CN116496265A - Synthesis method of posaconazole halocyclization intermediate - Google Patents

Synthesis method of posaconazole halocyclization intermediate Download PDF

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CN116496265A
CN116496265A CN202310516256.7A CN202310516256A CN116496265A CN 116496265 A CN116496265 A CN 116496265A CN 202310516256 A CN202310516256 A CN 202310516256A CN 116496265 A CN116496265 A CN 116496265A
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compound
synthesis
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substituted
acid
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肖霄
周高杰
洪鸣
林波
尹明星
石岳崚
陈喜
范慧敏
解慧萍
龚伟中
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Zhejiang Hisoar Pharmaceutical Co Ltd
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Zhejiang Hisoar Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides a synthesis method of posaconazole halogenate cyclized intermediate, which comprises the step of carrying out halogenation reaction on a raw material intermediate shown as a formula (1) and a halogenating reagent in an organic solvent in the presence of an acidic substance to obtain the posaconazole halogenate cyclized intermediate shown as a formula (2). The invention also provides a synthesis method of posaconazole. The synthesis method provided by the invention adopts the low-cost acidic substance to activate the halogenating reagent and carry out the halogenation reaction under the low-temperature condition, the prepared target product has the advantages of high yield, high diastereoselectivity and the like, the process is simple and convenient, the operation is convenient, the post-treatment is simple, the synthesis efficiency is obviously improved, the synthesis cost is reduced, the synthesis method provided by the invention has great potential for industrialized mass production, the industrial practicability is strong, the method has important significance for expanding the production and the application of posaconazole,

Description

Synthesis method of posaconazole halocyclization intermediate
Technical Field
The invention relates to the field of synthesis of medical intermediates, in particular to a synthesis method of posaconazole halogeno-cyclized intermediates and a synthesis method of posaconazole.
Background
Posaconazole (posaconazole) is a derivative of itraconazole, which is a second-generation triazole antifungal drug approved by the FDA in 2006, and has the trade name of N0XAFIL, and the original manufacturer is pioneering. Posaconazole has broad-spectrum antifungal activity, strong antibacterial efficacy, and good bactericidal effect on aspergillus and other fungi, and especially on polyene compounds and other triazole drug resistance or invasive fungal infection. In addition, posaconazole is also used clinically for the treatment of infection with conjugated bacteria, and can also be used for the salvage treatment of invasive aspergillus and coccidioidomycosis. The sales of posaconazole are increased annually since the market, wherein the global sales of posaconazole in 2021 exceeds 10 hundred million dollars, and the posaconazole has strong economic effects and application prospects.
India MSN Laboratories Limited in 2012 disclosed a synthetic route to posaconazole in patent US 2014343285 A1: the target product is obtained by Friedel-crafts acylation, wittig, condensed amide, methylolation, halogenated cyclization, reduction and substitution by taking m-difluorobenzene as a starting material, but the line is easy to produce intramolecular ring-closing impurities, and the yield is seriously affected although the impurities can be removed. The synthetic route is as follows:
the synthesis methods disclosed in the prior patent and literature have the defects of poor diastereoselectivity, low yield and large raw material consumption for the key halogen cyclization step. In view of the high cost of posaconazole synthesis, it is desirable to develop a high yield, high diastereoselective halocyclization process to increase intermediate yields and thereby reduce synthesis costs.
Disclosure of Invention
In order to make up for the defects existing in the prior art, the invention aims to provide a synthesis method of a posaconazole halogenate cyclized intermediate, which can obviously improve the yield and diastereoselectivity of the posaconazole halogenate cyclized intermediate, thereby obviously improving the synthesis efficiency of the posaconazole halogenate cyclized intermediate and reducing the synthesis cost.
Another object of the present invention is to provide a method for synthesizing posaconazole.
The first aspect of the invention provides a synthesis method of a posaconazole halogeno-cyclized intermediate, which comprises the steps of carrying out halogenation reaction on a raw material intermediate shown in a formula (1) and a halogenating reagent in an organic solvent in the presence of an acidic substance to prepare the posaconazole halogeno-cyclized intermediate shown in a formula (2);
wherein R is 1 Represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C12 aryl group, or a substituted or unsubstituted C7-C18 alkylene aryl group;
R 2 and R is 3 Each independently represents hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C12 aryl group,Or a substituted or unsubstituted C7-C18 alkylene aryl;
when R is 1 、R 2 And R is 3 When each independently represents a substituted group, the substituent is selected from C1-C4 alkyl, C1-C4 alkoxy or C6-C12 aryl;
x represents halogen.
The synthesis method of posaconazole halogenate intermediate provided by the invention is characterized in that the reaction is carried out in the presence of acidic substances, the halogenating reagent generates halogen acid in situ under the activation of the acidic substances, the halogen acid reacts with the raw material intermediate, and the activation of the halogenating reagent and the halogenation reaction are completed in one pot, so that the target product is obtained. Compared with halogenation reaction under neutral or alkaline conditions, the synthesis method provided by the invention can greatly improve the yield and diastereoselectivity of the target product, and then can improve the synthesis efficiency of the target product, reduce the synthesis cost and relieve the subsequent purification pressure.
In the synthesis method provided by the invention, R is as follows 1 May further represent a substituted or unsubstituted C1-C4 alkyl group (e.g., a substituted or unsubstituted methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, etc.), a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; the R is 2 And R is 3 May each independently further represent hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; when R is 1 、R 2 And R is 3 When each independently represents a substituted group, the substituents may be selected from C1-C4 alkyl groups.
In some preferred embodiments, the R 1 May further represent a C2-C4 alkyl group (e.g., isopropyl), phenyl or benzyl group. In other preferred embodiments, the R 2 And R is 3 May each independently further represent hydrogen or phenyl.
In the synthesis method provided by the invention, X can further represent Br or I.
In the synthesis method provided by the invention, the acidic substance can be selected from common inorganic acid, organic acid or acid salt (such as inorganic acid salt of alkali metal), and can activate the halogenating reagent to generate halogen acid. In some preferred embodiments, the acidic substance may be selected from one or more of hydrochloric acid (e.g., concentrated hydrochloric acid at a concentration of 10-12N), sulfuric acid (e.g., concentrated sulfuric acid at a concentration of 5-8N), nitric acid, carbonic acid, boric acid, orthophosphoric acid, p-toluenesulfonic acid (TsOH), camphorsulfonic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, potassium bisulfate, sodium bisulfate. In some more preferred embodiments, the acidic species may be selected from hydrochloric acid (e.g., concentrated hydrochloric acid at a concentration of 12N).
