KR101774812B1 - Preparation method for tebipenem pivoxil - Google Patents

Abstract

The present invention relates to a manufacturing process of tebipenem pivoxil. According to the present invention, a high yield of 5 times or more compared to a conventionally noticed process can be obtained, and a process of the present invention can be simplified. Thus, tebipenem pivoxil having excellent quality can be economically obtained. Methyl pivalate chloride is applied to a crystalline polymorph of (1R, 5S, 6S)-2-[1-(1,3-thiazoline-2-yl)azetidin-3-yl]-thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbene-2-em-3-carboxylic acid, and then is dissolved in at least one solvent selected from the group consisting of methyl acetate, acetone, and isopropyl alcohol to be cooled to -15 to -20C and stirred.

Description

PREPARATION METHOD FOR TEBIPENEM PIVOXIL [0002]

The present invention relates to a method for producing a tedpenem-coated chamber.

The tabipenem-covered chamber is one of the carbapenem antibiotics that form the beta-lactam family with penicillin, cephalosporin, monopag, or beta-lactamase inhibitors.

The carbapenem antibiotic is a substance having a basic skeleton represented by the following formula (1).

[Chemical Formula 1]

As described in Korean Patent Publication No. 331293, various kinds of carbapenem antibiotics have been developed over time. For example, the early-generation carbapenem antibiotic was represented by the following chemical formula (2).

(2)

The above substances can be obtained from nature and reported to have antibacterial activity against a wide range of bacteria, but lacking chemical stability, the following chemical formula 3 was developed.

(3)

However, since the above substance has been found to be decomposed in vivo to not exhibit the desired pharmacological effect and there is room for inactivation, it was improved to a substance of the following formula (4).

[Chemical Formula 4]

The above substance is referred to as " tabepenem ", and the " tabipenem covering room "

[Chemical Formula 5]

The present invention relates to a process for preparing a tabepenem-covered yarn of the above formula (5).

The known conventional manufacturing process of the tabbenem-covered chamber is accompanied by a large number of steps and involves individual purification at each step. Despite the fact that the simplicity of the process is advantageous in terms of manufacturing costs, the complexity of such a process has been recognized as indispensable in that it has stereospecificity.

The manufacturing process of the tabbenem-covered yarn disclosed in Korean Patent Registration No. 331293 mentioned above is examined.

3-acetylthio-1- (thiazolin-2-yl) azetidine of formula 9 is prepared according to scheme 1 below.

[Reaction Scheme 1]

Subsequently, the compound of Formula 9 was dissolved in anhydrous methanol, and 28% sodium methoxide-methanol solution was stirred under an ice bath and a nitrogen stream, and then p-nitrobenzyl (1R, 5S, 6S) -2 - [1- (thiazolin-2-yl) azetidin-3-yl] -thio-6 - [(R) -1-hydroxyethyl] To produce a chelate.

[Reaction Scheme 2]

Tetrahydrofuran, phosphate buffer solution and zinc powder are added from the compound of formula (12) to obtain the compound of formula (4) as shown in the following reaction formula (3).

[Reaction Scheme 3]

Finally, sodium bicarbonate is mixed with the compound of the formula (4) and lyophilized or the like is finally obtained to obtain a tablet of the formula (13) of the following formula (4).

[Reaction Scheme 4]

However, the total yield of the compound of formula (13) obtained according to the above process is only 13.6%, which is a problem in production efficiency.

Korean Registered Patent No. 331293

Although the criteria that are important in designing the production process of raw material drugs may vary depending on the viewpoint of the viewer, the first is the safety in the production process, the second is the reproducibility of the reaction considering the quality of the raw material drug, , The fourth environmental impact, and the fifth plant suitability are generally taken into account. The significance of each criterion is as follows.

Safety is concerned with life-threatening accidents such as explosions that may occur in the course of plant synthesis. Consider toxicity of the reagents, solvents and intermediates used, and the generation of toxic fumes or flammable toxins. Design.

Quality refers to the degree of purity and refers to the control of impurities, residual solvents, heavy metal content, or polymorphism. Reproducibility means that the same quality standard is met each time regardless of external variables such as those performed repeatedly in the same process. And a consistent process that yields an equivalent yield.

A manufacturer is a study of how to produce equal or better quality at a lower cost so as to achieve the company's fundamental goal of profit creation.

