TEDIZOLID INTERMEDIATE AND EFFICIENT PREPARATION METHOD THEREOF

Abstract

The efficient preparation method of a tedizolid intermediate includes the following steps: 1) subjecting 2-fluoro-4-substituted phenylacetic acid to a reaction with a Vilsmeier reagent, and adding a resulting reaction solution to an MX aqueous solution for quenching to obtain an intermediate shown in formula (II); and 2) subjecting the intermediate shown in formula (II) obtained in step 1) and 1-(2-methyl-2H-tetrazol-5-yl)ethanone to one-pot synthesis in the presence of an alkali and an ammonia source to obtain the intermediate shown in formula (I). In this method, a pyridine ring of the key intermediate shown in formula (I) is obtained through a ring-closing reaction of the 1-(2-methyl-2H-tetrazol-5-yl)ethanone and a Vinamidinium salt, and a key methyltetrazolyl group is introduced into the structure, which successfully avoids the use of highly-toxic sodium cyanide and sodium azide, the use of expensive palladium catalyst, and the use of methylation with low selectivity.

Claims

1. An preparation method of a tedizolid intermediate, wherein the tedizolid intermediate is shown in formula (I): ##STR00024## and the preparation method comprises the following steps: 1) subjecting 2-fluoro-4-substituted phenylacetic acid to a reaction with a Vilsmeier reagent, and adding a resulting reaction solution to an MX aqueous solution for quenching to obtain an intermediate shown in formula (II): ##STR00025## and 2) subjecting the intermediate shown in formula (II) obtained in step 1) and 1-(2-methyl-2H-tetrazol-5-yl) ethanone to a one-pot synthesis in the presence of an alkali and an ammonia source to obtain the tedizolid intermediate shown in formula (I): ##STR00026##

2. The preparation method of the tedizolid intermediate according to claim 1, wherein in step 1), R.sub.1 is selected from the group consisting of: nitro, benzyloxycarbonylamino, chlorine, bromine, iodine, trifluorosulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, and carboxylate.

3. The preparation method of the tedizolid intermediate according to claim 1, wherein in step 1), the Vilsmeier reagent is a combination of: N,N-dimethylformamide (DMF) and phosphorus oxychloride, DMF and oxalyl chloride, or DMF and thionyl chloride.

4. The preparation method of the tedizolid intermediate according to claim 1, wherein in step 1), the MX is selected from the group consisting of: sodium tetrafluoroborate, potassium tetrafluoroborate, sodium perchlorate, sodium hexafluorophosphate, and potassium hexafluorophosphate; and X.sup.⊖is selected from the group consisting of: a tetrafluoroborate ion, a perchlorate ion, and a hexafluorophosphate ion.

5. The preparation method of the tedizolid intermediate according to claim 1, wherein in step 1), an amount of the MX is 1 to 3 equivalents of an amount of the 2-fluoro-4-substituted phenylacetic acid.

6. The preparation method of the tedizolid intermediate according to claim 1, wherein the reaction in step 1) is conducted at 0° C. to 100° C.

7. The preparation method of the tedizolid intermediate according to claim 1, wherein the alkali in step 2) is selected from the group consisting of: potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, lithium N,N-diisopropylamide, sodium hydride, sodium amide, lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), 1,8-diazadispiro[5.4.0]undec-7-ene, 1,1,3,3-tetramethylguanidine, N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), pyrrolidine, piperidine, and morpholine.

8. The preparation method of the tedizolid intermediate according to claim 1, wherein a solvent used in step 2) is selected from the group consisting of: tetrahydrofuran (THF), dioxane, DMF, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMAC), and acetonitrile.

9. The preparation method of the tedizolid intermediate according to claim 1, wherein in step 2), an amount of the 1-(2-methyl-2H-tetrazol-5-yl)ethanone is 0.5 to 2.0 equivalents of an amount of the intermediate shown in formula (II).

10. The preparation method of the tedizolid intermediate according to claim 1, wherein the ammonia source in step 2) is: ammonia water, a solution of ammonia in methanol, ammonium acetate, ammonium chloride, ammonium sulfate, ammonium carbonate, or ammonium bicarbonate.

