Preparation method of obitavirs

Abstract

The present invention discloses a preparation method of obeticholic acid, and the preparation method comprises the following steps: S1. A compound of formula (I) reacts with acetylene under the conditions of a metal iridium bipyridine catalyst, a base and light to generate a compound of formula (II); S2. The compound of formula (II) is subjected to a reduction reaction to form a compound of formula (III); S3. The hydroxyl group of the compound of formula (III) is protected, and then it reacts with 4-tert-butylaniline to generate a compound of formula (IV); S4. The compound of formula (IV) undergoes a coupling reaction with a compound of formula (V-1) to obtain obeticholic acid; R is bromine or chlorine. The preparation method of the present invention has fewer reaction steps, reduces the use of metal reagents, improves the preparation yield of obeticholic acid, is more efficient and economical, and is environmentally friendly. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and more specifically, to a method for preparing ombitasvir. Background Art

[0002] Ombitasvir is an antiviral drug used to treat infectious liver diseases caused by hepatitis C virus (HCV) infection. HCV is a single-stranded RNA virus, which is divided into 9 different genotypes. Among them, genotype 1 is the most common in the United States, affecting 72% of chronic HCV patients. Ombitasvir is an inhibitor of NS5A, and NS5A is a protein necessary for viral replication and viral particle assembly. Since 2011, with the development of the direct-acting antiviral drug ombitasvir, the treatment regimen for chronic hepatitis C has made significant progress. The FDA has approved the combination of Technivie, which contains ombitasvir, paritaprevir, and ritonavir as active ingredients, and ribavirin for the treatment of genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis. Domestically, the hepatitis C treatment regimen of Weijianle (Ombitaprevir Tablets: a compound preparation of ombitasvir / paritaprevir / ritonavir) combined with Yiqirui (Dasabuvir Sodium Tablets) has been approved by the China Food and Drug Administration (CFDA) in 2017 for the treatment of adult genotype 1 chronic hepatitis C, including patients without cirrhosis or with compensated cirrhosis. The literature (J. Med. Chem. 2014, 57, 5, 204 - 2057) reported that ombitasvir was synthesized by the following route: 2-bromo-4'-nitroacetophenone reacts with 4-nitroacetophenone under the condition of equivalent zinc chloride to generate 1,4-bis(4-nitrophenyl)butane-1,4-dione, and then undergoes steps such as carbonyl reduction, hydroxyl protection, ring closure, nitro reduction, and amino acid condensation to synthesize ombitasvir (isomers), with an overall yield of 8.4%. Then chiral resolution is carried out to obtain ombitasvir. The core of this preparation technology is to simply and quickly prepare the (2S,5S)-diphenyl-substituted pyrrolidine parent nucleus structure, and then react with derivatives of proline and valine through a series of common unit reactions to conveniently obtain the target product ombitasvir, but it has the defects of many and complex synthesis route steps and a large amount of metal reagent consumption.

[0003] Summary of the Invention

[0004] The present invention aims to overcome the defects of many preparation steps and a large amount of metal reagent consumption, and provides a new method for preparing ombitasvir.

[0005] To achieve the above object, the technical solution adopted by the present invention is:

[0006] A method for preparing ombitasvir, comprising the following steps:

[0007] S1. The compound of formula (I) reacts with acetylene under the conditions of an iridium metal bipyridine catalyst, a base and light to form a compound of formula (II);

[0008] S2. The compound of formula (II) is subjected to a reduction reaction to form a compound of formula (III);

[0009] S3. The hydroxyl group of the compound of formula (III) is protected, and then it reacts with 4-tert-butylaniline to form a compound of formula (IV);

[0010] S4. The compound of formula (IV) is subjected to a coupling reaction with the compound of formula (V-1) to obtain obitaviroc;

[0011]

[0012] R is bromine or chlorine.

[0013] In the present invention, the obitaviroc compound is obtained by reacting a phenylglyoxylic acid compound with acetylene to form a 1,4-dicarbonyl compound and then performing reduction, ring closure and coupling reactions. Compared with the prior art, this method can shorten the reaction steps, reduce the use of metal reagents, improve the yield of preparing obitaviroc, and is more efficient, economical and environmentally friendly.

[0014] As an implementable solution, the preparation method of obitaviroc may further include the following steps:

[0015] S1. The compound of formula (I) reacts with acetylene under the conditions of an iridium metal bipyridine catalyst, a base and light to form a compound of formula (II);

[0016] S2. The compound of formula (II) is subjected to a reduction reaction to form a compound of formula (III);

[0017] S3. The hydroxyl group of the compound of formula (III) is protected, and then it reacts with 4-tert-butylaniline to form a compound of formula (IV);

[0018] S5. The compound of formula (IV) prepared in S3 is subjected to a coupling reaction with the compound of formula (V-2) to form a compound of formula (VI);

[0019] S6. After the Boc protection of the compound of formula (VI) is removed, it reacts with the compound of formula (V-3) to obtain obitaviroc;

[0020]

[0021] R is bromine or chlorine.

