Process for preparing an intermediate for avibactam

Abstract

A method for preparing an intermediate for avibactam, and specifically relates to a method for preparing ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt (II). With 5R-[(benzyloxy) amino] piperidine-2S-carboxylate oxalate (III) as the raw material is reacted with the amide of Formula IV via amidation to prepare the compound of Formula V; the resulting compound of Formula V is reacted with the carbonylation reagent via urea cyclization to obtain the compound of Formula VI; the benzyl or the substituted benzyl in the compound of Formula VI is removed by catalytic hydrogeneration, then the resulting compound is sulfatated by sulfur trioxide complex and is salinized into tetrabutylammonium to obtain the final product (II).

Claims

1. A process for preparing the chemical compound of formula II, comprising the following steps: (1) the compound of Formula III is reacted with an amide of Formula IV in solvent A and in the presence of base A via an amidation reaction to obtain a compound of Formula V; ##STR00011## wherein in the compound of Formula III: R is a C.sub.1-6 aliphatic group or alkyl-substituted phenyl; in the compound of Formula IV: R is selected from the group consisting of hydrogen, o-methoxy, o-methyl, p-methoxy and p-methyl; R in the compound of formula V is identical to R in the compound of formula IV; (2) the compound of formula V is reacted with a carbonylation reagent in solvent B and in the presence of base B via urea cyclization to obtain the compound of Formula VI; ##STR00012## wherein R in the compound of formula VI is identical to R in the compound of formula IV; (3) in solvent C and in the presence of base C, the benzyl or the substituted benzyl in the compound of Formula VI is removed by catalytic hydrogeneration, then the resulting compound is sulfatated by sulfur trioxide complex, to obtain a product; then, the product is salinized into tetrabutylammonium to obtain the compound of Formula II ##STR00013##

2. The process according to claim 1, wherein the solvent A in step (1) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, trichloromethane, tetrachloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methoxycyclopentane, methylbenzene, and combinations of two or more thereof; and in step (1), a mass ratio between the solvent A and the compound of Formula III is 420:1; and the base A is an inorganic base or an organic base; the inorganic base is one of potassium carbonate or sodium carbonate, or a mixture of the two, and the organic base is dibenzylamine; and a molar ratio between the base A and the compound of Formula III is 2.05.0:1.

3. The process according to claim 1, wherein in step (1), the amide of Formula IV is selected from the group consisting of dibenzylamine, di(o-methoxy) benzylamine, di(p-methoxy) benzylamine, di(o-methyl) benzylamine, and di(p-methyl) benzylamine; a molar ratio between the amide of Formula IV and the compound of Formula III is 14:1.

4. The process according to claim 1, wherein in step (1), the amidation reaction is conducted in the temperature of from 0 C. to 100 C.

5. The process according to claim 1, wherein in step (2), the solvent B is selected from the group consisting of dichloromethane, 1,2-dichloroethane, trichloromethane, tetrachloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methoxycyclopentane, n-butanol, tert-butanol or methylbenzene, and combinations of two or more thereof; and in step (2), a mass ratio between the solvent B and the compound of formula V is 427:1.

6. The process according to claim 1, wherein in step (2), a molar ratio between the carbonylation reagent and the compound of formula V is 0.33:1.

7. The process according to claim 1, wherein in step (2), the carbonylation reagent is selected from the group consisting of triphosgene, diphosgene, carbonyldiimidazole and di-tert-butyl dicarbonate; a molar ratio between triphosgene and the compound of formula V is 0.31.5:1; a molar ratio between diphosgene and the compound of formula V is 0.52.0:1; and a molar ratio between carbonyldiimidazole or di-tert-butyl dicarbonate and the compound of formula V is 1.03.0:1.

8. The process according to claim 1, wherein in step (2), the temperature for the urea cyclization reaction ranges from 20 C. to 100 C.

9. The process according to claim 1, wherein in step (3), the solvent C is selected from the group consisting of isopropanol, n-butanol, tert-butanol, tetrahydrofuran, N,N-dimethyl formamide, water, and mixtures of two or more thereof; and in step (3), a mass ratio between the solvent C and the compound of Formula VI is 420:1.