11. The preparation method of the tedizolid intermediate according to claim 1, wherein in step 2), an amount of the ammonia source is 5.0 to 10.0 equivalents of the amount of the intermediate shown in formula (II).

12. The preparation method of the tedizolid intermediate according to claim 1, wherein the one-pot synthesis in step 2) is conducted at −10° C. to 100° C.

13. An intermediate, wherein the intermediate is shown in formula II: ##STR00027## and the intermediate is prepared by a preparation method comprising the following steps: subjecting 2-fluoro-4-substituted phenylacetic acid to a reaction with a Vilsmeier reagent, and adding a resulting reaction solution to an MX aqueous solution for quenching to obtain the intermediate shown in formula (II): ##STR00028##

14. The intermediate according to claim 13, wherein R1 is selected from the group consisting of: nitro, benzyloxycarbonylamino, chlorine, bromine, iodine, trifluorosulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, and carboxylate.

15. The intermediate according to claim 13, wherein the Vilsmeier reagent is a combination of: N,N-dimethylformamide (DMF) and phosphorus oxychloride, DMF and oxalyl chloride, or DMF and thionyl chloride.

16. The intermediate according to claim 13, wherein the MX is selected from the group consisting of: sodium tetrafluoroborate, potassium tetrafluoroborate, sodium perchlorate, sodium hexafluorophosphate, and potassium hexafluorophosphate; and X.sup.⊖is selected from the group consisting of: a tetrafluoroborate ion, a perchlorate ion, and a hexafluorophosphate ion.

17. The intermediate according to claim 13, wherein an amount of the MX is 1 to 3 equivalents of an amount of the 2-fluoro-4-substituted phenylacetic acid.

18. The intermediate according to claim 13, wherein the reaction is conducted at 0° C. to 100° C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG. 1 is a proton nuclear magnetic resonance (HNMR) spectrum of formula Ia in the present disclosure.

[0038] FIG. 2 is an HNMR spectrum of formula Ib in the present disclosure.

[0039] FIG. 3 is an HNMR spectrum of formula Ic in the present disclosure.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0040] For better understanding the usage of the present disclosure, the following specific examples will be illustrated to describe the technical solutions clearly and completely. Apparently, the described examples are merely some rather than all of the examples of the present disclosure. All other examples obtained by a person of ordinary skill in the art based on the examples of the present disclosure without creative efforts shall fall within the protection scope of the present disclosure.

[0041] The raw materials and devices used in the specific embodiments of the present disclosure are all known products, and are all commercially available products, which, for example, can be purchased from Beijing J&K Scientific Ltd., Shanghai Shaoyuan Co., Ltd., and the like.

EXAMPLE 1

Preparation of (E)-N-(3-(dimethylamino)-2-(2-fluoro-4-nitrophenyl) allylidene)-N-methylmethylaminoperchlorate

[0042] ##STR00015##

[0043] Phosphorus oxychloride (191.7 g, 1.25 mol) was added dropwise to DMF (600 mL), where a temperature was controlled at 10° C. to 30° C. and the dropwise addition was conducted for 30 min; a reaction was conducted at room temperature for 30 min; then (2-Fluoro-4-nitrophenyl)acetic acid (99.5 g, 0.5 mol) was added, a resulting mixture was heated to 85° C. to allow a reaction for 3 hours, and a resulting reaction solution was cooled to room temperature, poured into a solution of sodium perchlorate (91.5 g, 0.75 mol) in water (1.2 L) for quenching, and stirred at room temperature for 1 hour; and a resulting mixture was filtered, and a resulting filter cake was washed with water (200 mL) and then dried to obtain a compound IIa (165 g, 90%), which was a khaki solid. 1HNMR (400 MHZ, DMSO) δ8.22-8.25 (dd,1H), 8.14-8.17 (dd, 1H),v8.14-8.17 (dd, 1H), 7.89 (s, 2H), 7.66-7.71 (m, 1H), 2.53 (s, 6H).