[0022] As an implementable solution, the preparation method of obitaviroc may further include the following steps:

[0023] S1. The compound of formula (I) reacts with acetylene under the conditions of an iridium bipyridine-based catalyst, a base, and light to form the compound of formula (II);

[0024] S2. The compound of formula (II) undergoes a reduction reaction to form the compound of formula (III);

[0025] S3. The hydroxyl group of the compound of formula (III) is protected, and then it reacts with 4-tert-butylaniline to form the compound of formula (IV);

[0026] S7. The compound of formula (IV) prepared in S3 reacts to form the compound of formula (VII);

[0027] S8. The compound of formula (VII) reacts with the compound of formula (V-4) to form the compound of formula (VI);

[0028] S9. After the Boc protection of the compound of formula (VI) is removed, it reacts with the compound of formula (V-3) to obtain obitaviral;

[0029]

[0030] The said R is bromine or chlorine.

[0031] Preferably, in step S1., the metal iridium bipyridine catalyst includes but is not limited to [Ir(ppy)2(dtbbpy)]PF6, Ir[dF(CF3)ppy]2bpyPF6, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir[dF(CF3)ppy]2(phen)PF6, Ir[dFCF3ppy]2(bpy)PF6, Ir[dFppy ]2(bpy)PF6, Ir[dFppy]2(dtbbpy)PF6, Ir[p-Fppy]2(bpy)PF6, Ir[p-Fppy]2(dtbpy)PF6, Ir [4-t-Bu-Phenyl-4-t-Bu-Py]2(dtbpy)PF6, Ir[dF(Me)ppy]2(dtbbpy)PF6, Ir(ppy)2(dtbbpy )PF6, Ir[dF(F)ppy]2(dCF3)PF6, [Ir(ppy)2(bpy)]PF6, Ir[pF(Me)ppy]2(dtbbpy)PF6, Ir[d (t-Bu)(CF3)ppy]2(dtbbpy)Cl, Ir[d(t-Bu)(CF3)ppy]2(dtbbpy)PF6, Fac-Ir(ppy)3, Fac-Ir (dFppy)3, Fac-Ir[dF(pt-Bu)ppy]3, Fac-Ir(p-CF3ppy)3, Fac-Ir(p-Fppy)3, Fac-Ir(pt-Bu- ppy)3, Fac-Ir(d-Fppy)3, Fac-Ir(3-t-Bu-ppy)3, Fac-Ir[(3-t-Bu-phenyl)-4-t-Bu-py)]3.

[0032] More preferably, the metal iridium bipyridine catalyst is more preferably Ir[dF(CF3)ppy]2bpyPF6, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir[dF(CF3)ppy]2(phen)PF6, Ir[dFCF3ppy]2(bpy)PF6, Ir[p-Fppy]2(bpy)PF6, Ir[d(t-Bu)(CF3)ppy]2(dtbbpy)PF6.

[0033] Preferably, the light irradiated in step S1 is monochromatic light or mixed light with a wavelength ranging from 200 to 800 nm.

[0034] When the light is monochromatic, it is more preferably violet light, blue light, cyan light, green light, yellow light, orange light or red light. Further, it is more preferably blue light or white light.

[0035] Preferably, the base in step S1 is potassium carbonate, cesium carbonate, potassium fluoride, potassium phosphate, potassium bicarbonate, sodium bicarbonate, dipotassium hydrogen phosphate, pyridine, 2,6-dimethylpyridine, triethylamine or tetramethylguanidine.

[0036] More preferably, the base is potassium fluoride or dipotassium hydrogen phosphate.

[0037] Preferably, the molar ratio of the compound of formula (I), the metal iridium bipyridine catalyst and the base in step S1 is 1:(0.005 - 0.1):(0.1 - 3).

[0038] More preferably, the molar ratio of the compound of formula (I), the metal iridium bipyridine catalyst and the base in step S1 is 1:(0.01 - 0.05):(1 - 1.5).

[0039] The acetylene in the reaction in step S1 is provided by a pressure vessel or prepared from calcium carbide.

[0040] Preferably, the acetylene in the reaction in step S1 is provided by a pressure vessel, and the pressure vessel refers to a container for collection and storage, such as a balloon, airbag, bladder, gas sampling bag, gas tank, steel cylinder.

[0041] Preferably, the solvent in step S1 is one or more of dichloromethane, dichloroethane, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or water.

[0042] Preferably, the addition amount of the solvent in step S1 is such that the concentration of the raw materials in the system is 0.01 M - 0.1 M.

[0043] Preferably, the solvent in step S1 is a mixture of water and dichloromethane, dichloroethane, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran or 1,4-dioxane.

[0044] More preferably, the feeding amount of water in the solvent is 5 - 60 equivalents of the compound shown in formula (I).

[0045] More preferably, the solvent in step S1 is more preferably a mixture of acetonitrile and water, a mixture of dichloromethane and water, or a mixture of tetrahydrofuran and water.

