Anti-platelet drugs, and methods of making the same

Abstract

The application relates to the technical field of drug intermediate synthesis, in particular to an anti-platelet reduction drug romiplostim intermediate and a preparation method thereof. The method of the application is as follows: starting from compound I, i.e. 2-halogenated phenol, reacting with paraformaldehyde to obtain compound II; the compound II is reacted with a methylating agent and a Grignard reagent in sequence to obtain intermediate IV; the alcohol hydroxyl group in the intermediate IV is oxidized to obtain compound V; the halogen in the compound V is replaced by a cyano group to obtain intermediate VI; the intermediate VI is subjected to asymmetric reduction to obtain intermediate VII; the hydroxyl group in the intermediate VII is continuously protected to obtain intermediate VIII, the cyano group in the intermediate VIII is subjected to a Grignard reaction to obtain intermediate IX; the intermediate IX is subjected to bromination to obtain compound X; and the compound X is ring-closed with thiourea to obtain intermediate XI. The synthesis route of the application avoids column chromatography in each step, is easy to operate, and the reaction yield of each step is relatively high, and can all reach more than 80%.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug intermediate synthesis, in particular to an anti-thrombocytopenia drug lusutrombopag intermediate and a preparation method thereof. BACKGROUND

[0002] Lusutrombopag is a thrombopoietin receptor agonist developed by Shionogi, and its trade name is Mulpleta. It is used for treating adult chronic liver disease (CLD) related thrombocytopenia before surgery, and can reduce platelet transfusion before surgery and reduce the risk of bleeding after surgery.

[0003] Lusutrombopag has been approved for marketing in Japan in September 2015, in the United States in August 2018, and in Europe in February 2019, for the treatment of chronic liver disease related thrombocytopenia in patients undergoing elective invasive surgery or diagnostic procedures.

[0004] In the case of blood product shortage, TPO receptor agonists have become an effective alternative therapy for platelet transfusion, and can reduce the risk of platelet transfusion.

[0005] However, due to the complex structure of lusutrombopag, its synthesis is difficult, and its source is greatly limited. The synthesis of the compound and the intermediate is developed by Shionogi (EP 2184279 A1). For the synthesis of intermediate XI, the original research company adopts the following strategy.

[0006]

[0007] Starting from 2,6-dibromophenol, methyl protection, butyllithium bromine removal, and reaction with acetaldehyde to obtain the corresponding alcohol, the alcohol is oxidized and asymmetrically reduced to obtain a chiral alcohol, which is n-propyl protected, butyllithium bromine is introduced into the carbonyl group, and then ring-closed with thiourea to obtain the corresponding intermediate XI. The total yield of this route is only 5% to 8%. In this route, the first carbonyl group is introduced by addition to aldehyde and oxidation, the yield is low, each step is a liquid, the chiral purification is difficult, and column purification is required, so the industrial production is more difficult. In addition, in the process of introducing the second carbonyl group, the yield is also relatively low (30% to 35%), and each step needs column chromatography purification, the cost and energy consumption are very high. SUMMARY

[0008] The purpose of the present application is to overcome the shortcomings of the existing synthesis method of lusutrombopag intermediate, and to provide an anti-thrombocytopenia drug lusutrombopag intermediate and a preparation method thereof. The embodiments of the present application are realized as follows:

[0009] The first aspect of the embodiment of the present application provides an intermediate shown in structural formula (XII):

[0010]

[0011] wherein R is

[0012] The second aspect of the embodiment of the present application provides a preparation method of an intermediate of an anti- thrombocytopenia drug, romiplostim, the intermediate of romiplostim including the intermediate VI when R is

[0013]

[0014] wherein X is chlorine or bromine; in the step of preparing the intermediate IV from the compound III, the Grignard reagent is methyl magnesium bromide or methyl lithium chloride; in the step of preparing the compound V from the intermediate IV, the oxidizing agent is sodium hypochlorite or potassium permanganate; in the step of preparing the intermediate VI from the compound V, the cyanating agent is cuprous cyanide, potassium cyanide or sodium cyanide.