EXAMPLE 2

Preparation of 5-(2-fluoro-4-nitrophenyl)-2-(2-methyl-2H-tetrazol-5-yl) pyridine

[0044] ##STR00016##

[0045] Method 1:

[0046] The compound IIa (15 g, 40 mmol) was added to THF (150 mL), and then 1-(2-methyl-2H-tetrazol-5-yl) ethanone (7.5 g, 60 mmol) was added; a resulting reaction solution was cooled to −10° C., then NaHMDS (2 M, 30 mL, 60 mmol) was slowly added dropwise, and then a reaction was conducted at −10° C. for 10 min; ammonium acetate (15.4 g, 0.2 mol) and water (45 mL) were then added, and a resulting mixture was heated to 70° C. to allow a reaction for 18 hours; when LCMS showed that the reaction was completed, a resulting reaction solution was cooled to room temperature, ethyl acetate (75 mL) was added for extraction, and a resulting organic phase was subjected to vacuum distillation to obtain a crude product; and the crude product was slurried with n-hexane (75 mL) and ethyl acetate (30 mL) and filtered, and a resulting filter cake was dried to obtain a compound Ia (6.36 g, 53%), which was a khaki solid. 1HNMR (400 MHZ, CDC13) δ8.98 (s, 1H), 8.38-8.40 (d,1H), 8.18-8.22 (dd, 1H), 8.10-8.14 (m, 2H), 7.61-7.75 (m, 1H), 4.49 (s, 3H), as shown in FIG. 1.

[0047] Method 2:

[0048] The compound IIa (15 g, 40 mmol) was added to THF (150 mL), and then 1-(2-methyl-2H-tetrazol-5-yl) ethanone (7.5 g, 60 mmol) was added; a resulting reaction solution was cooled to 0° C., then 1,1,3,3-tetramethylguanidine (9.2 g, 80 mmol) was added, and then a reaction was conducted at 0° C. for 1 hour; ammonium acetate (15.4 g, 0.2 mol) and water (45 mL) were then added, and a resulting mixture was heated to 70° C. to allow a reaction for 18 hours; when LCMS showed that the reaction was completed, a resulting reaction solution was cooled to room temperature, ethyl acetate (75 mL) was added for extraction, and a resulting organic phase was subjected to vacuum distillation to obtain a crude product; and the crude product was slurried with n-hexane (75 mL) and ethyl acetate (30 mL) and filtered, and a resulting filter cake was dried to obtain a compound Ia (5.08 g, 42.3%), which was a khaki solid. 1HNMR (400 MHZ, CDC13) δ8.98 (s, 1H), 8.38-8.40 (d, 1H), 8.18-8.22 (dd, 1H), 8.10-8.14 (m, 2H), 7.61-7.75 (m, 1H), 4.49 (s, 3H).

[0049] Method 3:

[0050] The compound IIa (15 g, 40 mmol) was added to THF (150 mL), and then 1-(2-methyl-2H-tetrazol-5-yl) ethanone (7.5 g, 60 mmol) was added; a resulting reaction solution was cooled to −10° C., then potassium tert-butoxide (9 g, 80 mmol) was added, and then a reaction was conducted at −10° C. for 1 hour; ammonium acetate (15.4 g, 0.2 mol) and water (45 mL) were then added, and a resulting mixture was heated to 70° C. to allow a reaction for 18 hours; when LCMS showed that the reaction was completed, a resulting reaction solution was cooled to room temperature, ethyl acetate (75 mL) was added for extraction, and a resulting organic phase was subjected to vacuum distillation to obtain a crude product; and the crude product was slurried with n-hexane (75 mL) and ethyl acetate (30 mL) and filtered, and a resulting filter cake was dried to obtain a compound Ia (7.5 g, 62.5%), which was a khaki solid. 1HNMR (400MHZ, CDC13) δ8.98 (s, 1H), 8.38-8.40 (d,1H), 8.18-8.22 (dd, 1H), 8.10-8.14 (m, 2H), 7.61-7.75 (m, 1H), 4.49 (s, 3H), as shown in FIG. 1.