[0046] More preferably, in step S1, the reaction can be carried out as follows: Add the compound of formula (I), dipotassium hydrogen phosphate, the catalyst, water, dichloromethane into the reaction vessel, remove oxygen by freezing with liquid nitrogen, insert an acetylene balloon; under irradiation with blue light of 12 w, stir at room temperature and then separate and purify to obtain the compound of formula (II), 1,4-bis(4-bromo / chlorophenyl)butane-1,4-dione.

[0047] Step S2 can be carried out with reference to the existing method.

[0048] More preferably, in step S2., the reaction can be carried out as follows: Take (S)-(-)-α,α-diphenylprolinol and stir it at room temperature in dry tetrahydrofuran. Add trimethyl borate and continue stirring for a period of time. After the reaction is cooled, slowly add N,N-diethylaniline borane with a syringe. Continue to cool the mixture and transfer it to a tetrahydrofuran solution of the compound of formula (II), 1,4-bis(4-bromo / chlorophenyl)butane-1,4-dione. Stir at room temperature until the reaction is completed. After cooling, quench with methanol and then carry out separation and purification to obtain the compound of formula (III), (1R,4R)-1,4-bis(4-bromo / chlorophenyl)butane-1,4-diol.

[0049] Step S3. can be carried out with reference to the existing method.

[0050] More preferably, in step S3., the reaction can be carried out as follows: Add the compound of formula (III), (1R,4R)-1,4-bis(4-bromo / chlorophenyl)butane-1,4-diol, to dichloromethane, cool down to 0 °C, add triethylamine, and stir. Then dropwise add methanesulfonyl chloride, continue the reaction while maintaining the temperature, and then remove the solvent under reduced pressure. Add 4-tert-butylaniline and N,N-dimethylformamide to the residue and stir for a period of time. After the reaction is completed, carry out separation and purification to obtain the compound of formula (IV), (2S,5S)-2,5-bis(4-bromo / chlorophenyl)-1-(4-(tert-butyl)phenyl)pyrrolidine.

[0051] Step S4. can be carried out with reference to the existing method.

[0052] More preferably, in step S4., the reaction can be carried out as follows: Under a nitrogen atmosphere, add the compound of formula (IV), (2S,5S)-2,5-bis(4-bromo / chlorophenyl)-1-(4-(tert-butyl)phenyl)pyrrolidine, the compound of formula (V-1), methyl ((R)-1-((R)-2-carbamoylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, which is prepared by condensing (S)-pyrrolidine-2-carboxamide with (methoxycarbonyl)-D-valine, tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, cesium carbonate, and dry dioxane. After adding the materials, replace the gas with nitrogen three times and heat the reaction. After the reaction is completed, carry out separation and purification to obtain obeticholic acid.

[0053] Step S5. can be carried out with reference to the existing method.

[0054] More preferably, in step S5, the reaction can be carried out as follows: Add the compound of formula (IV) (2S,5S)-2,5-bis(4-bromo / chlorophenyl)-1-(4-(tert-butyl)phenyl)pyrrolidine, the compound of formula (V-2) tert-butyl (R)-2-carbamoyl pyrrolidine-1-carboxylate, tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene, cesium carbonate, and dry dioxane. After the addition is complete, displace with nitrogen three times and heat the reaction. After the reaction is completed, carry out separation and purification to obtain the compound of formula (VI).

[0055] Step S6 can be carried out with reference to existing methods.

[0056] More preferably, in step S6, the reaction can be carried out as follows: Take the compound of formula (VI) and add dichloromethane and trifluoroacetic acid, and stir at room temperature. Concentrate and rotary evaporate the reaction solution, add saturated sodium bicarbonate solution, and concentrate the organic phase to obtain the intermediate crude product. Under a nitrogen atmosphere and at 0 °C, add N,N-dimethylformamide, then add the compound of formula (V-3) MOC-L-valine, 1-hydroxybenzotriazole, N-methylmorpholine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stir, and transfer to room temperature for reaction. After the reaction is completed, carry out separation and purification to obtain obitralvir.

[0057] Step S7 can be carried out with reference to existing methods.

[0058] More preferably, in step S7, the reaction can be carried out as follows: Under a nitrogen atmosphere, add the compound of formula (IV) (2S,5S)-2,5-bis(4-bromo / chlorophenyl)-1-(4-(tert-butyl)phenyl)pyrrolidine, copper(I) oxide, dimethyl sulfoxide, and ammonia water, and heat and stir. After the reaction is completed, carry out separation and purification to obtain the compound of formula (VII) 4,4'-((2S,5S)-1-(4-(tert-butyl)phenyl)pyrrolidine-2,5-diyl)dianiline.

[0059] Step S8 can be carried out with reference to existing methods.

[0060] More preferably, in step S8, the reaction can be carried out as follows: Add the compound of formula (VII) 4,4'-((2S,5S)-1-(4-(tert-butyl)phenyl)pyrrolidine-2,5-diyl)dianiline to the compound of formula (V-4) Boc-L-proline, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N,N-diisopropylethylamine (Hünig's base), and dimethyl sulfoxide, and stir at room temperature. After the reaction is completed, add ethyl acetate and water, and carry out separation and purification to obtain the compound of formula (VI).