[0015] In some embodiments, in the step of preparing the intermediate IV from the compound III, the molar ratio of the compound III to the Grignard reagent is 1:0.8-1.2; the reaction temperature ranges from -75℃ to -20℃.

[0016] In some embodiments, in the step of preparing the intermediate VI from the compound V, the molar ratio of the compound V to the cyanating agent is 1:0.8-1.2; the reaction temperature ranges from 100℃ to 120℃.

[0017] The third aspect of the embodiment of the present application provides a preparation method of an intermediate of an anti- thrombocytopenia drug, romiplostim, the intermediate of romiplostim including

[0018] the intermediate VI when R is The preparation method of the intermediate VI further includes:

[0019]

[0020] wherein X is chlorine or bromine; in the step of preparing the compound III from the compound II, the methylating agent is methyl iodide or dimethyl sulfate; in the step of preparing the intermediate IV from the compound III, the Grignard reagent is methyl magnesium bromide, methyl magnesium chloride or methyl lithium chloride; in the step of preparing the compound V from the intermediate IV, the oxidizing agent is sodium hypochlorite or potassium permanganate; in the step of preparing the intermediate VI from the compound V, the cyanating agent is cuprous cyanide, potassium cyanide or sodium cyanide.

[0021] ​The fourth aspect of the embodiment of the present application provides a preparation method of an intermediate of an anti-platelet reduction drug, romiplostim, the intermediate of the romiplostim comprising:

[0022] The R is The preparation method of the intermediate VII, when the R is

[0023]

[0024] The X is chlorine or bromine; in the step of preparing the intermediate IV from the compound III, the Grignard reagent is methyl magnesium bromide, methyl magnesium chloride or methyl lithium chloride; in the step of preparing the compound V from the intermediate IV, the oxidizing agent is sodium hypochlorite or potassium permanganate; in the step of preparing the intermediate VI from the compound V, the cyanation reagent is cuprous cyanide, potassium cyanide or sodium cyanide; in the step of preparing the intermediate VII from the intermediate VI, the reducing agent is borane or borane dimethyl sulfide.

[0025] In some embodiments, in the step of preparing the intermediate VII from the intermediate VI, the molar ratio of the intermediate VI to the reducing agent is 1:0.8-1.2; the reaction temperature ranges from 10℃ to 25℃.

[0026] The fifth aspect of the embodiment of the present application provides an intermediate of the romiplostim, the intermediate VIII comprising: The preparation method of the intermediate VIII comprises:

[0027]

[0028] The X is chlorine or bromine; in the step of preparing the intermediate IV from the compound III, the Grignard reagent is methyl magnesium bromide, methyl magnesium chloride or methyl lithium chloride; in the step of preparing the compound V from the intermediate IV, the oxidizing agent is sodium hypochlorite or potassium permanganate; in the step of preparing the intermediate VI from the compound V, the cyanation reagent is cuprous cyanide, potassium cyanide or sodium cyanide; in the step of preparing the intermediate VII from the intermediate VI, the reducing agent is borane tetrahydrofuran or borane dimethyl sulfide; in the step of preparing the intermediate VIII from the intermediate VII, the alcohol hydroxyl protection reagent is n-hexyl bromide or n-hexyl iodide.

[0029] In some embodiments, in the step of preparing the intermediate VIII from the intermediate VII, the molar ratio of the intermediate VII to the alcohol hydroxyl protection reagent is 1:0.8-1.2.

[0030] The sixth aspect of the embodiment of the present application provides a method for preparing an intermediate XI of the romiplostim from the intermediate VIII,

[0031] The preparation method of the intermediate XI comprises:

[0032] In the preparation of the intermediate IV from the compound III, the Grignard reagent is methyl magnesium bromide, methyl magnesium chloride or methyl lithium chloride; in the preparation of the compound V from the intermediate IV, the oxidizing agent is sodium hypochlorite or potassium permanganate; in the preparation of the intermediate VI from the compound V, the cyanylating agent is cuprous cyanide, potassium cyanide or sodium cyanide; in the preparation of the intermediate VII from the intermediate VI, the reducing agent is borane tetrahydrofuran or borane dimethyl sulfide; in the preparation of the intermediate VIII from the intermediate VII, the alcohol hydroxyl protecting agent is n-hexyl bromide or n-hexyl iodide; in the preparation of the intermediate IX from the intermediate VIII, the Grignard reagent is methyl magnesium bromide, methyl magnesium chloride or methyl lithium chloride; in the preparation of the compound X from the intermediate IX, the brominating agent is N-bromosuccinimide or liquid bromine.