Example 3

Preparation of 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)aniline

[0051] ##STR00017##

[0052] The compound Ia (2 g, 6.67 mmol) was added to ethanol (30 mL), then saturated ammonium chloride (10 mL) and a zinc powder (4.3 g, 66.7 mol) were added, and a resulting mixture was heated to 80° C. to allow a reaction for 2 hours; when LCMS showed that the reaction was completed, a resulting reaction solution was filtered, and a resulting filtrate was subjected to vacuum concentration to remove ethanol and then filtered; and a resulting filter cake was rinsed with water (4 mL) and then was dried to obtain a compound Ib (1.62 g, 90%), which was an off-white solid. 1HNMR (400 MHZ, DMSO) δ8.83 (s, 1H), 8.07-8.16 (m, 2H), 7.33-7.39 (m, 1H), 6.44-6.55 (m, 2H), 5.77 (s, 2H), 4.46 (s, 3H), as shown in FIG. 2.

EXAMPLE 4

Preparation of benzyl (3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl) phenyl)carbamate

[0053] ##STR00018##

[0054] The compound Ib (1 g, 3.7 mmol) was added to THF (10 mL), then sodium bicarbonate (0.93 g, 11.1 mmol) and benzyl chloroformate (0.95 g, 5.55 mmol) were added, and a reaction was conducted at room temperature for 2 hours; when LCMS showed that the reaction was completed, water (10 mL) was added, and then extraction was conducted twice with ethyl acetate (20 mL); resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and subjected to vacuum concentration to obtain a crude product; and the crude product was slurried with ethyl acetate (3 mL) and n-hexane (9 mL) and then filtered, and a resulting filter cake was dried to obtain a compound Ic (1.35 g, 90%), which was an off-white solid. 1HNMR (400 MHZ, DMSO) δ10.22 (s, 1H), 8.91 (s, 1H), 8.15-8.23 (m, 2H), 7.55-7.65 (m, 2H), 7.36-7.47 (m, 6H), 5.20 (s, 2H), 4.48 (s, 3H), as shown in FIG. 3.

EXAMPLE 5

Preparation of (E)-N-(3-(dimethylamino)-2-(2-fluoro-4-iodo)allylidene)-N-methylmethylaminoperchlorate

[0055] ##STR00019##

[0056] Phosphorus oxychloride (6.9 g, 45 mmol) was added dropwise to DMF (30 mL), where a temperature was controlled at 10° C. to 30° C. and the dropwise addition was conducted for 30 min; a reaction was conducted at room temperature for 30 min; then (2-Fluoro-4-nitrophenyl)acetic acid (5 g, 18 mmol) was added, a resulting mixture was heated to 85° C. to allow a reaction for 3 hours, and a resulting reaction solution was cooled to room temperature, poured into a solution of sodium perchlorate (3.3 g, 27 mmol) in water (60 mL) for quenching, and stirred at room temperature for 1 hour; and a resulting mixture was filtered, and a resulting filter cake was washed with water (10 mL) and then dried to obtain a compound IIb (7.1 g, 89%), which was a khaki solid.

EXAMPLE 6

Preparation of 5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl) pyridine

[0057] ##STR00020##

[0058] The compound IIb (5 g, 11.2 mmol) was added to THF (50 mL), and then 1-(2-methyl-2H-tetrazol-5-yl) ethanone (2.1 g, 16.8 mmol) was added; a resulting reaction solution was cooled to −10° C., then NaHMDS (2 M, 8.4 mL, 16.8 mmol) was slowly added dropwise, and then a reaction was conducted at −10° C. for 10 min; ammonium acetate (4.3 g, 56 mmol) and water (15 mL) were then added, and a resulting mixture was heated to 70° C. to allow a reaction for 18 hours; when LCMS showed that the reaction was completed, a resulting reaction solution was cooled to room temperature, ethyl acetate (20 mL) was added for extraction, and a resulting organic phase was subjected to vacuum distillation to obtain a crude product; and the crude product was slurried with n-hexane (20 mL) and ethyl acetate (10 mL) and filtered, and a resulting filter cake was dried to obtain a compound Ie (2.1 g, 49%), which was a yellow-brown solid. 1HNMR (400 MHZ, CDC13) δ8.89 (s, 1H), 8.32 (d, 1H), 8.07 (d, 1H), 7.70 (m, 1H), 7.56 (dd, 1H), 7.49 (d, 1H), 4.45 (s, 3H).