[0061] The amino acid compounds of formula (V-1), formula (V-2), formula (V-3), and formula (V-4) used in the present invention can be directly purchased or simply prepared by referring to the methods in known literature.

[0062]

[0063] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0064] The present invention provides a preparation method of obeticholic acid. By using the compound shown in formula (I) and acetylene as raw materials to react to form a 1,4-dicarbonyl compound, and then performing reduction, ring closure, and coupling reactions, the obeticholic acid compound can be obtained. Compared with the prior art, the method of the present invention can shorten the reaction steps, reduce the use of metal reagents, improve the yield of preparing obeticholic acid, and is more efficient, economical, and environmentally friendly. Detailed implementation manners

[0065] Unless otherwise specified, the raw materials, reagents, and solvents used in the present invention are all commercially purchased without any treatment or can be prepared by methods in the literature. To illustrate the present invention more clearly, the following further describes the present invention with reference to preferred embodiments. Those skilled in the art should understand that the specific content described below is illustrative rather than restrictive, and should not be used to limit the protection scope of the present invention.

[0066] Example 1

[0067] This example provides a preparation method of obeticholic acid, and the preparation method is as follows:

[0068]

[0069] S1. Under a nitrogen atmosphere, 4-bromophenylglyoxylic acid (I) (1.5 mmol, 345 mg), dipotassium hydrogen phosphate (1.8 mmol, 315 mg), Ir[dF(CF3)PPy]2(phen)PF6 (1%, 15.5 mg), water (0.5 ml), and dichloromethane (60 ml) were added to a dry Schlenk tube. Oxygen was removed by freezing with liquid nitrogen, and an acetylene balloon was inserted. After irradiating with 12w blue light and stirring at room temperature for 24 hours, the reaction solution was filtered by suction, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a white solid 1,4-bis(4-bromophenyl)butane-1,4-dione (II) (148 mg, 50%). 1 H NMR(500MHz,CDCl3)δ7.89(d,J=10.0Hz,4H),7.63(d,J=10.0Hz,4H),3.41(s,4H); 13 C NMR(126MHz,CDCl3)δ197.5,135.5,132.0,129.6,128.4,32.5.

[0070] S2. To a solution of (S)-(-)-α,α-diphenylprolinol (0.08 mmol, 20 mg) in tetrahydrofuran (1 ml), trimethyl borate (0.1 mmol, 11 mg) was added. After stirring at room temperature for 1.5 h, the reaction solution was cooled to 0 °C, and borane-N,N-diethylaniline (1.03 mmol, 168 mg) was slowly added dropwise, paying attention to the exothermic reaction and hydrogen generation. After the addition was complete, the mixture was stirred at a temperature below 10 °C for 20 min. It was slowly added dropwise to a solution of 1,4-bis(4-bromophenyl)butane-1,4-dione (II) (0.5 mmol, 148 mg) in tetrahydrofuran (1 ml). After completion, the reaction system was slowly restored to room temperature and stirred. After 3 h, TLC (petroleum ether:ethyl acetate = 2:1) detected that the raw materials had basically reacted completely. At 0 °C, methanol (4 mmol, 130 mg) was slowly added dropwise. After 20 min, it was transferred to room temperature and stirred. Ethyl acetate (30 ml) and 1 M hydrochloric acid (10 ml) were added. The organic phase was washed twice with 1 M hydrochloric acid, once with water, dried and concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain the white solid (1R,4R)-1,4-bis(4-bromophenyl)butane-1,4-diol (III) (184 mg, 92%). 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.7 Hz, 4H), 7.55 (d, J = 8.7 Hz, 4H), 5.51 (br s, 2H), 4.77–4.55 (m, 2H), 1.78–1.46 (m, 4H).

[0071] S3. Under a nitrogen atmosphere, (1R,4R)-1,4-bis(4-bromophenyl)butane-1,4-diol (III) (0.46 mmol, 184 mg) and dichloromethane (5 ml) were added and stirred at 0 °C. After 10 min, triethylamine (1.38 mmol, 140 mg) was added. After the reaction system became clear, methanesulfonyl chloride (1.15 mmol, 0.1 ml) was slowly added dropwise. After completion, the mixture was stirred at this temperature for 4 h. Subsequently, it was concentrated and dried by rotary evaporation. p-Tert-butylaniline (4.6 mmol, 686 mg) and N,N-dimethylformamide (3 ml) were added, and the mixture was heated to 40 °C in an oil bath and stirred for reaction. After 5 h, TLC (petroleum ether:ethyl acetate = 40:1) monitored that the raw materials had basically reacted completely. 1 M hydrochloric acid and ethyl acetate were added, the organic phases were combined, washed once with saturated brine, filtered by suction, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain (2S,5S)-2,5-bis(4-bromophenyl)-1-(4-(tert-butyl)phenyl)pyrrolidine (IV) (0.42 mmol, 217 mg, 92%), dr = 5.5:1.