The impact on the environment is to focus on minimizing the negative impact on the environment by reducing or properly treating the waste liquid, waste or gas generated during the process.

Factory conformance refers to the work of reducing the design and error range in the laboratory by carefully observing the characteristics of the equipment and work of the plant, reflecting the fact that the factory treats large capacity.

However, the known tabipenem covering yarn manufacturing process as described above has a drawback in that the yield is low in terms of manufacturing cost, among other things, although it exposes problems to other standards as well.

The present inventors aimed at designing a new manufacturing process which can reduce the manufacturing cost relatively by improving the yield, safety, quality, environmental impact, and factory suitability to be equal to or more than that of known processes. As a result, I have come to completion.

The present inventor has solved the above-mentioned problems by means of the following.

(1R, 5S, 6S) -2- [l- (l- (2-methylpiperidin-1-yl) -1,2,3,4-tetrahydroisoquinoline- Azetidin-3-yl] -thio-6 - [(R) -1-hydroxyethyl] -1-methylcarbapen-2-yl] -3-carboxylic acid Shape.

(2) A process for producing (1R, 5S, 6S) -2- [1-1, 3-thiazolin-2-yl ] Azetidin-3-yl] -thio-6 - [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-yl) -3-carboxylate.

(3) The process according to the above (2), wherein the crystalline polymorph according to (1) above is reacted by adding methyl pivalate chloride and then dissolving it in at least one solvent selected from the group consisting of methyl acetate, acetone and isopropyl alcohol (1R, 5S, 6S) -2- [l, 3-thiazolin-2-yl] azetidin- -Hydroxyethyl] -1-methyl-carbapen-2-yl) -3-carboxylate.

(4) The method according to (3), wherein the methyl pivalate chloride is chloromethyl pivalate. (1R, 5S, 6S) -2- [ -Yl] azetidin-3-yl] -thio-6 - [(R) -1-hydroxyethyl] -1-methyl-carbapen-2-yl) -3-carboxylate.

(5) The process according to the above (3), wherein the solvent is methyl acetyte, and the pivaloyloxymethyl (1R, 5S, 6S) -2- [1-1,3-thiazolin- Thiadiazol-3-yl] -thio-6 - [(R) -1-hydroxyethyl] -1-methyl-carbapen-2-yl) -3-carboxylate.

Conventionally, the process of producing the tabbenem-covered chamber is complicated using column purification and freeze-drying for each reaction step, and is not suitable because of high work cost and manufacturing cost, and the yield is low.

However, the process of the present invention is simple, and it is possible to crystallize the reaction intermediate and the compound of interest as a target compound, with high yield and excellent quality, without crystallizing the column and lyophilization. Specifically, the present invention has a yield increase of 5 times or more as compared with the conventionally known process, and is suitable for the production process by simplifying the process (no column and freeze-drying process) in all processes.

Further, the present invention is superior in safety and quality, environmental impact, and factory suitability, which is equal to or better than conventionally known manufacturing processes.

Figure 1 is a graph showing the effect of (1R, 5S, 6S) -2- [1- (thiazolin-2-yl) azetidin- ] -1-methyl-carbapen-2-yl) -3-carboxylic acid crystalline polymorph.

The above-mentioned conventionally known process for producing a tablet-coated bed of the present invention will be described in more detail step by step.

On the other hand, it is known that drug substance can exist in two or more crystalline polymorphism. However, the crystal polymorphism may differ in solubility and stability, and it may be desirable to produce the drug substance as a crystalline polymorph with a single purity as much as possible in order to distribute homogeneous quality drug substance.

Hereinafter, the crystallization step is also taken into consideration. According to Korean Patent Registration No. 331293 and Japanese Patent Publication No. 3317649, the known manufacturing process is summarized as follows.