10. The process according to claim 1, wherein in step (3), the reaction temperatures for the catalytic hydrogenolysis and the sulfatation both range from 10 C. to 60 C.

11. The process according to claim 4, wherein in step (1), the amidation reaction is conducted in the temperature of from 30 C. to 80 C.

12. The process according to claim 5, wherein in step (2), the base B is an organic base; and the molar ratio between the base B and the compound of formula V is 26:1.

13. The process according to claim 8, wherein in step (2), the temperature for the urea cyclization reaction ranges from 10 to 40 C.

14. The process according to claim 9, wherein in step (3), the base C is organic base; and a molar ratio between the base C and the compound of Formula VI is 0.1-0.3:1; the catalyst for the catalytic hydrogenolysis is palladium-on-carbon with 5% mass content 15 of palladium or palladium-on-carbon with 10% mass content of palladium; in the palladium-on-carbon, the water content is 555 wt %; in step (3), the mass of the catalyst for the catalytic hydrogenolysis is 1.020.0% of the mass of the compound of formula VI; and the hydrogen pressure used for the catalytic hydrogenolysis is 0.050.30 Mpa; the sulfur trioxide complex is one of trimethylamine sulfur trioxide, pyridine sulfur 20 trioxide, or triethylamine sulfur trioxide; the tetrabutyl ammonium source used for the tetrabutylammonium salinization is tetrabutylammonium hydroxide or tetrabutylammonium acetate; and a molar ratio between the tetrabutyl ammonium source used for the tetrabutylammonium salinization and the compound of formula VI is 0.81.2:1.

15. The process according to claim 10, wherein in step (3), the reaction temperature for the tetrabutylammonium salinization ranges from 0 C. to 50 C.

16. The process according to claim 15, wherein in step (3), the reaction temperature for the tetrabutylammonium salinization ranges from 10 C. to 30 C.

17. The process according to claim 1, wherein in the compound of Formula III: R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-amyl, hexyl, benzyl, o-methylbenzyl and p-methylbenzyl.

18. The process according to claim 10, wherein the reaction temperatures for the catalytic hydrogenolysis and the sulfatation both range from 10 C. to 40 C.

19. The process according to claim 14, wherein the molar ratio between the sulfur trioxide complex and the compound of formula VI is 1.02.0:1.

Description

EXAMPLES

(1) Hereinafter, the present application will be illustrated in detail with reference to the examples; however, the present application is not limited thereto.

(2) The percentages in the examples all refer to mass percentages, unless otherwise indicated.

(3) The raw material 5R-[(benzyloxy) amino] piperidine-2S-carboxylate oxalate (III) is easily accessible in the market (from Jinan Qinsi Pharmaceutical Company), which is a white powder with an optical purity of 99.6%.

(4) The reaction process and product purity were monitored by liquid chromatograph. A liquid chromatograph equipped with a chiral column (ES-OVS, 150 mm4.6 mm, Agilent) is used to detect the optical purity (area ratio %) and calculate the yield and e.e % value.

Example 1: Preparation of N, N-dibenzyl-5R-[(benzyloxy)amino]piperidine-2S-formamide (V1)

(5) To a 500 ml 4-neck flask equipped with a stirrer and a thermometer were charged 250 g of tetrahydrofuran, 28.0 g of potassium carbonate, 43.0 g (0.1 mol) of benzyl 5R-[(benzyloxy)amino]piperidine-2S-carboxylate oxalate (III), and 30 g (0.15 mol) of dibenzylamine, and then the reaction mixture was stirred for 5 hours between 40 C. to 45 C., then cooled to 20 C.25 C., and filtered. The filter cake was washed twice with tetrahydrofuran, 30 g for each time. Organic phases were combined and distilled to recover tetrahydrofuran. 40 g of methyl tert-butyl ether was charged to the residue, then mashed and washed, and filtered to obtain 41.1 g of N, N-dibenzyl-5R-[(benzyloxy)amino]piperidine-2S-formamide in a yield of 95.8% and a purity of 99.92% in HPLC.