[0072] S4. Under a nitrogen atmosphere, L-prolinamide hydrochloride (18 mmol, 2.71 g), MOC-L-valine (1.15 eq, 20.7 mmol), 1-hydroxybenzotriazole (HOBT, 1.25 eq, 22.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.25 eq, 22.5 mmol), N-methylmorpholine (NMM, 4 eq, 72 mmol), and dichloromethane (0.15 M) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated to dryness by rotary evaporation, water was added, and extraction was carried out with chloroform and isopropanol (chloroform:isopropanol = 3:1). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain methyl ((S)-1-((S)-2-carbamoyl pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate V-1 (4.338 g, 89%). (2S,5S)-2,5-Bis(4-bromophenyl)-1-(4-(tert-butyl)phenyl)pyrrolidine (IV) (0.42 mmol, 217 mg), methyl ((S)-1-((S)-2-carbamoyl pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate V-1 (2.2 eq, 0.93 mmol), tris(dibenzylideneacetone)dipalladium (6%, 0.025 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene (18%, 0.075 mmol), cesium carbonate (2.8 eq, 1.18 mmol), and dry dioxane (5 ml) were added. After the addition was complete, the mixture was purged with nitrogen three times and heated at 100 °C for 16 hours. Water, 1 N hydrochloric acid, and ethyl acetate were added, the organic phases were combined, washed once with saturated brine, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain obeticholic acid (180 mg, 48%). The overall yield was 20.3%.

[0073] 11H NMR (500 MHz, CDCl3) δ 9.28 (s, 2H), 7.38 (d, J = 7.5, 4H), 7.08 (dd, J = 8.5, 2.5 Hz, 4H), 6.97 (d, J = 7.5 Hz, 2H), 6.22 (d, J = 8.5 Hz, 2H), 5.90 - 5.73 (m, 2H), 5.08 (d, J = 6.0 Hz, 2H), 4.78 - 4.73 (m, 2H), 4.37 - 4.31 (m, 2H), 3.85 - 3.77 (m, 2H), 3.67 - 3.60 (m, 8H), 2.46 - 2.44 (m, 2H), 2.20 - 2.12 (m, 2H), 2.06 - 1.87 (m, 8H), 1.71 - 1.65 (m, 2H), 1.15 (d, J = 2.0 Hz, 9H), 0.97 (d, J = 6.7 Hz, 6H), 0.94 (d, J = 6.7 Hz, 6H).

[0074] Examples 2 - 9

[0075] This example provides a series of preparation methods of obitaviral. The preparation methods and raw materials are the same as those in Example 1, and obitaviral is obtained by using different iridium - bipyridine - based metal catalysts. See Table 1 for details. The yield is represented by the yield of step S1:

[0076] Table 1 Examples 2 - 9

[0077] Example Catalyst Yield % 2 <![CDATA[Ir[dF(CF3)ppy]2bpyPF6]]> 38 3 <![CDATA[Ir[dF(CF3)ppy]2(dtbbpy)PF6]]> 33 4 <![CDATA[Ir[dFCF3ppy]2(bpy)PF6]]> 35 5 <![CDATA[Ir[p-Fppy]2(bpy)PF6]]> 25 6 <![CDATA[Ir[d( t- Bu)(CF3)ppy]2(dtbbpy)PF6]]> 23 7 <![CDATA[Fac-Ir(ppy)3]]> 13 8 <![CDATA[Ir[dFppy]2(bpy)PF6]]> 29 9 <![CDATA[Fac-Ir[(3- t- Bu-phenyl)-4- t- Bu-py)]3]]> 22

[0078] Example 10

[0079] This example provides a preparation method of obitaviral. White light is used instead of blue light in Example 1, and the rest of the operations remain unchanged. The yield of 1,4 - bis(4 - bromophenyl)butane - 1,4 - dione in step S1 is 39%.

[0080] Example 11

[0081] This example provides a preparation method of obitaviral. Ultraviolet light is used instead of blue light in Example 1, and the rest of the operations remain unchanged. The yield of 1,4 - bis(4 - bromophenyl)butane - 1,4 - dione in step S1 is 33%.

[0082] Example 12

[0083] This example provides a preparation method of obitaviral. Potassium fluoride is used instead of dipotassium hydrogen phosphate in Example 1, and the rest of the operations remain unchanged. The yield of 1,4 - bis(4 - bromophenyl)butane - 1,4 - dione in step S1 is 49%.

[0084] Example 13

[0085] This embodiment provides a preparation method of obeticholic acid, using potassium carbonate instead of dipotassium hydrogen phosphate in Example 1, with the remaining operations unchanged. The yield of 1,4-bis(4-bromophenyl)butane-1,4-dione in step S1 is 26%.

[0086] Example 14

[0087] This embodiment provides a preparation method of obeticholic acid, using cesium carbonate instead of dipotassium hydrogen phosphate in Example 1, with the remaining operations unchanged. The yield of 1,4-bis(4-bromophenyl)butane-1,4-dione in step S1 is 26%.