Step 1) p-Nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6 - [(R) -hydroxyethyl] (MAP) and 1- (4,5-dihydro-2-thiazolyl) -3-azetidinol hydrochloride and diisopropylethylamine were stirred in an ice bath and a nitrogen stream for 2 hours and then diluted with ethyl acetate EA) is added, and the separated organic layer is washed with a saturated aqueous sodium bicarbonate solution and a saturated brine solution. The solvent was removed and the resulting residue was purified by silica gel column chromatography using chloroform: acetone (1: 2) to give the target compound p-nitrobenzyl (1R, 5S, 6S) -2- [1- (thiazoline- (R) -1-hydroxyethyl] -1-methyl-carbapen-2-yl) -3-carboxylate (PTBP) Yield. ≪ / RTI >

Step 2) Tetrahydrofuran (THF), 0.38 M phosphate buffer solution and zinc powder were added to the obtained PTBP, and the reaction mixture was vigorously stirred for 2 hours. After termination of the reaction, the reaction mixture was filtered off with celite, the filtrate was washed with ethyl acetate (EA), the pH was adjusted to 5.5, the filtrate was concentrated and purified using a Diaion HP-40R column (5% isopropyl alcohol- The resulting residue was purified by silica gel column chromatography to obtain (1R, 5S, 6S) -2- [1- (thiazolin-2-yl) azetidin- -Carbapen-2-yl) -3-carboxylic acid (CTBP) in 64% yield.

Step 3) After lyophilization of the mixed solution of the obtained CTBP and sodium bicarbonate, the resulting amorphous solid was dissolved in dimethylformamide (DMF), pivalic acid iodomethyl ester was added, and the reaction mixture was stirred at room temperature for 1 hour Ethyl acetate (EA) is then added to the reaction mixture, and the organic layer is washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was removed, and the resulting residue was purified by silica gel column chromatography (10% methanol-chloroform) to give crude pivaloyloxymethyl (1R, 5S, 6S) -2- [1-1,3-thiazolin- 3-yl] -thio-6 - [(R) -1-hydroxyethyl] -1-methylcarbapen- 2- 3-carboxylate (crude TBPM- % ≪ / RTI > yield.

The total yield of crude TBPM-PI finally obtained through the above step 1-3 is 31%.

Step 4) The obtained crude TBPM-PI was dissolved in ethyl acetate (EA) solution according to Japanese Patent Publication No. 3317649 and stirred at room temperature for 30 minutes to obtain a crystalline product of pivaloyloxymethyl (1R, 5S, 6S Yl) azetidin-3-yl] -thio-6 - [(R) -1-hydroxyethyl] -1-methyl-carbapen- -M-3-carboxylate (TBPM-PI) in a yield of 44.0%.

The total yield is only 13.6% (1 step: 65%, 2 steps: 64%, 3-4 steps: 32.8%) for the preparation of a specific crystalline form of TBPM-PI through steps 1-4 above.

On the other hand, the melting point of the TBPM-PI crystal form obtained in the above step 4 is 140.5 to 142 ° C, and the characteristic 2? Values on the crystalline type X-ray powder diffraction pattern are 8.34 °, 11.78 °, 12.00 °, 13.64 °, 14.82 °, 15.24 degrees, 16.78 degrees, 17.12 degrees, 18.14 degrees, 19.40 degrees, 20.38 degrees, 21.26 degrees, 21.64 degrees, 22.56 degrees, 23.72 degrees, 24.14 degrees, 25.88 degrees, 28.68 degrees, 29.20 degrees.

On the other hand, the production process and the yield according to the present invention are as follows.

Step 1) Synthesis of 4-nitrobenzyl (4R, 5S, 6S) -3- (diphenyloxy) phosphoryloxy-6 - [(1R) -1-hydroxyethyl] -4- 2-ene-2-carboxylate (MAP, 298 g) and 1- (4,5-dihydro-2-thiazolyl) -3-azetidinethiol hydrochloride (116 g) Is suspended in 2,000 mL of acetonitrile (ACN) solvent and the temperature is maintained at 0-5 < 0 > C. The solvent may be appropriately selected in addition to acetonitrile. Diisopropylethylamine (DIEA, 142 g) was added dropwise to the reaction solution over 20 minutes, and the reaction was continued at 0-5 DEG C for 2 hours. When the reaction is complete, add 600 mL of distilled water and stir for 30 minutes at the same temperature. The resulting solid is filtered off and washed with 600 mL of an acetonitrile-water (1: 1) mixed solution. The obtained solid was dried in a vacuum oven at 40 캜 for 4 hours to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (thiazolin-2-yl) Carboxylate (PTBP, 243.2 g, yield 93.8%, purity 95.2%) was obtained in the form of a white solid.

The qualitative analysis results for the above obtained compounds are as follows.