EXAMPLE 7

Preparation of (E)-N-(3-(dimethylamino)-2-(2-fluoro-4-methoxycarbonyl) allylidene)-N-methylmethylaminoperchlorate

[0059] ##STR00021##

[0060] Phosphorus oxychloride (19.2g, 0.125 mol) was added dropwise to DMF (60 mL), where a temperature was controlled at 10° C. to 30° C. and the dropwise addition was conducted for 30 min; a reaction was conducted at room temperature for 30 min; then (2-Fluoro-4-nitrophenyl)acetic acid (10.6 g, 50 mmol) was added, a resulting mixture was heated to 85° C. to allow a reaction for 3 hours, and a resulting reaction solution was cooled to room temperature, poured into a solution of sodium perchlorate (9.2 g, 75 mmol) in water (150 mL) for quenching, and stirred at room temperature for 1 hour; and a resulting mixture was filtered, and a resulting filter cake was washed with water (20 mL) and then dried to obtain a compound IIc (14.0 g, 74%), which would be directly used in the next step.

EXAMPLE 8

Preparation of 5-(2-fluoro-4-methoxycarbonylphenyl)-2-(2-methyl-2H-tetrazol-5-yl) pyridine

[0061] ##STR00022##

[0062] The compound IIc (10 g, 26.4 mmol) was added to THF (100 mL), and then 1-(2-methyl-2H-tetrazol-5-yl) ethanone (5 g, 40 mmol) was added; a resulting reaction solution was cooled to −10° C., then NaHMDS (2 M, 20 mL, 40 mmol) was slowly added dropwise, and then a reaction was conducted at −10° C. for 10 min; ammonium acetate (10.2 g, 0.132 mol) and water (30 mL) were then added, and a resulting mixture was heated to 70° C. to allow a reaction for 18 hours; when LCMS showed that the reaction was completed, a resulting reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added for extraction, and a resulting organic phase was subjected to vacuum distillation to obtain a crude product; and the crude product was slurried with n-hexane (50 mL) and ethyl acetate (20 mL) and filtered, and a resulting filter cake was dried to obtain a compound Ma (3.06 g, 37%), which would be directly used in the next step.

Example 9: Preparation of benzyl (3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl) phenyl)carbamate

[0063] ##STR00023##

[0064] The compound Ma (3 g, 9.6 mmol) was added to a mixture of methanol (10 mL) and water (10 mL), then lithium hydroxide monohydrate (0.8 g, 19.2 mmol) was added, and a resulting mixture was stirred overnight at room temperature; when it was determined by TLC that the reaction was completed, a pH of a resulting reaction solution was adjusted to 2 to 3 with a 1 N aqueous hydrochloric acid solution, and a resulting solid was filtered out, washed with water (50 mL), subjected to suction filtration, and dried under reduced pressure to obtain crude carboxylic acid (2.9 g).

[0065] The crude carboxylic acid (2.9 g) was dissolved in toluene (30 mL), then TEA (2 g, 19.8 mmol) and DPPA (3.2 g, 11.6 mmol) were added, and a resulting mixture was heated to 100° C. to allow a reaction for 7 hours; then benzyl alcohol (2.1 g, 19.4 mmol) was added, and a resulting mixture was continuously stirred for 8 hours; when it was monitored by TLC that the reaction was completed, toluene was removed under reduced pressure, ethyl acetate (20 mL) and water (20 mL) were added, and a resulting aqueous phase was subjected to extraction with ethyl acetate (10 mL ×2); resulting organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain a crude product; and the crude product was purified by a silica gel column with petroleum ether : ethyl acetate (1:1) to obtain a compound Ic (1.88 g, 48%).

[0066] The above are merely preferred examples of the present disclosure, and are not intended to limit the present disclosure in any form. Although the present disclosure has been disclosed by the above examples, the examples are not intended to limit the present disclosure. Any person skilled in the art may make some changes or modifications to obtain equivalent examples with equivalent changes using the method and technical content disclosed above without departing from the scope of the technical solution of the present disclosure. Any simple modification, equivalent change, and modification made to the above examples according to the technical essence of the present disclosure without departing from the content of the technical solution of the present disclosure shall fall within the scope of the technical solution of the present disclosure.