(6) NMR (Nuclear Magnetic Resonance) data of the resulting product are provided below: .sup.1H-NMR (400 MHz, DMSO-d.sub.6)

(7) .sup.1H-NMR (400 MHz, DMSO-d6) : 1.12 (1H, q), 1.29 (1H, q), 1.86 (2H, d), 2.29 (1H, t), 2.76 (1H, m), 2.95 (1H, d), 3.18 (1H, d), 4.62 (4H, s), 4.83 (2H, s), 6.50 (1H, d), 7.28-7.47 (15H, m).

Example 2: Preparation of N, N-dibenzyl-5R-[(benzyloxy)amino]piperidine-2S-formamide (V1)

(8) To a 500 ml 4-neck flask equipped with a stirrer and a thermometer were charged 300 g of 1,2-dichloroethane, 43.0 g (0.1 mol) of benzyl 5R-[(benzyloxy)amino]piperidine-2S-carboxylate oxalate (III), and 60 g (0.30 mol) of dibenzylamine, and then the reaction mixture was stirred for 4 hours between 50 C. to 55 C., then cooled to 20 C.25 C., and filtered. The filter cake was washed twice with 1,2-dichloroethane, 30 g for each time. Organic phases were combined and distilled to recover 1,2-dichloroethane. 50 g of methyl tert-butyl ether was charged to the residue, then mashed and washed, and filtered to obtain 40.5 g of N, N-dibenzyl-5R-[(benzyloxy) amino] piperidine-2S-formamide in a yield of 94.4% and a purity of 99.86% in HPLC.

Example 3: Preparation of N,N-di(p-methoxybenzyl)-5R-[(benzyloxy)amino]piperidine-2S-formamide (V2)

(9) To a 500 ml 4-neck flask equipped with a stirrer and a thermometer were charged 250 g of tetrahydrofuran, 28.0 g of potassium carbonate, 37.0 g (0.1 mol) of ethyl 5R-[(benzyloxy)amino]piperidine-2S-carboxylate oxalate (III), and 40 g (0.16 mol) of di(p-methoxy)benzylamine, and then the reaction mixture was stirred for 4 hours between 50 C. to 55 C., then cooled to 20 C.25 C., and filtered. The filter cake was washed twice with tetrahydrofuran, 30 g for each time. Organic phases were combined and distilled to recover tetrahydrofuran. 40 g of methyl tert-butyl ether was charged to the residue, then mashed and washed, and filtered to obtain 45.7 g of N,N-di(p-methoxybenzyl)-5R-[(benzyloxy)amino] piperidine-2S-formamide in a yield of 93.5% and a purity of 99.93% in HPLC.

(10) NMR (Nuclear Magnetic Resonance) data of the resulting product are provided below: .sup.1HNMR (400 MHz, DMSO-d.sub.6)

(11) .sup.1H-NMR (400 MHz, DMSO-d6) : 1.15 (1H, q), 1.34 (1H, q), 1.88 (2H, d), 2.30 (1H, t), 2.90 (1H, m), 3.01 (1H, d), 3.21 (1H, d), 3.80 (6H, s), 4.46 (4H, s), 4.76 (2H, s), 6.48 (1H, d), 6.90 (4H, d), 7.25 (4H, d), 7.55 (5H, m).

Example 4: Preparation of N,N-di(p-methylbenzyl)-5R-[(benzyloxy) amino] piperidine-2S-formamide (V3)

(12) To a 500 ml 4-neck flask equipped with a stirrer and a thermometer were charged 250 g of 2-methyltetrahydrofuran, 30.0 g of potassium carbonate, 39.5 g (0.1 mol) of tert-butyl 5R-[(benzyloxy)amino]piperidine-2S-carboxylate oxalate (III), and 40 g (0.18 mol) of di(p-methyl)benzylamine, and then the reaction mixture was stirred for 4 hours between 60 C. to 65 C., then cooled to 20 C.25 C., and filtered. The filter cake was washed twice with 2-methyltetrahydrofuran, 30 g for each time. Organic phases were combined and distilled to recover 2-methyltetrahydrofuran. 40 g of methyl tert-butyl ether was charged to the residue, then mashed and washed, and filtered to obtain 43.6 g of N,N-di(p-methylbenzyl)-5R-[(benzyloxy) amino] piperidine-2S-formamide in a yield of 95.5% and a purity of 99.89% in HPLC.