[0033] The beneficial effects of the present application: the preparation of the intermediates VI, VII, VIII and XI of the anti-platelet drug romiplostim, the present application starts from the compound I, i.e. 2-halogenated phenol, which is reacted with paraformaldehyde to obtain the compound II; the compound II is reacted with a methylating agent and a Grignard reagent in sequence to obtain the intermediate IV; the alcohol hydroxyl in the intermediate IV is oxidized to obtain the compound V; the halogen in the compound V is replaced by a cyanyl group to obtain the intermediate VI; the intermediate VI is subjected to asymmetric reduction to obtain the intermediate VII, i.e. a chiral alcohol, which is a solid and can be purified to obtain a chiral alcohol compound; the hydroxyl in the intermediate VII is further protected to obtain the intermediate VIII, and the cyanyl group in the intermediate VIII is obtained by Grignard reaction to obtain the intermediate IX; the intermediate IX is subjected to bromination to obtain the compound X; and the compound X is subjected to ring closure with thiourea to obtain the intermediate XI.

[0034] The present synthetic route adopts a relatively effective method to avoid column chromatography at each step, is very easy to operate, and the yield of each step is above 85%. Compared with the low yield in the original research literature, the yield of each reaction in the present synthetic route is high, and the post-treatment operation is simple and easy to scale up production.

[0035] Meanwhile, in the present synthetic route, a cyanyl group is first introduced, and then reacted with a methyl Grignard reagent to obtain a carbonyl group. In the ring closure, a bromide is used instead of a chloride, so that the ring closure yield is high. DETAILED DESCRIPTION

[0036] To enable persons skilled in the art to understand the features and effects of the present application, the following is a general description and definition of the terms and phrases mentioned in the specification and claims. Unless otherwise specified, all technical and scientific words used herein are used in the sense commonly understood by one skilled in the art of the present application, and in the event of a conflict between the definition of the present specification and the commonly understood meanings, the definition of the present specification shall control.

[0037] Theories and mechanisms described and disclosed herein, whether correct or not, should not be considered limiting of the scope of the present application, as the present application can function without being adhered to any particular theory or mechanism.

[0038] Herein, all features defined by numerical ranges or percentage ranges, such as numerical values, amounts, contents and concentrations, are for the sake of brevity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to have encompassed and specifically disclosed all possible sub-ranges and individual numerical values (including integers and fractions) within the range.

[0039] Herein, for the sake of brevity, all possible combinations of the various technical features in the various embodiments or examples are not described. Therefore, the various technical features in the various embodiments or examples can be combined with each other as long as there is no contradiction, and all possible combinations should be considered to be within the scope of the present specification.

[0040] The present application is further illustrated by the following specific examples. It is to be understood that these examples are merely illustrative of the present application and do not limit the scope of the present application. Furthermore, it is to be understood that various equivalents and modifications can be made to the present application by those skilled in the art, and such equivalents and modifications are also to be considered to be within the scope of the present application as defined by the appended claims.

[0041] In the following examples, the instruments and apparatuses of the art are used. In the following examples, the experimental methods not otherwise specified are usually performed according to the conventional conditions, or according to the conditions suggested by the manufacturers. In the following examples, various raw materials are used, and unless otherwise specified, the conventional commercially available products are used, and the specifications are the conventional specifications in the art. In the specification of the present application and the following examples, unless otherwise specified, "%" means weight percent, "parts" means weight parts, and the ratio means weight.

[0042] The preparation method of the intermediate of the anti- thrombocytopenia drug, crizanlizumab, provided in the present application is further described below in conjunction with specific examples.