[0088] Example 15

[0089] This embodiment provides a preparation method of obeticholic acid, using pyridine instead of dipotassium hydrogen phosphate in Example 1, with the remaining operations unchanged. The yield of 1,4-bis(4-bromophenyl)butane-1,4-dione in step S1 is 20%.

[0090] Example 16

[0091] This embodiment provides a preparation method of obeticholic acid, using triethylamine instead of dipotassium hydrogen phosphate in Example 1, with the remaining operations unchanged. The yield of 1,4-bis(4-bromophenyl)butane-1,4-dione in step S1 is 20%.

[0092] Example 17

[0093] This embodiment provides a preparation method of obeticholic acid, reducing the feed of dipotassium hydrogen phosphate to 0.1 equivalent, with the remaining operations unchanged. The yield of 1,4-bis(4-bromophenyl)butane-1,4-dione in step S1 is 30%.

[0094] Example 18

[0095] This embodiment provides a preparation method of obeticholic acid. Using 4-chlorophenylglyoxylic acid instead of 4-bromophenylglyoxylic acid in Example 1, with other operations the same as in Example 1, 1,4-bis(4-chlorophenyl)butane-1,4-dione (92 mg, 40%) is obtained.

[0096] The remaining steps (2), (3), and (4) are the same as in Example 1, and finally obeticholic acid (isomer mixture) 100 mg is obtained, with a total yield of 11.3%.

[0097] Example 19

[0098] This embodiment provides a preparation method of obeticholic acid, and the preparation method is as follows:

[0099]

[0100] S5. (2S,5S)-2,5-Bis(4-bromophenyl)-1-(4-(tert-butyl)phenyl)pyrrolidine (IV) (1.2 mmol, 616 mg) prepared by the method of Example 1 was added with (R)-tert-butyl 2-carbamoyl-1-pyrrolidinecarboxylate V-2 (3.12 mmol, 668 mg), tris(dibenzylideneacetone)dipalladium (6%, 0.072 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18%, 0.22 mmol), cesium carbonate (2.8 eq, 3.36 mmol), and dry dioxane (15 ml). After the addition was complete, the mixture was purged with nitrogen three times and heated at 100 °C for 12 hours. Water, 1N hydrochloric acid, and ethyl acetate were added. The organic phases were combined, washed once with saturated brine, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain compound VI (0.97 mmol, 753 mg, 80%). 1 H NMR (500 MHz, CDCl3) δ 9.44 (s, 2H), 7.44 (d, J = 8.5 Hz, 4H), 7.13 (d, J = 8.0 Hz, 4H), 6.99 (d, J = 8.5 Hz, 2H), 6.25 (d, J = 9.0 Hz, 2H), 5.11 (d, J = 6.0 Hz, 2H), 4.51 - 4.32 (m, 2H), 3.51 - 3.34 (m, 4H), 2.52 - 2.46 (m, 3H), 2.01 - 1.85 (m, 7H), 1.75 - 1.70 (m, 2H), 1.48 (s, 18H), 1.17 (s, 9H).

[0101] S6. Compound VI (0.97 mmol, 753 mg) was added with dichloromethane (6 ml) and trifluoroacetic acid (6 ml), and stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness by rotary evaporation, saturated sodium bicarbonate solution, chloroform, and isopropanol (chloroform:isopropanol = 3:1) were added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. A portion of the residue (0.638 mmol, 500 mg) was added with N,N-dimethylformamide, cooled to 0 °C, and MOC-L-valine (1.15 eq, 0.74 mmol), 1-hydroxybenzotriazole (HOBT, 1.25 eq, 0.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.25 eq, 0.8 mmol), and N-methylmorpholine (NMM, 4 eq, 2.55 mmol) were added. After stirring for 10 minutes, the mixture was transferred to room temperature and reacted for 12 hours. Water and ethyl acetate were added. The organic phases were combined, washed twice with saturated brine, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain obitaviral (304 mg, 85%). The overall yield was 28.8%.

[0102] Example 20

[0103] This example provides a preparation method of obeticholic acid, and the preparation method is as follows:

[0104]

[0105] S7. (2S,5S)-2,5-Bis(4-bromophenyl)-1-(4-(tert-butyl)phenyl)pyrrolidine (IV) (0.15 mmol, 77 mg) prepared by the method of Example 1 was added with copper(I) oxide (0.015 mmol, 2.2 mg), dimethyl sulfoxide (5 ml), ammonia water (0.34 ml), and heated and stirred at 100 °C for 24 hours. Water and ethyl acetate were added, the organic phases were combined, washed once with saturated brine, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 4,4'-((2S,5S)-1-(4-(tert-butyl)phenyl)pyrrolidine-2,5-diyl)dianiline (VII) (24 mg, 42%). 1 H NMR(500MHz,Chloroform-d)δ7.43(d,J=8.3Hz,2H),7.10(d,J=8.3Hz,2H),7.03(d,J=8.7Hz,2H),6.99(d,J=8.2Hz,2H),6.65(d,J=8.2Hz,2H),6.27(d,J=8.8Hz,2H),5.14–5.04(m,2H),2.63–2.35(m,2H),1.75(td,J=12.0,5.9Hz,2H),1.21(s,9H).