In the synthesis method provided by the invention, the amount of the acidic substance may be 1-50 mol% of the raw material intermediate, including but not limited to about 1mol%, about 5mol%, about 8mol%, about 10mol%, about 12mol%, about 15mol%, about 18mol%, about 20mol%, about 25mol%, about 30mol%, about 35mol%, about 40mol%, about 45mol%, about 50mol%, etc. or any mole percentage interval. In some preferred embodiments, the acidic material may be used in an amount of 5 to 15mol% of the starting intermediate.
In the synthesis method provided by the invention, the halogenating reagent can be selected from common halogenating reagents, and can be activated by acidic substances to generate halogen acid. In some preferred embodiments, the halogenating agent may be selected from iodine (I 2 ) N-iodosuccinimide (NIS), N-iodophthalimide, liquid bromine (Br) 2 ) One or more of dibromohydantoin (DBDMH), diiodohydantoin, N-bromosuccinimide (NBS), and N-bromophthalimide. In some more preferred embodiments, the halogenating agent may be selected from I 2 Or NBS.
The amount of the halogenating agent used in the synthesis process provided by the present invention may be from 1.0 to 5.0 equivalents of the starting intermediate, including but not limited to about 1.0 equivalent, about 1.2 equivalent, about 1.5 equivalent, about 1.8 equivalent, about 2.0 equivalent, about 2.2 equivalent, about 2.5 equivalent, about 2.8 equivalent, about 3.0 equivalent, about 3.5 equivalent, about 4.0 equivalent, about 4.5 equivalent, about 5.0 equivalent, or any equivalent interval. In some preferred embodiments, the halogenating agent can be used in an amount of 1.2 to 2.5 equivalents of the starting intermediate.
In the synthesis method provided by the invention, the organic solvent can be selected from common organic solvents such as acetates, nitriles and the like. In some preferred embodiments, the organic solvent may be selected from, for example, CH 3 COOR 'is an organic solvent wherein R' may be a C1-C6 alkyl group, preferably a C1-C4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.). In some more preferred embodiments, the organic solvent may be selected from one or more of acetonitrile, butyronitrile, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate.
In the synthesis method provided by the present invention, the reaction temperature of the halogenation reaction may be-10 to-78 ℃, including, but not limited to, about-10 ℃, about-20 ℃, about-25 ℃, about-30 ℃, about-35 ℃, about-40 ℃, about-45 ℃, about-50 ℃, about-55 ℃, about-60 ℃, about-65 ℃, about-70 ℃, about-75 ℃, about-78 ℃, and the like, or any temperature interval. Lower reaction temperatures are advantageous for increasing diastereoselectivity, and in some preferred embodiments the reaction temperature of the halogenation reaction may be from-10 to-40 c, based on factors such as production costs.
In the synthesis method provided by the invention, the reaction time of the halogenation reaction can be 1-10 h. In some preferred embodiments, the reaction time of the halogenation reaction may be from 2 to 5 hours.
The second aspect of the invention provides a method for synthesizing posaconazole, which comprises a step of synthesizing a posaconazole halogenate cyclized intermediate, wherein the step of synthesizing adopts the method for synthesizing the posaconazole halogenate cyclized intermediate according to any one of the technical schemes.
The synthesis method of the posaconazole halogenate intermediate provided by the invention adopts an inexpensive acidic substance to activate a halogenating reagent and carries out halogenation reaction under a low-temperature condition, and the prepared target product has the advantages of high yield, high diastereoselectivity and the like, is simple in process, convenient to operate and simple in post-treatment, and can obviously improve the synthesis efficiency and reduce the synthesis cost, and gram-scale reaction (shown as an example 69) can be realized, so that the synthesis method has great potential of industrial scale production and strong industrial practicability, and has important significance in expanding the production and application of posaconazole.
Detailed Description
The technical scheme of the invention is further described in detail below with reference to specific embodiments.
The raw materials or reagents used in the examples and comparative examples of the present invention were all commercially available products, and the operating methods and test methods used were all conventional methods in the art, unless otherwise specified.
The hydrochloric acid used in the examples and comparative examples of the present invention was 12N concentrated hydrochloric acid, and the sulfuric acid used was 6N concentrated sulfuric acid.
The percentages used in the examples and comparative examples of the present invention are mass percentages unless otherwise specified.
Example 1 Synthesis of (R) -4-phenyl-3- ((3S, 5R) -5- (2, 4)) -difluorophenyl-5-iodomethyltetrahydrof-ran-3-carbonyl-oxazolidin-2-one (2 a)
In a dry schlenk tube, 1a (387 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0.003mL) was added. The mixture was cooled to-40℃and I was added 2 (383mg, 1.5 mmol). The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and clear, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and the compound 2a of 463mg is prepared, the yield is 90%, and dr=18:1.
1 H NMR(400MHz,CDCl 3 )δ7.43–7.28(m,4H),7.20(d,J＝6.9Hz,2H),6.85–6.79(m,1H),6.73(ddd,J＝11.2,8.6,2.5Hz,1H),5.36(dd,J＝8.7,3.8Hz,1H),4.64(t,J＝8.8Hz,1H),4.25–4.17(m,2H),4.13–4.01(m,2H),3.63–3.55(m,2H),2.72(dd,J＝13.2,7.1Hz,1H),2.61(ddd,J＝13.2,8.1,2.0Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ173.41,163.84,163.62,160.94,160.81,160.13,157.43,157.28,153.52,138.63,129.71,129.56,121.65,110.42,104.56,104.38,104.19,87.39,87.21,70.53,69.71,57.49,44.37,39.01,38.95,38.43,38.40,28.91.
EXAMPLE 2 Synthesis of Compound 2a
Except that NIS (338 mg,1.5 mmol) was used in place of I 2 Except for the other steps, the procedure was the same as in example 1, to obtain compound 2a 433mg in a yield of 82%, dr=16:1.
EXAMPLE 3 Synthesis of Compound 2a
Except that N-iodophthalimide (410 mg,1.5 mmol) was used in place of I 2 Except for the other steps, the same as in example 1, compound 2a, 447mg was produced in a yield of 85%, dr=16:1.