(13) NMR (Nuclear Magnetic Resonance) data of the resulting product are provided below: .sup.1HNMR (400 MHz, DMSO-d.sub.6)

(14) .sup.1H-NMR (400 MHz, DMSO-d6) : 1.13 (1H, q), 1.31 (1H, q), 1.85 (2H, d), 2.06 (6H, s), 2.27 (1H, t), 2.85 (1H, m), 2.91 (1H, d), 3.17 (1H, d), 4.60 (4H, s), 4.78 (2H, s), 6.54 (1H, d), 7.08 (4H, d), 7.19 (4H, d), 7.48 (5H, m).

(15) Structural Formulae of Compounds V.sub.1, V.sub.2, and V.sub.3 are as follows:

(16) ##STR00009##

Example 5: Preparation of N,N-dibenzyl-(2S, 5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide (VI1)

(17) To a 1000 ml 4-neck flask equipped with a stirrer and a thermometer were charged 250 g of tetrahydrofuran, 43 g (0.1 mol) of N, N-dibenzyl-5R-[(benzyloxy)amino]piperidine-2S-formamide (V.sub.1) prepared according to Example 1, and 50 g of triethylamine, and then cooled to 10 C.0 C., then charged 30 g (0.1 mol) of triphosgene and 100 g of tetrahydrofuran solution, and then the reaction mixture was stirred for 8 hours between 1020 C. The reaction liquid was poured into a 400 g of ice-water mixture and separated, and aqueous phase was extracted thrice with dichloromethane, 100 g for each time. Organic phases were combined, and then washed twice with saturated aqueous solution of sodium chloride, 50 g for each time; after the solvent was recovered from the resulting organic phase, 60 g of methyl tert-butyl ether was added to the residue; the residue was mashed, washed, and then filtered, to obtain 42.1 g of N,N-dibenzyl-(2S, 5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide in a yield of 92.5% and a purity of 99.96% in HPLC.

(18) NMR (Nuclear Magnetic Resonance) data of the resulting product are provided below: .sup.1H-NMR (400 MHz, DMSO-d6) : 1.65 (2H, m), 1.84 (1H, br), 2.06 (1H, m), 2.90 (2H, s), 3.62 (1H, s), 4.58 (4H, s), 4.93 (2H, dd), 7.287.47 (15H, m).

Example 6: Preparation of N,N-dibenzyl-(2S, 5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide (Vii)

(19) To a 500 ml 4-neck flask equipped with a stirrer and a thermometer were charged 60 g of tetrahydrofuran, 4.3 g (0.01 mol) of N, N-dibenzyl-5R-[(benzyloxy)amino]piperidine-2S-formamide (V.sub.1) prepared according to Example 1, and 5.0 g of tri-n-butylamine, and then cooled to 10 C.-0 C., then charged 3.0 g (0.015 mol) of diphosgene and 20 g of tetrahydrofuran solution, and then the reaction mixture was stirred for 8 hours between 1020 C. The reaction liquid was poured into a 200 g of ice-water mixture and separated, and aqueous phase was extracted thrice with dichloromethane, 50 g for each time. Organic phases were combined, and then washed twice with saturated aqueous solution of sodium chloride, 20 g for each time; after the solvent was recovered from the resulting organic phase, 20 g of methyl tert-butyl ether was added to the residue; the residue was mashed, washed, and then filtered, to obtain 4.15 g of N,N-dibenzyl-(2S, 5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide in a yield of 91.2% and a purity of 99.9% in HPLC.