[0043] Synthesis of compound II in Example 1

[0044] In a reaction vessel, compound I 2-bromophenol (519 g, 3.0 mol) was added and dissolved in acetonitrile (2.5 L), anhydrous magnesium chloride (380 g, 4.0 mol) was added, and then paraformaldehyde (315 g, 3.5 mol) was added. The reaction was carried out at a temperature range of 40-60 °C (preferably at 50 °C) until the starting material was consumed, as indicated by the control. After the reaction was completed, the mixture was filtered, and the solid was washed with acetonitrile. The organic phases were combined and concentrated. The organic phase was diluted with ethyl acetate, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound II, 548.8 g, in a yield of 91% by calculation.

[0045] The solvent acetonitrile can also be replaced with an equal volume of dichloromethane or dichloroethane or toluene, and the compound I can also be replaced with 2-chlorophenol.

[0046] Example 2: Reaction of compound II with a methylating agent to give compound III

[0047] In a reaction vessel, compound II (402 g, 2.0 mol) was added and dissolved in N,N-dimethylformamide (1.8 L), and then sodium hydride (60% by mass, 160 g, 4.0 mol) was added. Iodomethane (312 g, 2.2 mol) was slowly added dropwise, and the reaction was carried out at a temperature range of 60-100 °C (preferably at 50 °C) until the starting material was consumed, as indicated by the control. After the reaction was completed, water and ethyl acetate were added, and the mixture was separated. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound III, 404.2 g, in a yield of 94% by calculation.

[0048] The iodomethane can also be replaced with dimethyl sulfate in the same amount.

[0049] Example 3: Grignard reaction of compound III to give compound IV

[0050] In a reaction vessel, compound III (400 g, 1.86 mol) was added and dissolved in tetrahydrofuran (2 L), and then a tetrahydrofuran solution of methylmagnesium chloride (3.0 M, 1.24 L) was added dropwise at -78 °C. The reaction was carried out for 3 h, and then saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined and washed with brine. After being concentrated, compound IV, 391.1 g, was obtained in a yield of 91% by calculation.

[0051] The tetrahydrofuran solution of methylmagnesium chloride can also be replaced with a tetrahydrofuran solution of methyl lithium chloride in the same amount.

[0052] Compound IV in Example 4 was oxidized to obtain compound V

[0053] Compound IV (381 g, 1.65 mol) was added into a reactor, dichloromethane (2 L) was added to dissolve it, sodium bromide (170 g, 1.65 mol) was added, then sodium chlorite aqueous solution (1520 g) was added dropwise, the reaction was carried out at a reaction temperature of 0-10 °C for 2 h, after the reaction was completed, the liquid was separated, the water was extracted, the organic phases were combined, and the organic phase was concentrated to obtain compound V, a total of 359.1 g, and the yield of compound V was calculated to be 95.0%.

[0054] The dichloromethane in the solvent can also be replaced with an equal volume of chloroform, and the sodium chlorite aqueous solution can also be replaced with an equal amount of potassium permanganate aqueous solution.

[0055] The halogen of compound V in Example 5 was replaced with a cyano group to obtain intermediate VI

[0056] Compound V (350 g, 1.53 mol) was added into a reactor, N,N-dimethylformamide (2 L) was added to dissolve it, cuprous cyanide (138.8 g, 1.55 mol) was added, the reaction was carried out at a reaction temperature of 100-120 °C (preferably at a reaction temperature of 110 °C) for 12 h, after the reaction was completed, ethyl acetate was added for dilution, water was washed, filtered, separated, and the salt was washed with brine, the organic phases were combined, and concentrated to obtain intermediate VI, a total of 235.9 g, and the yield of intermediate VI was calculated to be 88.0%. For intermediate VI, (ESI-TOF) m / z: [M+1] + calcd for C 10 H9NO2: 175.19; found: 175.

[0057] The cuprous cyanide can also be replaced with an equal amount of potassium cyanide or sodium cyanide.