EXAMPLE 4 Synthesis of Compound 2a
Except that diiodohydantoin (570 mg,1.5 mmol) was used in place of I 2 Except for the other steps, the same as in example 1 was conducted to obtain compound 2a 459mg in a yield of 87%, dr=17:1.
EXAMPLE 5 Synthesis of Compound 2a
The procedure was the same as in example 1 except that sulfuric acid (0.1 mmol, 0.002mL) was used instead of HCl, to obtain compound 2a 469mg in a yield of 89%, dr=17:1.
EXAMPLE 6 Synthesis of Compound 2a
The procedure was the same as in example 1 except that L- (-) camphorsulfonic acid (0.1 mmol,23 mg) was used instead of HCl, to obtain compound 2a 460 mg in 88% yield dr=17:1.
EXAMPLE 7 Synthesis of Compound 2a
The procedure was the same as in example 1 except that TsOH (0.1 mmol,17 mg) was used instead of HCl, to obtain compound 2a 459mg in a yield of 87%, dr=16:1.
EXAMPLE 8 Synthesis of Compound 2a
The procedure was repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl, to obtain compound 2a 460 mg in a yield of 88% dr=17:1.
Example 9 Synthesis of (R) -4-phenyl-3- ((3S, 5R) -5- (2, 4)) -difluorophenyl-5-bromomethyltetrahydrof-ran-3-carbonyl-oxazolidin-2-one (2 b)
In a dry schlenk tube, 1a (387 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0.003mL) was added. The mixture was cooled to-40℃and NBS (267 mg,1.5 mmol) was added. The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and clear, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and the compound 2b 410mg is prepared, and the yield is 88 percent, dr=17:1.
1 H NMR(400MHz,CDCl 3 )δ7.43(td,J＝8.9,6.5Hz,1H),7.35–7.27(m,3H),7.21(d,J＝1.8Hz,1H),7.19(d,J＝2.8Hz,1H),6.85–6.79(m,1H),6.74(ddd,J＝11.3,8.6,2.5Hz,1H),5.36(dd,J＝8.7,3.8Hz,1H),4.64(t,J＝8.8Hz,1H),4.25–4.18(m,2H),4.11–4.02(m,2H),3.69(d,J＝1.2Hz,2H),2.72(dd,J＝13.4,6.8Hz,1H),2.55(ddd,J＝13.6,7.8,2.1Hz,1H)； 13 CNMR(100MHz,CDCl 3 )δ171.50,163.99,163.87,161.51,161.39,160.17,157.83,157.71,153.49,138.59,129.42,129.01,125.73,111.22,104.76,104.50,104.24,84.21,84.17,70.26,69.90,57.88,44.47,39.27,39.23,38.59,38.55,29.71.
EXAMPLE 10 Synthesis of Compound 2b
The procedure was the same as in example 9 except that sulfuric acid (0.1 mmol, 0.002mL) was used instead of HCl, to obtain 402mg of compound 2b in 86% yield, dr=17:1.
EXAMPLE 11 Synthesis of Compound 2b
The procedure was the same as in example 9 except that TsOH (0.1 mmol,17 mg) was used instead of HCl, to obtain compound 2b 284 mg in a yield of 84%, dr=17:1.
EXAMPLE 12 Synthesis of Compound 2b
The procedure was the same as in example 9 except that camphorsulfonic acid (0.1 mmol,23 mg) was used instead of HCl, to obtain compound 2b 390 mg in a yield of 85%, dr=16:1.
EXAMPLE 13 Synthesis of Compound 2b
The same procedures as in example 9 were repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl to give 400mg of compound 2b in a yield of 85% dr=16:1.
EXAMPLE 14 Synthesis of Compound 2b
In a dry schlenk tube, 1a (387 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0.003mL) was added. The mixture was cooled to-40℃and dibromohydantoin (429 mg,1.5 mmol) was added. The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and clear, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and the compound 2b 405mg is prepared, and the yield is 87 percent, dr=17:1.
EXAMPLE 15 Synthesis of Compound 2b
The procedure was the same as in example 14 except that sulfuric acid (0.1 mmol, 0.002mL) was used instead of HCl, to obtain compound 2b 405mg in a yield of 87%, dr=16:1.
EXAMPLE 16 Synthesis of Compound 2b
The procedure was the same as in example 14 except that TsOH (0.1 mmol,17 mg) was used instead of HCl, to obtain compound 2b 390 mg in a yield of 85%, dr=15:1.
EXAMPLE 17 Synthesis of Compound 2b
The procedure was the same as in example 14 except that camphorsulfonic acid (0.1 mmol,23 mg) was used instead of HCl, to obtain compound 2b 390 mg in a yield of 85% dr=15:1.
EXAMPLE 18 Synthesis of Compound 2b
The same procedures as in example 14 were repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl to obtain compound 2b 393mg in a yield of 83%, dr=15:1.
Example 19 Synthesis of (R) -4-benzyl-3- ((3S, 5R) -5- (2, 4)) -difluorophenyl-5-iodomethyltetrahydrof-ran-3-carbonyl-oxazolidin-2-one (2 c)
In a dry schlenk tube, 1b (400 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0.003mL) was added. The mixture was cooled to-40℃and I was added 2 (383mg, 1.5 mmol). The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol was added, the temperature was raised to 70℃and the solution was stirred and cleared, naturally cooled to room temperature and stirred for crystallization for 3 hours, filtration was carried out, the solid was rinsed with isopropanol and dried to prepare 2c 480mg of compound with a yield of 91%, dr=18:1.
1 H NMR(400MHz,CDCl 3 )δ7.41(td,J＝8.9,6.5Hz,1H),7.26(dd,J＝8.0,6.4Hz,2H),7.21–7.17(m,1H),7.15–7.08(m,2H),6.81(td,J＝8.3,2.6Hz,1H),6.72(ddd,J＝11.2,8.6,2.5Hz,1H),4.67–4.55(m,1H),4.21–4.11(m,3H),4.06–3.99(m,1H),3.74(d,J＝10.7Hz,1H),3.67(d,J＝10.7Hz,1H),3.18(dd,J＝13.5,3.4Hz,1H),2.79(ddd,J＝27.6,13.4,8.0Hz,2H),2.57(ddd,J＝13.4,8.4,2.1Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ174.56,163.33,163.19,160.97,160.85,160.72,158.53,158.31,153.23,140.25,140.24,135.29,130.54,130.52,130.47,130.41,129.50,128.94,126.39,124.87,124.84,124.80,124.76,115.24,111.24,111.20,111.07,111.01,104.87,104.67,103.99,66.29,63.54,54.73,44.54,37.93,33.58,33.54.
