METHOD FOR PREPARING TULATHROMYCIN

Abstract

A method for preparing tulathromycin, and two intermediate compounds shown in formula V and formula VI are provided. The method includes the following synthetic route:

##STR00001##

Claims

1. A method for preparing tulathromycin, comprising the following synthetic route: ##STR00006##

2. A compound having the chemical structure of formula V according to claim 1.

3. The compound having the chemical structure of formula V according to claim 2, wherein the compound is obtained by reacting the compound of formula IV with the trimethylsilyl cyanide (TMSCN) under an action of the tetrabutylammonium fluoride (TBAF), wherein R in formula IV is hydrogen (H), methyl (Me), or nitrogen dioxide (NO.sub.2), and R in formula V is H, Me, or NO.sub.2.

4. A compound having the chemical structure of formula VI according to claim 1.

5. The compound having the chemical structure of formula VI according to claim 4, wherein the compound is obtained by a hydrogenation reaction in a presence of the acetic acid (HOAc) under a condition of the palladium on activated carbon (Pd/C) as a catalyst, and the solvent used in the hydrogenation reaction is at least one selected from the group consisting of methanol (MeOH), ethyl alcohol (EtOH), and isopropyl alcohol (i-PrOH), and a pressure of hydrogen in the hydrogenation reaction is 2-10 atm.

6. The method according to claim 1, wherein the tulathromycin is obtained by reacting the compound of formula VI with the compound of formula VII under an action of the alkali, the alkali is at least one selected from the group consisting of 4-dimethylaminopyridine (DMAP), triethylamine (Et.sub.3N), Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, and N,N-Diisopropylethylamine (DIPEA), and X in formula VII is iodine (I) or bromine (Br).

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0029] The present invention can be more specifically understood through the following embodiments, but it is illustrative rather than limiting the scope of the present invention.

EMBODIMENTS

Embodiment 1. Preparation of the Compound of Formula III (R=Me)

[0030] The compound of formula I (500 g, 645.16 mmol) and CH.sub.2Cl.sub.2 (3.5 L) were added to a 10 L four-neck flask. The system was fully stirred, and then the temperature of the system was maintained at about 20 C. p-methylbenzyl chloroformate (formula II, R=Me, 180 g, 975 mmol) was slowly added dropwise to the reaction system through a dropping funnel, and the temperature of the system was maintained at about 20 C. during the dropwise addition. After the dropwise addition was completed, the system reacted at the temperature for 3 hours. Then, the system was slowly added with 4 L of saturated aqueous sodium hydrogen carbonate solution to quench the reaction. After the addition was complete, the system was stirred at room temperature for 2 hours. The system was set aside for 2 hours and then separated. The organic phase was washed with 1 L of water, and then the organic phase was added with 250 g of anhydrous sodium sulfate and stirred to dry. Filtration and reduced pressure concentration of the organic phase were performed until no obvious cut fractions were produced to obtain the compound of formula III (R=Me, oily matter, 636 g, the product was used directly in the subsequent step without purification).

Embodiment 2. Preparation of the Compound of Formula IV (R=Me)

[0031] The compound of formula III (R=Me, 600 g) obtained in Embodiment 1 and anhydrous CH.sub.2Cl.sub.2 (2.5 L) were added to a 10 L four-necked flask. The system was subjected to nitrogen gas replacement three times, and the subsequent addition process was protected with nitrogen. Anhydrous DMSO (1.2 L) was added to the reaction system, the temperature of the system was reduced to 70 C. with stirring, and then trifluoroacetic anhydride (410 g) was slowly added through a dropping funnel at the temperature of about 70 C. After the addition was completed, the system was stirred for 1.5 hours at the temperature. Then, triethylamine (270 g) was slowly added dropwise through the dropping funnel. After the addition was completed, the system was stirred and reacted for 1.5 hours, and then H.sub.2O (3 L) was slowly added through the dropping funnel. After the system was slowly heated to about 20 C. and stirred for 1 hour, the system was set aside for 2 hours, and then the organic phase was separated. The organic phase was washed once with H.sub.2O (1.5 L), and then the organic phase was separated. The organic phase was concentrated under reduced pressure until no obvious cut fractions were produced, and then was concentrated again with 1 L of isopropyl alcohol until no obvious cut fractions were produced. The residue was added with 0.5 L of isopropyl alcohol and heated to dissolve. After being dissolved, the system was slowly cooled to about 10 C. under stirring overnight, and then filtered to obtain a solid. The solid was dried to obtain the compound of formula IV (R=Me, 389 g, and the yield in the two steps was 69%).