[0058] Intermediate VI in Example 6 was asymmetrically reduced to obtain intermediate VII

[0059] A 1.0 M catalyst (R)-2-methyl-CBS-oxazaborolidine toluene solution (0.86 L) was added into a reactor, borane dimethyl sulfide tetrahydrofuran solution (100 g, 1.31 mol) was added, the reaction was carried out at a reaction temperature of 10-25 °C (preferably at a reaction temperature of 20 °C) for 2 h, then a tetrahydrofuran solution of intermediate VII (230 g, 1.31 mol) was added dropwise, the reaction was continued at a reaction temperature of 10-25 °C (preferably at a reaction temperature of 20 °C) for 2 h, after the reaction was completed, methanol was added for quenching, concentrated, and column chromatography was performed to obtain intermediate VII, a total of 215.9 g, and the yield of intermediate VII was calculated to be 93%. For intermediate VII, (ESI-TOF) m / z: [M+1] +C 10 H 11 NO2: 177.22; found: 177.

[0060] The catalyst (R)-2-methyl-CBS-oxazaborolidine in the reaction can also be replaced by an equal amount of (S)-2-methyl-CBS-oxazaborolidine, and the borane dimethyl sulfide can also be replaced by an equal amount of borane.

[0061] Example 7 Protection of the hydroxyl group in intermediate VII to obtain intermediate VIII

[0062] The reaction kettle was charged with intermediate VII (215 g, 1.21 mol), and anhydrous N,N-dimethylformamide (3.2 L) was added to dissolve it. NaH (96.8 g, 2.42 mol) was added, followed by n-hexyl bromide (259 g, 1.57 mol), and tetrabutylammonium bromide (19.5 g, 0.06 mol). The reaction was carried out at a reaction temperature of 10-25°C (preferably at 20°C) until the raw material was consumed, as indicated by the control. After the reaction was quenched by adding an ammonium chloride solution, ethyl acetate was added for extraction, and then concentrated to obtain 272 g of intermediate VIII, with a calculated yield of 86% for intermediate VIII.

[0063] Intermediate VIII synthesized in the manner shown in Example 7 was subjected to nuclear magnetic hydrogen spectrum testing, and the test results were as follows:

[0064] 1 HNMR (400 MHz, C6D6) δ 7.484-7.503 (d, 1H), 6.938-6.961 (d, 1H), 6.542-6.581 (m, 1H), 4.617-4.665 (m, 1H), 3.606 (s, 3H), 3.086-3.146 (m, 2H), 1.481-1.509 (m, 2H), 1.171-1.291 (m, 10H), 0.839-0.875 (t, 3H).

[0065] The solvent anhydrous N,N-dimethylformamide in the reaction can also be replaced by an equal volume of tetrahydrofuran, N,N-dimethylformamide, or a mixture of the two. The n-hexyl bromide can also be replaced by an equal amount of n-hexyl iodide, and tetrabutylammonium bromide can also be replaced by an equal amount of tetrabutylammonium iodide.

[0066] Example 8 Condensation of intermediate VIII after Grignard reaction to obtain intermediate IX

[0067] Into a reactor was added intermediate VIII (272 g, 1.04 mol), anhydrous tetrahydrofuran (2 L) was added to dissolve it, then methyl magnesium bromide (3.0 M, 1 L) was added dropwise, and the reaction was carried out at a reaction temperature of 0-25 °C (preferably at 20 °C) for 12 h. After the reaction was completed, saturated ammonium chloride was added for quenching, and then ethyl acetate was added for dilution. After washing with brine, concentration was carried out to obtain 252 g of compound IX, and the yield of intermediate IX was calculated to be 87%.

[0068] The methyl magnesium bromide can also be replaced by the same amount of methyl magnesium chloride.

[0069] Intermediate IX in Example 9 was subjected to bromination to obtain compound X

[0070] Into a reactor was added intermediate IX (250 g, 0.9 mol), dichloromethane (1.6 L) was added to dissolve it, and then a catalyst toluenesulfonic acid (85 g) was added. N-bromosuccinimide (195.5 g, 1.1 mol) was slowly added in batches, and the reaction was carried out at a reaction temperature of 15-25 °C (preferably at 20 °C) for 3 h. After the reaction was completed, ethyl acetate was added for dilution, and then water and saturated brine were added for washing. Concentration was carried out to obtain 305 g of compound X, and the yield of compound X was calculated to be 95%.

[0071] The solvent dichloromethane can be replaced by the same volume of dichloroethane or toluene, and the catalyst toluenesulfonic acid can be replaced by the same amount of camphorsulfonic acid. The N-bromosuccinimide can also be replaced by the same amount of liquid bromine.