EXAMPLE 20 Synthesis of Compound 2c
The procedure was repeated except for using sulfuric acid (0.1 mmol, 0.002mL) instead of HCl, to obtain 469mg of compound 2c in a yield of 89%, dr=18:1.
EXAMPLE 21 Synthesis of Compound 2c
The procedure was followed in the same manner as in example 19 except for using TsOH (0.1 mmol,17 mg) instead of HCl, to obtain compound 2c 457mg in a yield of 83%, dr=17:1.
EXAMPLE 22 Synthesis of Compound 2c
The procedure was repeated except for using camphorsulfonic acid (0.1 mmol,23 mg) instead of HCl, to obtain compound 2c 447mg in 82% yield dr=17:1.
EXAMPLE 23 Synthesis of Compound 2c
The same operation was repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl in the same manner as in example 19 to obtain compound 2c 447mg in a yield of 82% dr=17:1.
EXAMPLE 24 Synthesis of Compound 2c
In a dry schlenk tube, 1b (400 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0.003mL) was added. The mixture was cooled to-40℃and NIS (338 mg,1.5 mmol) was added. The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and cleared, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and the compound 2c 473mg is prepared, the yield is 88%, and dr=17:1.
EXAMPLE 25 Synthesis of Compound 2c
The procedure was the same as in example 24 except that sulfuric acid (0.1 mmol, 0.002mL) was used instead of HCl, to obtain compound 2c 45mg in a yield of 85%, dr=16:1.
EXAMPLE 26 Synthesis of Compound 2c
The procedure was repeated except for using TsOH (0.1 mmol,17 mg) instead of HCl, to obtain compound 2c 447mg in 83% yield dr=17:1.
EXAMPLE 27 Synthesis of Compound 2c
The procedure was repeated except for using camphorsulfonic acid (0.1 mmol,23 mg) instead of HCl, to obtain 450mg of compound 2c in a yield of 84% dr=16:1.
Example 28 Synthesis of (R) -4-benzyl-3- ((3S, 5R) -5- (2, 4)) -difluorophenyl-5-bromomethyltetrahydrof-ran-3-carbonyl-oxazolidin-2-one (2 d)
In a dry schlenk tube, 1b (400 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0.003mL) was added. The mixture was cooled to-40℃and NBS (267 mg,1.5 mmol) was added. The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and clear, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and the compound 2d 410mg is prepared, and the yield is 88%, dr=18:1.
1 H NMR(400MHz,CDCl 3 )δ7.45(td,J＝8.8,6.4Hz,1H),7.27(dd,J＝8.0,6.4Hz,2H),7.18(s,1H),7.16–7.09(m,2H),6.82(td,J＝8.3,2.6Hz,1H),6.74(ddd,J＝11.2,8.7,2.5Hz,1H),4.61(ddt,J＝9.2,7.0,3.4Hz,1H),4.20–4.12(m,3H),4.01(tt,J＝8.0,5.8Hz,1H),3.87–3.73(m,2H),3.19(dd,J＝13.4,3.4Hz,1H),2.78(ddd,J＝28.2,13.4,8.0Hz,2H),2.52(ddd,J＝13.4,8.5,2.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ174.73,163.62,163.49,161.25,161.13,161.01,158.77,158.65,153.43,140.36,140.35,135.15,130.77,130.72,130.68,130.62,129.50,128.94,127.37,125.09,125.06,124.95,124.91,118.75,111.34,111.30,111.13,111.09,104.43,104.17,103.91,66.18,63.85,55.49,44.26,37.76,35.32,35.29.
EXAMPLE 29 Synthesis of Compound 2d
The procedure was followed except for using sulfuric acid (0.1 mmol, 0.002mL) instead of HCl, to obtain 410mg of compound 2d in 88% yield (dr=17:1) in the same manner as in example 28.
EXAMPLE 30 Synthesis of Compound 2d
The procedure was repeated except for using TsOH (0.1 mmol,17 mg) instead of HCl, to obtain 2d 408mg of compound, with a yield of 85%, dr=16:1.
EXAMPLE 31 Synthesis of Compound 2d
The procedure was repeated except for using camphorsulfonic acid (0.1 mmol,23 mg) instead of HCl, to obtain 2d 408mg of compound (2 d) in a yield of 85% dr=17:1.
EXAMPLE 32 Synthesis of Compound 2d
The same procedures were repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl in the same manner as in example 28 to obtain compound 2d 399mg in a yield of 82%, dr=16:1.
Example 33 Synthesis of (R) -4-isopropyl-3- ((3S, 5R) -5- (2, 4)) -difluorophenyl-5-iodomethyltetrahydrof-ran-3-carbonyl-oxazolidin-2-one (2 e)
In a dry schlenk tube, 1c (353 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0.003mL) was added. The mixture was cooled to-40℃and I was added 2 (383mg, 1.5 mmol). The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol was added and the temperature was raisedStirring to dissolve at 70 ℃, naturally cooling to room temperature, stirring and crystallizing for 3 hours, filtering, leaching the solid with isopropanol, and drying to obtain compound 2e 425mg with the yield of 89%, dr=17:1.
1 H NMR(400MHz,CDCl 3 )δ7.41(td,J＝8.9,6.5Hz,1H),6.83(td,J＝8.2,2.5Hz,1H),6.74(ddd,J＝11.2,8.6,2.5Hz,1H),4.38(dt,J＝7.4,3.5Hz,1H),4.23(td,J＝8.4,6.2Hz,2H),4.19–4.03(m,4H),3.71(q,J＝10.7Hz,2H),2.82(dd,J＝13.3,6.5Hz,1H),2.57(ddd,J＝13.2,8.1,2.2Hz,1H),2.30(ddt,J＝10.9,7.0,3.9Hz,1H),0.86(d,J＝7.0Hz,3H),0.81(d,J＝6.9Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ171.74,163.87,163.74,161.39,161.27,160.53,157.79,157.67,152.85,129.73,125.88,111.11,110.97,104.59,104.34,104.18,84.25,84.21,70.62,63.45,58.67,44.29,39.41,39.25,38.21,37.95,27.94,17.57,14.63.