Embodiment 3. Preparation of the Compound of Formula V (R=Me)

[0032] The compound of formula IV (R=Me, 120 g, 130 mmol) obtained in Embodiment 2 was added to a 2 L reaction flask. CH.sub.2Cl.sub.2 (1 L) was added to the system. After the system was stirred and dissolved, the system was cooled to about 0 C., and then trimethylsilyl cyanide (15.5 g, 156 mmol) was slowly added through a dropping funnel. After the dropwise addition was completed, the temperature of the system naturally raised to room temperature and reacted overnight. Then, TBAF (1 M in THF, 160 mL) was slowly added to the system, and reacted at the temperature for 5 hours after the dropwise addition was completed. The reaction system was quenched by slowly adding H.sub.2O (500 mL). The system was placed to separate into layers and obtain the organic phase. The organic phase was washed twice with a saturated sodium chloride solution (2500 mL) and then dried with anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure until no obvious cut fractions were produced. The residue was dissolved by adding ethyl acetate (35 mL), then added with n-heptane (250 mL), and was heated to 70-80 C. to dissolve completely. Subsequently, the temperature was slowly reduced to 5 C., and the solution was stirred for 12 hours, and suction filtered to obtain a product. Then, the product was vacuum dried to obtain the compound of formula V (R=Me, 92 g, 75%).

Embodiment 4. Preparation of the Compound of Formula VI

[0033] The compound of formula V (R=Me, 52 g, 55 mmol) obtained in Embodiment 3 was added to 2 L autoclave, then methanol (500 mL) and HOAc (150 mL) were added. After stirring and dissolving completely, Pd/C (8 g, 10%) was added under the protection of nitrogen. The system was subjected to nitrogen gas replacement for 3 times and hydrogenated at 35 C. and 5 atm for 12 hours. After the reaction was completed, the reaction solution was taken out and filtered. The filter cake was washed with methanol (100 mL). The filtrate was collected and concentrated with no obvious cut fractions. The residue was added with ethyl acetate (30 mL), stirred and dissolved completely. Then, heptane (150 mL) was slowly added dropwise, and stirred for 3 hours. A large number of white solids were precipitated in the system, and then filtered to obtain a filter cake. The filter cake was washed with a small amount of cooled heptane and then dried to obtain the compound of formula VI (34.5 g, 82%).

Embodiment 5. Preparation of Tulathromycin

[0034] The compound of formula VI (22 g, 28.8 mmol), DMAP (3.5 g), and CH.sub.2Cl.sub.2 (80 mL) were added to a 500 mL reaction flask. After stirring and dissolving completely, the temperature of the system was reduced to 0 C. The CH.sub.2Cl.sub.2 solution (5 mL) containing 1-iodopropane (5.5 g) was slowly added dropwise through a dropping funnel, and the temperature of the system was kept at about 0 C. during the dropwise addition. The temperature of the system naturally raised to room temperature and the system reacted with stirring for 5 hours. The reaction was quenched by adding H.sub.2O (50 mL). The organic phase was separated, and the water phase was extracted with CH.sub.2Cl.sub.2 (230 mL). The organic phase was collected and washed twice with a saturated sodium chloride solution (240 mL). Then, the organic phase was desolvated under reduced pressure with no obvious cut fractions. The system was desolvated by adding n-heptane (50 mL) with no obvious cut fractions. Subsequently, the residue was added with ethyl acetate (12 mL) and stirred, and then n-heptane (90 mL) was added. The system was heated to 70-80 C. and stirred to dissolve completely. Then, the system was slowly cooled to about 5 C., stirred for 5 hours, and suction filtered to obtain a solid. The obtained solid was vacuum dried at 40 C. to obtain tulathromycin (white solid, 18.2 g, 78%).

Embodiment 6. Preparation of the Compound of Formula III (RNO.SUB.2.)

[0035] The compound of formula I (50.0 g, 64.5 mmol) and CH.sub.2Cl.sub.2 (300 mL) were added to a 1000 ml four-neck flask. The system was fully stirred to dissolved completely. p-nitrobenzyl chloroformate (formula II, R=NO.sub.2, 18.0 g, 83.5 mmol) was slowly added dropwise to the reaction system through a dropping funnel at a temperature of about 20 C. The temperature of the system was maintained at about 205 C. during the dropwise addition. After the dropwise addition was completed, the system reacted at the temperature for 5 hours. Then, the system was slowly added with saturated aqueous sodium hydrogen carbonate solution (250 mL) to quench the reaction. After the addition was complete, the system was stirred at room temperature for 2 hours and then separated. The organic phase was washed with saturated sodium chloride solution (100 mL), and then the organic phase was dried by adding anhydrous sodium sulfate. Filtration and high vacuum reduced pressure concentration of the organic phase were performed until no obvious cut fractions were produced to obtain the compound of formula III (R=NO.sub.2, 60.2 g, the product was used directly in the subsequent step without purification).

Embodiment 7. Preparation of the Compound of Formula IV (RNO.SUB.2.)