Melting point: 179.1 DEG C

FT-IR (analytical instrument: Jasco FT / IR-4200, υ, KBr): 3411.4, 1762.6, 1614.1, 1521.5, 1335.4, 1137.8, 852.3, 739.5 cm ^-1

¹ H-NMR (measuring _{instrument: Bruker, AvanceⅢ 400MHz, CDCl 3} , δ): 1.20 (3H, d, J = 7.2 Hz), 1.30 (3H, d, J = 6.0 Hz), 3.14 (1H, m), 3.23 (1H, dd, J = 2.4, 6.0 Hz), 3.34 (2H, t, J = 7.6 Hz) 3.86 (1H, m), 3.99 (3H, m), 4.10 (1H, m), 4.23 (2H, m), 4.34 (2H, m ), 5.22 (1H, d, J = 14.0 Hz), 5.49 (1H, d, J = 14.0 Hz), 7.64 (2H, d, J = 8.8 Hz), 8.19 (2H, d, J = 8.4 Hz)

¹³ C-NMR (measuring instrument: Bruker, Avance III 400 MHz, CDCl ₃ , 隆): 16.98, 22.04, 33.07, 36.45, 43.82, 56.13, 57.95, 59.95, 60.09, 61.03, 65.37, 65.52, 123.87, 124.82, , 143.04, 147.73, 149.68, 160.40, 164.35, 172.80

Step 2) The obtained PTBP (40 g) is put into a reactor together with 400 mL of tetrahydrofuran (THF) and stirred. Add 6.5 g of NaHCO _{3 in} 400 mL of distilled water to the reactor, add 10 g of 10% Pd-C catalyst. The hydrogen pressure in the reactor is maintained at 3 ± 2 atm and the mixture is stirred at 20 ± 5 ° C for 2 hours. The hydrogen gas in the reactor is discharged and removed, 5 g of activated carbon is added, and the mixture is further stirred at the same temperature for 10 minutes. The reaction solution is filtered and washed with 100 mL of THF: H ₂ O (1: 1) solvent. Cool the filtered filtrate to 0-5 ° C. 1,600 mL of acetone is added dropwise for 20 minutes, and the mixture is stirred at 0 to 5 ° C for 3 hours to complete the crystallization. The resulting solid is filtered and washed with 400 mL of acetone. The obtained solid was dried in a vacuum oven at 40 占 폚 for 3 hours to obtain the objective compound (1R, 5S, 6S) -2- [1- (thiazolin-2-yl) azetidin- ) -1-hydroxyethyl] -1-methyl-carbapen-2-yl) -3-carboxylic acid (29.2 g of CTBP, yield 98.6%, purity ≥99%).

The qualitative analysis results of the above obtained compounds are as follows.

Melting point: 91.7 ° C

FT-IR (analytical instrument: Jasco FT / IR-4200, υ, KBr): 3406.6, 1732.7, 1649.8, 1575.5, 1537.9, 1381.7, 1289.1, 1139.7, 656.6 cm ^-1

¹ H-NMR (measuring _{instrument: Bruker, AvanceⅢ 400MHz, D 2} O, δ): 1.17 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.4 Hz), 3.20 (1H, dq, J = 7.2, 9.0 Hz), 3.43 (1H, dd, J = 2.4, 6.0 Hz), 3.64 (2H, t, J = 7.6 Hz), 4.00 (2H, t, J = 7.6 Hz), 4.19 ~ 4.25 ( 4H, m), 4.35-4.39 (1H, m), 4.72-4.79 (2H, m)

¹³ C-NMR (measuring _{instrument: Bruker, AvanceⅢ 400MHz, D 2} O, δ): 15.88, 20.08, 32.24, 32.32, 42.63, 49.75, 56.10, 58.41, 59.41, 61.72, 65.12, 132.27, 139.26, 167.61, 171.05, 176.24

The two-theta values of the crystal form are 7.98 °, 8.99 °, 11.17 °, 13.22 °, 14.09 °, 15.58 °, 18.60 °, 21.78 °, 23.21 °, 23.61 °, 24.5 °, 25.03 °, 25.18 °, 32.35 °, 35.8 ° . The more specific 2? Values are 8.99, 11.17, 15.58, 21.78 and 23.61, and the more characteristic 2? Values are 8.99, 11.17 and 23.61. Powder XRD was measured using a Bruker AXS D8 Discover with GADDS instrument, with a step time of 0.2 seconds and CuKα line condition. The overall pattern is shown in FIG.