EXAMPLE 34 Synthesis of Compound 2e
The procedure was the same as in example 33 except that sulfuric acid (0.1 mmol, 0.002mL) was used instead of HCl, to obtain compound 2e 407mg in a yield of 85%, dr=16:1.
EXAMPLE 35 Synthesis of Compound 2e
The procedure was followed in the same manner as in example 33 except for using TsOH (0.1 mmol,17 mg) instead of HCl, to obtain compound 2e 3838 mg in a yield of 81%, dr=15:1.
EXAMPLE 36 Synthesis of Compound 2e
The procedure was repeated except for using camphorsulfonic acid (0.1 mmol,23 mg) instead of HCl, to obtain compound 2e 3996 mg in a yield of 83%, dr=16:1, in the same manner as in example 33.
EXAMPLE 37 Synthesis of Compound 2e
The same procedures were repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl in the same manner as in example 33 to obtain compound 2e 387mg in a yield of 81% dr=15:1.
EXAMPLE 38 Synthesis of Compound 2e
In a dry schlenk tube, 1c (353 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0.003mL) was added. The mixture was cooled to-40℃and NIS (338 mg,1.5 mmol) was added. The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and cleared, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is rinsed with isopropanol and dried, and the compound 2e 398mg is prepared, and the yield is 84%, dr=16:1.
EXAMPLE 39 Synthesis of Compound 2e
The procedure was the same as in example 38 except that sulfuric acid (0.1 mmol, 0.002mL) was used instead of HCl, to obtain compound 2e 3838 mg in a yield of 81%, dr=15:1.
EXAMPLE 40 Synthesis of Compound 2e
The procedure was followed except for using TsOH (0.1 mmol,17 mg) instead of HCl, and the same procedures as in example 38 were repeated to obtain compound 2e 374mg in a yield of 79% and dr=15:1.
EXAMPLE 41 Synthesis of Compound 2e
The same procedures as in example 38 were repeated except for using camphorsulfonic acid (0.1 mmol,23 mg) instead of HCl to give compound 2e 369mg in a yield of 78% dr=15:1.
EXAMPLE 42 Synthesis of Compound 2e
The same procedures were repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl in the same manner as in example 38 to obtain compound 2e 369mg in a yield of 78% dr=15:1.
Example 43 Synthesis of (R) -4-isopropyl-3- ((3S, 5R) -5- (2, 4)) -difluorophenyl-5-bromomethyltetrahydrof-ran-3-carbonyl-oxazolidin-2-one (2 f)
In a dry schlenk tube, 1c (353 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0) was added.003 mL). The mixture was cooled to-40℃and NBS (267 mg,1.5 mmol) was added. The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and cleared, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and the compound 2f 376mg is prepared, and the yield is 87%, dr=16:1.
1 H NMR(400MHz,CDCl 3 )δ7.45(td,J＝8.9,6.5Hz,1H),6.86–6.80(m,1H),6.77–6.71(m,1H),4.38(ddd,J＝8.2,3.9,3.1Hz,1H),4.23(dt,J＝9.3,7.8Hz,2H),4.18–4.11(m,2H),4.05(tt,J＝8.1,5.9Hz,1H),3.84(d,J＝10.9Hz,1H),3.78(dd,J＝10.9,0.9Hz,1H),2.86–2.77(m,1H),2.50(ddd,J＝13.4,8.4,2.3Hz,1H),2.30(qt,J＝7.0,3.5Hz,1H),0.86(d,J＝7.0Hz,3H),0.81(d,J＝6.9Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ172.06,163.96,163.84,161.49,161.37,160.23,157.89,157.77,153.85,129.23,125.88,111.21,111.00,104.77,104.52,104.26,84.25,84.21,70.62,63.69,58.67,44.65,39.53,39.49,38.37,38.33,28.44,17.96,14.74.
EXAMPLE 44 Synthesis of Compound 2f
The procedure was the same as in example 43 except that sulfuric acid (0.1 mmol, 0.002mL) was used instead of HCl, to obtain 367mg of compound 2f in 85% yield, dr=15:1.
EXAMPLE 45 Synthesis of Compound 2f
The procedure was followed in the same manner as in example 43 except for using TsOH (0.1 mmol,17 mg) instead of HCl, to obtain compound 2f 356 mg in a yield of 82%, dr=15:1.
EXAMPLE 46 Synthesis of Compound 2f
The procedure was followed in the same manner as in example 43 except for using camphorsulfonic acid (0.1 mmol,23 mg) instead of HCl, to obtain 360mg of compound 2f in a yield of 82%, dr=16:1.
EXAMPLE 47 Synthesis of Compound 2f
The same procedures were repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl in the same manner as in example 43 to obtain 2f 352mg of compound 2 in a yield of 80% dr=15:1.
EXAMPLE 48 Synthesis of Compound 2f
The procedure was the same as in example 43 except that DBDMH (429 mg,1.5 mmol) was used instead of NBS, to obtain compound 2f 356 mg in 83% yield dr=16:1.
Example 49 Synthesis of (R) -4-phenyl-3- ((3S, 5R) -5- (2, 4)) -difluorophenyl-5-iodomethyltetrahydrof-ran-3-carbonyl-5, 5-diphenyloxazolidin-2-one (2 g)
In a dry schlenk tube, 1d (539 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0.003mL) was added. The mixture was cooled to-40℃and I was added 2 (383mg, 1.5 mmol). The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. Adding 5mL of isopropanol, heating to 70 ℃ and stirring to dissolve, naturally cooling to room temperature and stirring to crystallize for 3h, filtering, leaching the solid with isopropanol, and drying to obtain 2g of compound (565 mg) with a yield of 85%, dr>20:1。
1 H NMR(400MHz,CDCl 3 )δ7.55(d,J＝7.7Hz,2H),7.34(dt,J＝15.7,7.5Hz,4H),7.04(s,3H),6.98–6.90(m,7H),6.80(td,J＝8.3,2.5Hz,1H),6.70(ddd,J＝11.3,8.6,2.5Hz,1H),4.25–4.16(m,1H),4.07–3.95(m,2H),3.57–3.47(m,2H),2.88(d,J＝26.1Hz,1H),2.54(qd,J＝13.4,12.9,7.2Hz,2H). 13 C NMR(100MHz,CDCl 3 )δ171.11,170.66,152.59,141.51,137.64,134.27,128.89,128.55,128.37,128.15,127.79,127.64,126.67,126.15,125.99,125.94,125.78,111.15,110.93,104.74,104.48,89.37,83.85,83.81,69.14,65.68,44.98,43.92,38.87,38.29.