[0106] S8. 4,4'-((2S,5S)-1-(4-(tert-butyl)phenyl)pyrrolidine-2,5-diyl)dianiline (VII) (24 mg, 0.062 mmol) was added with Boc-L-proline (V-4) (2.2 eq), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 2.2 eq), N,N-diisopropylethylamine (Hünig's base, 4 eq), and dimethyl sulfoxide (1 ml), and stirred at room temperature for 1 hour. After the reaction was completed, ethyl acetate and water were added, the organic phase was washed, dried over sodium sulfate, concentrated, and separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 -  10:5) to obtain compound (VI) (48.3 mg, 99%).

[0107] Compound VI (0.062 mmol, 48.3 mg) was added to dichloromethane (1 ml) and trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness by rotary evaporation, saturated sodium bicarbonate solution was added, and chloroform and isopropanol (chloroform:isopropanol = 3:1) were used. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was added to N,N-dimethylformamide (1 ml), cooled to 0 °C, and MOC-L-valine (1.15 eq, 0.071 mmol), 1-hydroxybenzotriazole (HOBT, 1.25 eq, 0.078 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.25 eq, 0.078 mmol), and N-methylmorpholine (NMM, 4 eq, 0.25 mmol) were added. After stirring for 10 minutes, the reaction was transferred to room temperature and continued for 12 hours. Water and ethyl acetate were added, the organic phases were combined, washed twice with saturated brine, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain obitaviral (47 mg, 85%). The overall yield was 35.6%.

[0108] Obviously, the above-mentioned embodiments of the present invention are merely examples for clearly explaining the present invention, rather than limitations on the implementation manners of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all implementation manners here. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included within the protection scope of the claims of the present invention.

Claims

1. A preparation method of obitaviral, characterized in that, It includes the following steps: S1. The compound of formula (I) reacts with acetylene under the conditions of an iridium metal bipyridine catalyst, a base and light irradiation to form the compound of formula (II); S2. The compound of formula (II) undergoes a reduction reaction to form the compound of formula (III); S3. The hydroxyl group of the compound of formula (III) is protected, and then it reacts with 4-tert-butylaniline to form the compound of formula (IV); S4. The compound of formula (IV) undergoes a coupling reaction with the compound of formula (V-1) to obtain obitavirin; The R is bromine or chlorine; The metal iridium bipyridine catalysts are [Ir(ppy)2(dtbbpy)]PF6, Ir[dF(CF3)ppy]2bpyPF6, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir[dF(CF3)ppy]2(phen)PF6, Ir[dFCF3ppy]2(bpy)PF6, Ir[dFppy]2(bpy)PF6, Ir[dFppy]2(dtbbpy)PF6, Ir[p-Fppy]2(bpy)PF6, Ir[p-Fppy]2(dtbpy)PF6, Ir[4- t- Bu-Phenyl-4- t- Bu-Py]2(dtbpy)PF6, Ir[dF(Me)ppy]2(dtbbpy)PF6, Ir(ppy)2(dtbbpy)PF6, Ir[dF(F)ppy]2(dCF3)PF6, [Ir(ppy)2(bpy)]PF6, Ir[p-F(Me)ppy]2(dtbbpy)PF6, Ir[d( t- Bu)(CF3)ppy]2(dtbbpy)Cl, Ir[d( t- Bu)(CF3)ppy]2(dtbbpy)PF6, Fac-Ir(ppy)3, Fac-Ir(dFppy)3, Fac-Ir[d-F(p- t- Bu)ppy]3, Fac-Ir(p-CF3ppy)3, Fac-Ir(p-Fppy)3, Fac-Ir(p- t- Bu-ppy)3, Fac-Ir(d-Fppy)3, Fac-Ir(3- t- Bu-ppy)3 or Fac-Ir[(3- t- Bu-phenyl)-4- t- Bu-py)]3; The light for the light irradiation is monochromatic light or mixed light with a wavelength range of 200-800 nm.