Step 3) 50 g of the obtained CTBP and benzyltriethylammonium chloride (59.4 g) were dissolved in 1,000 mL of dimethylformamide (DMF), and chloromethyl pivalate (39.3 g) and triethylamine (TEA, 26.4 g) , The temperature of the reaction solution is raised to 60 ± 10 ° C., and the mixture is stirred for 1 hour ± 30 minutes. Then, the temperature of the reaction solution is cooled to 0 to 5 ° C. and 1,000 mL of ethyl acetate (EA) and 1,000 mL of distilled water are added. The organic layer was washed with 1,000 mL of a saturated aqueous sodium chloride solution, dried with 100 g of magnesium sulfate, filtered and concentrated under reduced pressure to remove the solvent to give crude pivaloyloxymethyl (1R, 5S, 6S) -2- [ Thiazol-2-yl] azetidin-3-yl] -thio-6 - [(R) -1-hydroxyethyl] -PI, yield ~ 100%).

step 4) The obtained crude TBPM-PI is dissolved in at least one solvent selected from the group consisting of methyl acetate, acetone and isopropyl alcohol. Considering the yield, it is preferably dissolved in 1,400 mL of methyl acetate (MA), cooled to -15 to -20 DEG C, and stirred for 3 hours. The resulting solid is filtered and washed with 70 mL of methyl acetate (MA). The resulting solid was dried in a vacuum oven at 40 캜 for 3 hours to obtain the target compound pivaloyloxymethyl (1R, 5S, 6S) -2- [1-1,3-thiazolin-2-yl] azetidin- Carboxylate (TBPM-PI, yield 75.3%, purity 99.5%) was obtained in high yield and yielded the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) It was obtained with excellent quality.

The qualitative analysis results of the obtained compound are as follows.

FT-IR (analytical instrument: Jasco FT / IR-4200, υ, KBr): 3399.8, 2971.7, 2932.2, 2870.5, 1775.1, 1613.1, 1345.1, 1115.6, 980.6 cm ^-1

¹ H-NMR (measuring _{instrument: Bruker, AvanceⅢ 400MHz, CDCl 3} , δ): 1.21 ~ 1.23 (12H, m), 1.32 (3H, d, J = 6.4 Hz), 3.16 (1H, dq, J = 7.6, 9.2 Hz), 3.21 (1H, dd, J = 2.4, 6.8 Hz), 3.36 (2H, t, J = 7.2 Hz), 3.93 ~ 4.02 (4H, m), 4.11 ~ 4.23 (3H, m), 4.36 ~ 4.41 (2H, m), 5.82 (1H, d, J = 5.6 Hz), 5.95 (1H, d, J = 5.2 Hz)

¹³ C-NMR (measuring _{instrument: Bruker, AvanceⅢ 400MHz, CDCl 3} , δ): 16.90, 22.05, 26.99, 33.30, 36.48, 38.87, 44.05, 56.36, 58.25, 59.96, 60.06, 61.13, 65.85, 79.94, 124.68, 150.46 , 159.50, 164.32, 172.49, 177.07

The overall yield of the final object through steps 1-4 is 69.6% (1step: 93.8%, 2step: 98.6%, 3 - 4step: 75.3%).

Claims (5)

(1R, 5S, 6S) -2- [1- (1,3 < RTI ID = 0.0 & -Thiazolin-2-yl) azetidin-3-yl] -thio-6 - [(R) -1-hydroxyethyl] -1-methylcarbapen- Adding methyl pivalate chloride to the polymorph and then dissolving it in at least one solvent selected from the group consisting of methyl acetate, acetone and isopropyl alcohol, cooling to -15 to -20 占 폚 and stirring, 6 - [(R) -1-hydroxyethyl] - (2-oxo- Methyl-carbapen-2-yl) -3-carboxylate. delete delete 2. The compound according to claim 1, wherein the methyl pivalate chloride is chloromethyl pivalate. (1R, 5S, 6S) -2- [1- (1,3-thiazolin- Azetidin-3-yl] -thio-6 - [(R) -1-hydroxyethyl] -1-methyl-carbapen-2-yl) -3-carboxylate. 2. The compound of claim 1, wherein the solvent is methyl acetate. (1R, 5S, 6S) -2- [1- (1,3-Thiazolin- Yl-thio-6 - [(R) -1-hydroxyethyl] -1-methyl-carbapen-2-yl) -3-carboxylate.

Images