EXAMPLE 50 Synthesis of Compound 2g
The procedure was the same as in example 49 except that sulfuric acid (0.1 mmol, 0.002mL) was used instead of HCl, to obtain 2g of 539mg of the compound in a yield of 81%, dr >20:1.
EXAMPLE 51 Synthesis of Compound 2g
The procedure was followed in the same manner as in example 49 except for using TsOH (0.1 mmol,17 mg) instead of HCl, to obtain 2g 545mg of the compound in 82% yield dr=19:1.
EXAMPLE 52 Synthesis of Compound 2g
The procedure was followed in the same manner as in example 49 except for using camphorsulfonic acid (0.1 mmol,23 mg) instead of HCl, to obtain 2g 552mg of the compound in 83% yield dr >20:1.
EXAMPLE 53 Synthesis of Compound 2g
The same procedures as in example 49 were repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl to give 2g of compound 540 mg in a yield of 80% dr=19:1.
EXAMPLE 54 Synthesis of Compound 2g
Except that NIS (338 mg,1.5 mmol) was used in place of I 2 Except for the other steps, the procedure of example 49 was followed to obtain 2g 525mg of the compound in a yield of 79% dr=18:1.
EXAMPLE 55 Synthesis of Compound 2g
The procedure was the same as in example 54 except that sulfuric acid (0.1 mmol, 0.002mL) was used instead of HCl, to obtain 2g of compound 520mg in a yield of 78% dr=18:1.
EXAMPLE 56 Synthesis of Compound 2g
The procedure was followed in the same manner as in example 54 except for using TsOH (0.1 mmol,17 mg) instead of HCl, to obtain 2g 502mg of the compound in a yield of 76% dr=18:1.
EXAMPLE 57 Synthesis of Compound 2g
The procedure was repeated except for using camphorsulfonic acid (0.1 mmol,23 mg) instead of HCl, in the same manner as in example 54, to obtain 2g of compound (542 mg) in a yield of 81%, dr=19:1.
EXAMPLE 58 Synthesis of Compound 2g
The same procedures as in example 54 were repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl to obtain 2g 509mg of the compound in 73% yield dr=18:1.
Example 59 Synthesis of (R) -4-phenyl-3- ((3S, 5R) -5- (2, 4)) -difluorophenyl-5-bromomethyltetrahydrof-ran-3-carbonyl-5, 5-diphenyloxazolidin-2-one (2 h)
In a dry schlenk tube, 1d (539 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and hydrochloric acid (0.1 mmol, 0.003mL) was added. The mixture was cooled to-40℃and NBS (267 mg,1.5 mmol) was added. The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. Adding 5mL of isopropanol, heating to 70 ℃ and stirring to dissolve, naturally cooling to room temperature and stirring to crystallize for 3h, filtering, leaching the solid with isopropanol, and drying to obtain compound 2h 507mg with a yield of 82%, dr>20:1。
1 H NMR(400MHz,CDCl 3 )δ7.55(d,J＝7.6Hz,2H),7.40–7.31(m,4H),7.06(dd,J＝5.2,1.8Hz,3H),6.97–6.93(m,7H),6.81(td,J＝8.3,2.6Hz,1H),6.71(ddd,J＝11.2,8.5,2.5Hz,1H),4.23(t,J＝8.1Hz,1H),4.08–3.98(m,2H),3.63(s,2H),2.71–2.33(m,3H). 13 C NMR(100MHz,CDCl 3 )δ171.11,170.66,152.59,141.51,137.64,135.33,129.08,129.03,128.52,128.39,127.79,127.64,127.26,126.15,126.11,125.94,125.78,111.22,111.00,104.74,104.48,89.60,84.15,84.11,69.57,66.28,44.98,44.46,39.16,38.64.
EXAMPLE 60 Synthesis of Compound 2h
The procedure was the same as in example 59 except for using sulfuric acid (0.1 mmol, 0.002mL) instead of HCl, to obtain compound 2h 494mg in 80% yield dr=19:1.
EXAMPLE 61 Synthesis of Compound 2h
The procedure was the same as in example 59 except that TsOH (0.1 mmol,17 mg) was used instead of HCl, to obtain 2h 480mg of compound in 78% yield dr=19:1.
EXAMPLE 62 Synthesis of Compound 2h
The procedure was the same as in example 59 except that camphorsulfonic acid (0.1 mmol,23 mg) was used instead of HCl, to obtain compound 2h 503mg in a yield of 81%, dr >20:1.
EXAMPLE 63 Synthesis of Compound 2h
The same procedures as in example 59 were repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl to give compound 2h 493mg in a yield of 79% dr=19:1.
Synthesis of Compound 2h from example 64
Except that DBDMH (429 mg,1.5 mmol) was used in place of I 2 The procedure was otherwise as in example 59 to give compound 2h 488mg in 79% yield dr>20:1。
Synthesis of Compound 2h from example 65
The procedure was the same as in example 64 except that sulfuric acid (0.1 mmol, 0.002mL) was used instead of HCl, to obtain compound 2h 474mg in a yield of 76%, dr=19:1.
EXAMPLE 66 Synthesis of Compound 2h
The procedure was the same as in example 64 except that TsOH (0.1 mmol,17 mg) was used instead of HCl, to obtain 2h 480mg of the compound in 78% yield dr=19:1.
Synthesis of Compound 2h from EXAMPLE 67
The procedure was the same as in example 64 except that camphorsulfonic acid (0.1 mmol,23 mg) was used instead of HCl, to obtain compound 2h 470 mg in a yield of 76%, dr=19:1.
EXAMPLE 68 Synthesis of Compound 2h
The same procedures as in example 64 were repeated except for using potassium hydrogen sulfate (0.1 mmol,13 mg) instead of HCl to obtain compound 2h 457mg in a yield of 73%, dr=19:1.
EXAMPLE 69 Synthesis of Compound 2a
In a dry schlenk tube, 1a (1.16 g,3 mmol) was dissolved in ethyl acetate (24 mL) at room temperature and hydrochloric acid (0.3 mmol,0.009 mL) was added. The mixture was cooled to-40℃and I was added 2 (1.14 g,4.5 mmol). The resulting solution was stirred at-40℃for 3h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 15mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and clear, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and the compound 2a 1.4g is prepared, and the yield is 91%, dr=18:1.