[0036] The compound of formula III (R=NO.sub.2, 52 g) obtained in Embodiment 6 and anhydrous CH.sub.2Cl.sub.2 (200 mL) were added to a 1 L four-necked flask. The reaction system was added with anhydrous DMSO (105 mL) under the protection of nitrogen. The temperature of the system was reduced to 75 C. with stirring, and then trifluoroacetic anhydride (36 g) was slowly added through a dropping funnel. The temperature of the system was maintained between 70 C. and 75 C. during the dropwise addition. After the dropwise addition was completed, the system was stirred for 1.5 hours at the temperature. Then, triethylamine (24 g) was slowly added dropwise through the dropping funnel. After the dropwise addition was completed, the system was stirred and reacted for 1.5 hours at the temperature, and then H.sub.2O (250 mL) was slowly added dropwise through the dropping funnel. After the system was slowly heated to about 20 C. and stirred for 1 hour, the system was placed and the organic phase was separated. The organic phase was washed once with H.sub.2O (120 mL), and then the organic phase was separated. The organic phase was concentrated under reduced pressure with no obvious cut fractions, and then was concentrated again with isopropyl alcohol (80 mL) with no obvious cut fractions. The residue was added with isopropyl alcohol (40 mL) and heated to dissolve. After being dissolved, the system was slowly cooled to about 10 C. under stirring overnight, and then filtered to obtain a solid. The solid was dried to obtain the compound of formula IV (R=NO.sub.2, 31.1 g, and the yield in the two steps is 59%).

Embodiment 8. Preparation of the Compound of Formula V (RNO.SUB.2.)

[0037] The compound of formula IV (R=NO.sub.2, 25 g, 26.3 mmol) obtained in Embodiment 7 was added to a 500 mL reaction flask. CH.sub.2Cl.sub.2 (180 mL) was added to the system. After the system was stirred and dissolved, the system was cooled to about 0 C. in an icy salt bath, and then trimethylsilyl cyanide (3.3 g, 33.3 mmol) was slowly added through an injection syringe. After the injection was completed, the temperature of the system naturally raised to room temperature and reacted overnight. Then, TBAF (1 M in THF, 35 mL) was slowly added dropwise to the system, and reacted at the temperature for 3 hours after the dropwise addition was completed. The reaction system was quenched by slowly adding H.sub.2O (100 mL). The system was placed to separate into layers and obtain the organic phase. The organic phase was washed twice with a saturated sodium chloride solution (280 mL) and then dried with anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure with no obvious cut fractions. The residue was dissolved by adding ethyl acetate (7 mL), then added with n-heptane (50 mL), and was heated to about 75 C. to dissolve completely. Subsequently, the temperature was slowly reduced to 5 C., and the solution was stirred for 12 hours, and suction filtered to obtain a product. Then, the product was vacuum dried to obtain the compound of formula V (R=NO.sub.2, 20.2 g, 78%).

Embodiment 9. Preparation of the Compound of Formula VI

[0038] The compound of formula V (R=NO.sub.2, 16 g, 16.3 mmol) obtained in Embodiment 8 was added to 500 mL minitype autoclave, then isopropanol (120 mL) and HOAc (45 mL) were added. After stirring and dissolving completely, Pd/C (2.5 g, 10%) was added under the protection of nitrogen. The system was subjected to nitrogen gas replacement for 3 times and hydrogenated at 35 C. and 5 atm for 24 hours. After the reaction was completed, the reaction solution was taken out and filtered twice with a Buchner funnel. The filter cake was washed with isopropanol (20 mL). The filtrate was collected and concentrated under high vacuum reduced pressure with no obvious cut fractions. The residue was added with ethyl acetate (10 mL), stirred and dissolved completely. Then, heptane (50 mL) was slowly added dropwise, and stirred overnight. A large number of white solids were precipitated in the system, and then filtered to obtain a filter cake. The filter cake was washed with a small amount of cooled heptane and then dried to obtain the compound of formula VI (9.2 g, 73.9%).

Embodiment 10. Preparation of Tulathromycin

[0039] The compound of formula VI (8.6 g, 11.3 mmol), DIPEA (1.5 g, 11.6 mmol), and CH.sub.2Cl.sub.2 (30 mL) were added to a 200 mL reaction flask. After stirring and dissolving completely, the temperature of the system was reduced to 0 C. The CH.sub.2Cl.sub.2 solution (2 mL) containing 1-iodopropane (1.4 g, 11.4 mmol) was slowly added dropwise through an injection syringe, and the temperature of the system was kept at about 0 C. during the dropwise addition. After the dropwise addition was completed, NaI (100 mg) was added to the system. The temperature of the system naturally raised to room temperature and the system reacted with stirring for 12 hours. The reaction was quenched by adding H.sub.2O (20 mL). The organic phase was separated, and the water phase was extracted with CH.sub.2Cl.sub.2 (230 mL). The organic phase was collected and washed twice with a saturated sodium chloride solution (240 mL). Then, the organic phase was desolvated under reduced pressure with no obvious cut fractions. The system was desolvated by adding n-heptane (30 mL) with no obvious cut fractions. Subsequently, the residue was added with ethyl acetate (5 mL) and stirred, and then n-heptane (35 mL) was added. The system was heated to 70-80 C. and stirred to dissolve completely. Then, the system was slowly cooled to about 5 C., stirred for 5 hours, and suction filtered to obtain a solid. The obtained solid was vacuum dried at 40 C. to obtain tulathromycin (white solid, 5.86 g, 64.3%).