <NUM>-carbonyl-bicyclo[<NUM>.<NUM>]octane-<NUM>-carboxylate with the chiral amine of formula (III) in the presence of an acid to give the <NUM>-amino-bicyclo[<NUM>.<NUM>]octene-<NUM>-carboxylate, the acid is a strong organic acid;
S2, carrying out reduction with a reducing agent or metal-catalyzed hydrogenation of the <NUM>-amino-bicyclo[<NUM>.<NUM>]octene-<NUM>-carboxylate to give the (2R,<NUM>)-<NUM>-amino-bicyclo[<NUM>.<NUM>]octane-<NUM>-carboxylate;
S3, under strong base conditions, carrying out the ester configuration flip of the (2R,<NUM>)-<NUM>-amino-bicyclo[<NUM>.<NUM>]octane-<NUM>-carboxylate to give the (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>.<NUM>]octane-<NUM>-carboxylate, the strong base comprises at least one selected from the group consisting of sodium tert-butoxide, sodium tert-amylate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide; and
S4, carrying out hydrogenation of the (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>.<NUM>]octane-<NUM>-carboxylate of formula VI to remove the protecting group to give the (<NUM>,<NUM>)-<NUM>-amino-bicyclo[<NUM>.<NUM>]octane-<NUM>-carboxylate of formula I.