EXAMPLE 70 Synthesis of Compound 2a
Except that the solvent for the reaction and washing was replaced with methyl acetate, the remaining steps were the same as in example 1 to obtain compound 2a 433mg in a yield of 82%, dr=16:1.
EXAMPLE 71 Synthesis of Compound 2a
Except that the solvent for the reaction and washing was replaced with isopropyl acetate, the remaining steps were the same as in example 1 to obtain compound 2a 417mg in a yield of 79%, dr=16:1.
EXAMPLE 72 Synthesis of Compound 2a
Except that the solvent for the reaction and washing was replaced with n-butyl acetate, the procedure was the same as in example 1, except that 2a 422mg of compound was obtained in 80% yield, dr=16:1.
Comparative example 1 Synthesis of Compound 2a
Except that no acid was added to the reaction system and the reaction time was prolonged to 12 hours, the other steps were the same as in example 1 to obtain 284 mg of compound 2a in a yield of 54% dr=6:1.
Comparative example 2 Synthesis of Compound 2a
1a (387 mg,1 mmol) was dissolved in ethyl acetate (8 mL) in a dry schlenk tube at room temperature and the mixture cooled to-40℃and added I 2 (3831 mg,1.5 mmol) and sodium carbonate (159 mg,1.5 mmol). The resulting solution was stirred at-40℃for 12h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and cleared, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is rinsed with isopropanol and dried, and the compound 2a 370mg is prepared, the yield is 72%, and dr=9:1.
Comparative example 3 Synthesis of Compound 2a
Except that the solvent for the reaction and washing was replaced with dichloromethane, the same procedure as in example 1 was repeated to obtain compound 2a 243mg in a yield of 46%, dr=4:1.
Comparative example 4 Synthesis of Compound 2a
Except that the solvent for the reaction and washing was replaced with tetrahydrofuran, the procedure was otherwise identical to that of example 1, to obtain 2a 332mg of compound 2a in a yield of 63%, dr=1:2.
Comparative example 5 Synthesis of Compound 2a
Except that the solvent for the reaction and washing was replaced with toluene, the procedure was otherwise identical to that of example 1, to obtain 2a 332mg of compound 2a in a yield of 54%, dr=2:1.
Comparative example 6 Synthesis of Compound 2a
The procedure of example 2 was repeated except that the reaction system was not charged with any acid and the reaction time was prolonged to 12 hours, to obtain 290mg of compound 2a in a yield of 55% dr=5:1.
Comparative example 7 Synthesis of Compound 2b
Except that no acid was added to the reaction system and the reaction time was prolonged to 12 hours, the other steps were the same as in example 9 to obtain 335mg of compound 2b in a yield of 72%, dr=5:1.
Comparative example 8 Synthesis of Compound 2b
In a dry schlenk tube, 1a (387 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and the mixture was cooled to-40℃and NBS (267 mg,1.5 mmol) and sodium carbonate (1593 mg,3 mmol) were added. The resulting solution was stirred at-40℃for 12h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and clear, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and compound 2b 350mg is obtained, the yield is 75%, and dr=8:1.
Comparative example 9 Synthesis of Compound 2c
The procedure of example 19 was repeated except that the reaction system was not charged with any acid and the reaction time was prolonged to 12 hours, to obtain compound 2c 416mg in a yield of 79% and dr=7:1.
Comparative example 10 Synthesis of Compound 2c
1b (400 mg,1 mmol) was dissolved in ethyl acetate (8 mL) in a dry schlenk tube at room temperature and the mixture cooled to-40℃and added I 2 (3831 mg,1.5 mmol) and sodium carbonate (159 mg,1.5 mmol). The resulting solution was stirred at-40℃for 12h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and cleared, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and the compound 2c 427mg is prepared, and the yield is 81%, dr=10:1.
Comparative example 11 Synthesis of Compound 2d
The procedure of example 28 was repeated except that the reaction system was not charged with any acid and the reaction time was prolonged to 12 hours, to obtain compound 2d 349mg in a yield of 65% and dr=5:1.
Comparative example 12 Synthesis of Compound 2d
In a dry schlenk tube, 1b (400 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and the mixture was cooled to-40℃and NBS (267 mg,1.5 mmol) and sodium carbonate (1599 mg,1.5 mmol) were added. The resulting solution was stirred at-40℃for 12h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and cleared, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and 2d 360mg of compound is prepared, the yield is 75%, and dr=8:1.
Comparative example 13 Synthesis of Compound 2e
The procedure of example 33 was repeated except that the reaction system was not charged with any acid and the reaction time was prolonged to 12 hours, to obtain compound 2e 399 mg in a yield of 75%, dr=6:1.
Comparative example 14 Synthesis of Compound 2e
1c (353 mg,1 mmol) was dissolved in ethyl acetate (8 mL) in a dry schlenk tube at room temperature and the mixture cooled to-40℃and added I 2 (3831 mg,1.5 mmol) and sodium carbonate (159 mg,1.5 mmol). The resulting solution was stirred at-40℃for 12h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and cleared, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and the compound 2e 373mg is prepared, the yield is 79%, and dr=8:1.
Comparative example 15 Synthesis of Compound 2f
The procedure of example 43 was repeated except that the reaction system was not charged with any acid and the reaction time was prolonged to 12 hours, to obtain compound 2f 272mg in a yield of 63% dr=5:1.
Comparative example 16 Synthesis of Compound 2f
In a dry schlenk tube, 1c (353 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and the mixture was cooled to-40℃and NBS (267 mg,1.5 mmol) and sodium carbonate (159 mg,1.5 mmol) were added. The resulting solution was stirred at-40℃for 12h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol was added, the temperature was raised to 70℃and the solution was stirred and cleared, naturally cooled to room temperature and stirred for crystallization for 3 hours, filtration was carried out, the solid was rinsed with isopropanol and dried to prepare compound 2f 316mg in 73% yield, dr=8:1.
Synthesis of Compound 2g of comparative example 17
The procedure of example 49 was repeated except that the reaction system was not charged with any acid and the reaction time was prolonged to 12 hours, to obtain 2g 470 mg of the compound in a yield of 71%, dr=6:1.