2. A preparation method of obitaviral, characterized in that, It includes the following steps: S1. The compound of formula (I) reacts with acetylene under the conditions of an iridium metal bipyridine catalyst, a base and light irradiation to form the compound of formula (II); S2. The compound of formula (II) undergoes a reduction reaction to form the compound of formula (III); S3. The hydroxyl group of the compound of formula (III) is protected, and then it reacts with 4-tert-butylaniline to form the compound of formula (IV); S5. The compound of formula (IV) prepared in S3 undergoes a coupling reaction with the compound of formula (V-2) to form the compound of formula (VI); S6. After the Boc protection of the compound of formula (VI) is removed, it reacts with the compound of formula (V-3) to obtain obitavirin; The R is bromine or chlorine; The metal iridium bipyridine catalysts are [Ir(ppy)2(dtbbpy)]PF6, Ir[dF(CF3)ppy]2bpyPF6, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir[dF(CF3)ppy]2(phen)PF6, Ir[dFCF3ppy]2(bpy)PF6, Ir[dFppy]2(bpy)PF6, Ir[dFppy]2(dtbbpy)PF6, Ir[p-Fppy]2(bpy)PF6, Ir[p-Fppy]2(dtbpy)PF6, Ir[4- t- Bu-Phenyl-4- t- Bu-Py]2(dtbpy)PF6, Ir[dF(Me)ppy]2(dtbbpy)PF6, Ir(ppy)2(dtbbpy)PF6, Ir[dF(F)ppy]2(dCF3)PF6, [Ir(ppy)2(bpy)]PF6, Ir[p-F(Me)ppy]2(dtbbpy)PF6, Ir[d( t- Bu)(CF3)ppy]2(dtbbpy)Cl, Ir[d( t- Bu)(CF3)ppy]2(dtbbpy)PF6, Fac-Ir(ppy)3, Fac-Ir(dFppy)3, Fac-Ir[d-F(p- t- Bu)ppy]3, Fac-Ir(p-CF3ppy)3, Fac-Ir(p-Fppy)3, Fac-Ir(p- t- Bu-ppy)3, Fac-Ir(d-Fppy)3, Fac-Ir(3- t- Bu-ppy)3 or Fac-Ir[(3- t- Bu-phenyl)-4- t- Bu-py)]3; The light for the light irradiation is monochromatic light or mixed light with a wavelength range of 200-800 nm.

3. A preparation method of obitaviral, characterized in that, It includes the following steps: S1. The compound of formula (I) reacts with acetylene under the conditions of an iridium metal bipyridine catalyst, a base and light irradiation to form the compound of formula (II); S2. The compound of formula (II) undergoes a reduction reaction to form the compound of formula (III); S3. The hydroxyl group of the compound of formula (III) is protected, and then it reacts with 4-tert-butylaniline to form the compound of formula (IV); S7. The compound of formula (IV) prepared in S3 reacts to form the compound of formula (VII); S8. The compound of formula (VII) reacts with the compound of formula (V-4) to form the compound of formula (VI); S9. After the Boc protection of the compound of formula (VI) is removed, it reacts with the formula (V-3) to obtain obitavirin; The R is bromine or chlorine; The metal iridium bipyridine-based catalysts are [Ir(ppy)2(dtbbpy)]PF6, Ir[dF(CF3)ppy]2bpyPF6, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir[dF(CF3)ppy]2(phen)PF6, Ir[dFCF3ppy]2(bpy)PF6, Ir[dFppy]2(bpy)PF6, Ir[dFppy]2(dtbbpy)PF6, Ir[p-Fppy]2(bpy)PF6, Ir[p-Fppy]2(dtbpy)PF6, Ir[4- t- Bu-Phenyl-4- t- Bu-Py]2(dtbpy)PF6, Ir[dF(Me)ppy]2(dtbbpy)PF6, Ir(ppy)2(dtbbpy)PF6, Ir[dF(F)ppy]2(dCF3)PF6, [Ir(ppy)2(bpy)]PF6, Ir[p-F(Me)ppy]2(dtbbpy)PF6, Ir[d( t- Bu)(CF3)ppy]2(dtbbpy)Cl, Ir[d( t- Bu)(CF3)ppy]2(dtbbpy)PF6, Fac-Ir(ppy)3, Fac-Ir(dFppy)3, Fac-Ir[d-F(p- t- Bu)ppy]3, Fac-Ir(p-CF3ppy)3, Fac-Ir(p-Fppy)3, Fac-Ir(p- t- Bu-ppy)3, Fac-Ir(d-Fppy)3, Fac-Ir(3- t- Bu-ppy)3 or Fac-Ir[(3- t- Bu-phenyl)-4-t-Bu-py)]3; The light for the light irradiation is monochromatic light or mixed light with a wavelength range of 200-800 nm.

4. The preparation method according to any one of claims 1 to 3, characterized in that, The light for the light irradiation in step S1 is blue light or white light.

5. According to the preparation method described in any one of claims 1 to 3, characterized in that, The base in step S1 is potassium carbonate, cesium carbonate, potassium fluoride, potassium phosphate, potassium bicarbonate, sodium bicarbonate, dipotassium hydrogen phosphate, pyridine, 2,6-dimethylpyridine, triethylamine or tetramethylguanidine.

6. The preparation method according to claim 1, wherein The molar ratio of the compound of formula (I), the iridium metal bipyridine catalyst and the base in step S1 is 1:(0.005-0.1):(0.1-3).

7. According to the preparation method described in claim 1, characterized in that, The acetylene in step S1 is provided by a pressure vessel.

8. The preparation method according to claim 1, characterized in that The solvent in step S1 is one or more of dichloromethane, dichloroethane, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or water.

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