[0072] Compound X in Example 10 was subjected to thioamide cyclization to obtain intermediate XI

[0073] Into a reactor was added compound X (300 g, 0.84 mol), dichloromethane (1.5 L) was added to dissolve it, and then thioamide (64.7, 0.85 mol) was added. The reaction was carried out at a reaction temperature of 15-25 °C (preferably at 20 °C) for 4 h until the raw material was consumed. After concentration, ethyl acetate was added for dissolution, and then water was added for washing 3 times. After concentration, crystallization was carried out to obtain white powder solid, and then ethyl acetate was added for recrystallization to obtain white crystal intermediate XI, which was 224.8 g, and the yield of intermediate XI was calculated to be 80%.

[0074] The solvent dichloromethane can also be replaced by the same volume of dichloroethane or toluene.

[0075]

[0076] Intermediate XI synthesized in the manner shown in Example 10 was subjected to nuclear magnetic hydrogen spectrum test, and the test results were as follows: 1HNMR (400 MHz, CDC13) δ 8.19-8.22 (dd, J = 8.0, 2.0 Hz, 1H), 7.56-7.58 (dd, J = 7.8, 1.6 Hz, 1H), 7.14-7.16 (t, J = 8.0 Hz, 1H), 7.10-7.12 (s, 1H), 4.94-4.99 (m, 1H), 4.63 (m, 2H), 3.41 (s, 3H), 3.28-3.39 (m, 2H), 1.56-1.62 (m, 2H), 1.54 (d, J = 6.8 Hz, 3H), 1.18-1.22 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H). It can be seen from the nuclear magnetic hydrogen spectrum test result that the luspatercept intermediate with the structural formula XI is successfully prepared.

[0077] Although the present application has been disclosed in the preferred embodiments as above, it is not intended to limit the present application, and any person skilled in the art can make various modifications and modifications without departing from the spirit and scope of the present application, and therefore the protection scope of the present application should be defined by the claims.

Claims

1. A method for preparing intermediate VII of the antithrombocytopenic drug rutrombopag, characterized in that, The preparation method of the intermediate VII includes: Wherein, X is chlorine or bromine; in the step of preparing intermediate IV from compound III, the Grignard reagent is methyl magnesium bromide, methyl magnesium chloride, or methyl lithium chloride; in the step of preparing compound V from intermediate IV, the oxidant is sodium hypochlorite or potassium permanganate; in the step of preparing intermediate VI from compound V, the cyaniding reagent is cuprous cyanide, potassium cyanide, or sodium cyanide; in the step of preparing intermediate VII from intermediate VI, the reducing agent is borane or borane dimethyl sulfide.

2. The method for preparing intermediate VII of the antithrombocytopenic drug rutrombopag according to claim 1, characterized in that, In the step of preparing intermediate VII from intermediate VI, the molar ratio of intermediate VI to the reducing agent is 1:0.8 to 1.2; the reaction temperature range is 10℃ to 25℃.

3. A method for preparing intermediate VIII of the antithrombocytopenic drug rutrombopag, characterized in that, The preparation method of the intermediate VIII includes: Wherein, X is chlorine or bromine; in the step of preparing intermediate IV from compound III, the Grignard reagent is methyl magnesium bromide, methyl magnesium chloride, or methyl lithium chloride; in the step of preparing compound V from intermediate IV, the oxidant is sodium hypochlorite or potassium permanganate; in the step of preparing intermediate VI from compound V, the cyaniding reagent is cuprous cyanide, potassium cyanide, or sodium cyanide; in the step of preparing intermediate VII from intermediate VI, the reducing agent is borane tetrahydrofuran or borane dimethyl sulfide; in the step of preparing intermediate VIII from intermediate VII, the alcohol hydroxyl protecting agent is n-hexyl bromide or n-hexyl iodide.

4. The method for preparing intermediate VIII of the antithrombocytopenic drug rutrombopag according to claim 3, characterized in that, In the step of preparing intermediate VIII from intermediate VII, the molar ratio of intermediate VII to the alcohol hydroxyl protecting agent is 1:0.8 to 1.2.

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