Synthesis of Compound 2g of comparative example 18
In a dry schlenk tube, 1d (539 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and the mixture cooled to-40℃and added I 2 (3831 mg,1.5 mmol) and sodium carbonate (159 mg,1.5 mmol). The resulting solution was stirred at-40℃for 12h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol was added and the temperature was raisedStirring and clearing at 70 ℃, naturally cooling to room temperature, stirring and crystallizing for 3 hours, filtering, leaching the solid with isopropanol, and drying to obtain 2g of compound (4815 mg) with the yield of 73%, dr=11:1.
Synthesis of Compound 2h of comparative example 19
The procedure of example 59 was repeated except that the reaction system was not charged with any acid and the reaction time was prolonged to 12 hours, to obtain 2h 401mg of the compound in a yield of 65% dr=6:1.
Synthesis of Compound 2h of comparative example 20
In a dry schlenk tube, 1d (539 mg,1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature and the mixture was cooled to-40℃and NBS (267 mg,1.5 mmol) and sodium carbonate (1599 mg,1.5 mmol) were added. The resulting solution was stirred at-40℃for 12h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, taken up with Na 2 SO 4 Dried, filtered and concentrated. 5mL of isopropanol is added, the temperature is raised to 70 ℃ and the solution is stirred and clear, the solution is naturally cooled to room temperature and stirred and crystallized for 3 hours, the solution is filtered, the solid is leached by the isopropanol and dried, and the compound 2h 458mg is prepared, and the yield is 74 percent, dr=13:1.
Comparative example 21 Synthesis of Compound 2a
Except that the reaction temperature was changed to ordinary temperature (25 ℃), the procedure was the same as in comparative example 2 (i.e., the conditions in patent US 2014343285 A1), to obtain compound 2a 345 mg in a yield of 65%, dr=5:1.
Comparative example 22 Synthesis of Compound 2b
The procedure was the same as in example 9 except that HBr (1.5 mmol,0.005 ml) was used as it was instead of hydrochloric acid and NBS, and no reaction was monitored.
As can be seen from comparative examples 1-2 and 6-20, the yields and diastereoselectivity of posaconazole halocyclized intermediates are very unsatisfactory without adding an activating reagent or adding an alkaline activating reagent (such as sodium carbonate), even if the reaction time is greatly prolonged (from 3h to 12 h), the halogenation reaction is carried out in the presence of an acidic substance, the yields and diastereoselectivity of the target products are obviously improved, and excellent reaction results can be obtained without longer reaction time. As can be seen from comparative examples 3 to 5, the synthesis method of the present invention is suitably carried out in an acetate-based organic solvent. It can be seen from comparative example 21 that it is difficult to obtain the desired yields and diastereoselectivities described therein under the conditions disclosed in patent US 2014343285 A1. As can be seen from comparative example 22, the reaction did not proceed at all using HBr directly as the halogenating agent.
Unless otherwise defined, all terms used herein are intended to have the meanings commonly understood by those skilled in the art.
The described embodiments of the present invention are intended to be illustrative only and not to limit the scope of the invention, and various other alternatives, modifications, and improvements may be made by those skilled in the art within the scope of the invention, and therefore the invention is not limited to the above embodiments but only by the claims.

Claims (10)

1. A synthesis method of posaconazole halogeno-cyclized intermediate is characterized in that in the presence of acidic substances, raw material intermediate shown in a formula (1) and halogenating reagent carry out halogenation reaction in organic solvent to prepare posaconazole halogeno-cyclized intermediate shown in a formula (2);
wherein R is 1 Represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C12 aryl group, or a substituted or unsubstituted C7-C18 alkylene aryl group;
R 2 and R is 3 Each independently represents hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C12 aryl group, or a substituted or unsubstituted C7-C18 alkylene aryl group;
when R is 1 、R 2 And R is 3 When each independently represents a substituted group, the substituent is selected from C1-C4 alkyl, C1-C4 alkoxy or C6-C12 aryl;
x represents halogen.
2. The synthetic method of claim 1 wherein R is 1 Represents a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group;
the R is 2 And R is 3 Each independently represents hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group;
when R is 1 、R 2 And R is 3 When each independently represents a substituted group, the substituents are selected from C1-C4 alkyl groups;
the X represents Br or I;
preferably, said R 1 Represents a C2-C4 alkyl group, a phenyl group or a benzyl group;
the R is 2 And R is 3 Each independently represents hydrogen or phenyl.
3. The synthetic method according to claim 1 or 2, characterized in that the acidic substance is selected from one or more of inorganic acids, organic acids, acid salts, preferably from one or more of hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, boric acid, orthophosphoric acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, potassium bisulfate, sodium bisulfate.
4. A synthetic method according to claim 3, characterized in that the acidic substance is used in an amount of 1 to 50mol%, preferably 5 to 15mol%, of the raw material intermediate.
5. The method according to any one of claims 1 to 4, wherein the halogenating reagent is selected from one or more of iodine, N-iodosuccinimide, N-iodophthalimide, liquid bromine, dibromohydantoin, diiodohydantoin, N-bromosuccinimide, N-bromophthalimide.
6. The synthetic method according to claim 5, wherein the halogenating agent is used in an amount of 1.0 to 5.0 equivalents, preferably 1.2 to 2.5 equivalents, of the starting intermediate.
7. The method according to any one of claims 1 to 6, wherein the organic solvent is selected from acetate or nitrile organic solvents, preferably from CH 3 An organic solvent represented by COOR ', wherein R' represents a C1-C6 alkyl group, preferably a C1-C4 alkyl group;
preferably, the organic solvent is selected from one or more of acetonitrile, butyronitrile, methyl acetate, ethyl acetate, isopropyl acetate and n-butyl acetate.
8. The synthetic method according to any one of claims 1 to 7, characterized in that the reaction temperature of the halogenation reaction is-10 to-78 ℃, preferably-10 to-40 ℃.
9. The synthetic method according to any one of claims 1 to 8, characterized in that the reaction time of the halogenation reaction is 1 to 10 hours, preferably 2 to 5 hours.
10. A method for synthesizing posaconazole, comprising a step of synthesizing a posaconazole halocyclized intermediate, wherein the step of synthesizing the posaconazole halocyclized intermediate employs the method for synthesizing the posaconazole halocyclized intermediate according to any one of claims 1 to 9.
CN202310516256.7A 2023-05-09 2023-05-09 Synthesis method of posaconazole halocyclization intermediate Pending CN116496265A (en)

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