Example 7: Preparation of N,N-di (p-methoxy) benzyl-(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide (VI2)

(20) To a 500 ml 4-neck flask equipped with a stirrer and a thermometer were charged 100 g of dichloromethane, 4.9 g (0.01 mol) of N,N-di(p-methoxybenzyl)-5R-[(benzyloxy)amino]piperidine-2S-formamide (V.sub.2) prepared according to Example 3, and 5.0 g of tri-n-butylamine, and then cooled to 10 C.0 C., then charged 3.0 g (0.01 mol) of triphosgene and 20 g of dichloromethane solution, and then the reaction mixture was stirred for 8 hours between 1020 C. The reaction liquid was poured into a 200 g of ice-water mixture and separated, and aqueous phase was extracted thrice with dichloromethane, 50 g for each time. Organic phases were combined, and then washed twice with saturated aqueous solution of sodium chloride, 20 g for each time; after the solvent was recovered from the resulting organic phase, 20 g of methyl tert-butyl ether was added to the residue; the residue was mashed, washed, and then filtered to obtain 4.75 g of N,N-di (p-methoxy) benzyl-(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide in a yield of 92.2% and a purity of 99.92% in HPLC.

(21) NMR (Nuclear Magnetic Resonance) data of the resulting product are provided below: .sup.1H-NMR (400 MHz, DMSO-d6) : 1.60 (2H, m), 1.81 (1H, br), 2.02 (1H, m), 2.88 (2H, s), 3.59 (1H, s), 3.62 (1H, d), 3.78 (6H, s), 4.55 (4H, s), 4.85 (2H, dd), 6.82 (4H, d), 7.16 (4H, d), 7.47 (5H, m).

Example 8: Preparation of N,N-di(p-methyl)benzyl-(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide (VI3)

(22) To a 500 ml 4-neck flask equipped with a stirrer and a thermometer were charged 100 g of dichloromethane, 4.6 g (0.01 mol) of N,N-di(p-methylbenzyl)-5R-[(benzyloxy)amino]piperidine-2S-formamide (V.sub.3) prepared according to Example 4, and 4.0 g of triethylamine, and then cooled to 0 C.-10 C., then charged 3.0 g (0.01 mol) of triphosgene and 20 g of dichloromethane solution, and then the reaction mixture was stirred for 6 hours between 2030 C. The reaction liquid was poured into a 200 g of ice-water mixture and separated, and aqueous phase was extracted thrice with dichloromethane, 50 g for each time. Organic phases were combined, and then washed twice with saturated aqueous solution of sodium chloride, 20 g for each time; after the solvent was recovered from the resulting organic phase, 20 g of methyl tert-butyl ether was added to the residue; the residue was mashed, washed, and then filtered to obtain 4.47 g of N,N-di(p-methyl)benzyl-(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide in a yield of 92.5% and a purity of 99.96% in HPLC.

(23) NMR (Nuclear Magnetic Resonance) data of the resulting product are provided below: .sup.1H-NMR (400 MHz, DMSO-d6) : 1.63 (2H, m), 1.85 (1H, br), 2.05 (1H, m), 2.10 (6H, s), 2.91 (2H, s), 3.62 (1H, s), 3.68 (1H, d), 3.83 (6H, s), 4.61 (4H, s), 4.88 (2H, dd), 6.84 (4H, d), 7.19 (4H, d), and 7.51 (5H, m).

(24) Structural Formulae of Compounds VI.sub.1, VI.sub.2, and VI.sub.3 are as follows:

(25) ##STR00010##

Example 9: Preparation of ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt

(26) To a stainless steel reactor were charged 14 g of isopropanol, 17 g of water, 4.9 g (0.01 mol) of N,N-dibenzyl-(2S, 5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide (VI.sub.1) prepared according to the process of Example 5, 1.56 g (0.0112 mol) of sulfur trioxide-trimethylamine, 0.2 g (0.002 mol) of triethylamine, and 0.11 g of palladium-on-carbon (with a water content of 55 wt %) with a palladium mass content of 10%; after the caldron was closed, nitrogen gas protection was introduced. The reactor was intermittently introduced with hydrogen to maintain the pressure of hydrogen gas at 0.070.13 Mpa; the reactor was insulated at the room temperature for 1 hour, till the raw material VI.sub.1 was completely reacted (at this point, the pressure would rise). After replacement with the nitrogen gas, the reactor continued to be insulated at the room temperature for another 1.5 h. After 0.16 g (0.0026 mol) of acetic acid was charged to neutralize, the palladium-on-carbon was filtered out, and the filter cake was washed with 8.6 g of water. The filtrate was washed with 26 ml of n-butyl acetate and separated, and then the aqueous phase was taken.

(27) 3.68 g (0.0122 mol) of tetrabutylammonium acetate and 0.06 g (0.001 mol) of acetic acid were pre-dissolved into 6.5 g of water to prepare a tetrabutylammonium acetate solution. 70 wt % of tetrabutylammonium acetate solution was charged into the washed and separated aqueous phase and salinized at the room temperature for 12 h. 26 ml of dichloromethane was applied to extract organic phases; the solution was then separated to obtain organic phases. The remaining 30 wt % of tetrabutyl ammonium acetate solution was charged into the organic phase and salinized at the room temperature for 12 h, and then extracted with 9 ml of dichloromethane. After the organic phases were combined and concentrated to 20 ml. Then, 50 ml methyl isobutyl ketone was charged, and then the mixture was concentrated to 40 ml and cooled to 0 C., and filtered. The filter cake was then washed with 10 ml of methyl isobutyl ketone, and then vacuum dried, and finally 4.5 g of ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt (II) was obtained in a yield of 88.7% and a purity of 99.3% in HPLC.

(28) NMR (Nuclear Magnetic Resonance) data of the resulting product are provided below: .sup.1H-NMR (400 MHz, CDCl.sub.3) : 1.00 (12H, t), 1.45 (8H, m), 1.67 (9H, m), 1.87 (1H, m), 2.16 (1H, m), 2.37 (1H, dd), 2.87 (1H, d), 3.31 (9H, m), 3.91 (1H, d), 4.33 (1H, s), 5.87 (1H, s), 6.69 (1H, s).

Example 10: Preparation of ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt (II)

(29) To a hydrogenation reaction caldron were charged 16 g of isopropanol, 20 g of water, 4.9 g (0.01 mol) of N,N-di (p-methoxy) benzyl-(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide (VI.sub.2) prepared according to Example 7, 1.56 g (0.0112 mol) of sulfur trioxide-trimethylamine, 0.2 g (0.002 mol) of triethylamine, and 0.12 g of palladium-on-carbon (with a water content of 55 wt %) with a palladium mass content of 10%; after the reactor was closed, nitrogen gas protection was applied. The reactor was intermittently introduced with hydrogen to maintain the pressure of hydrogen gas at 0.070.13 MPa; the reactor was insulated at the room temperature for 1 hour, till the raw material VI.sub.2 was completely reacted (at this point, the pressure would rise). After replacement with the nitrogen gas, the reactor continued to be insulated at the room temperature for another 1.5 h. After 0.16 g (0.0026 mol) of acetic acid was charged to neutralize, the palladium-on-carbon was filtered out, and the filter cake was washed with 10 g of water. The filtrate was washed with 30 ml of n-butyl acetate and separated, and then the aqueous phase was taken.

(30) 3.68 g (0.0122 mol) of tetrabutylammonium acetate and 0.06 g (0.001 mol) of acetic acid were pre-dissolved into 7.5 g of water to prepare a tetrabutylammonium acetate solution. 70 wt % of tetrabutyl ammonium acetate solution was charged into the washed and separated aqueous phase and salinized at the room temperature for 12 h. 30 ml of dichloromethane was applied to extract organic phases; the solution was then separated to obtain organic phases. The remaining 30 wt % of tetrabutylammonium acetate solution was charged into the organic phase and salinized at the room temperature for 12 h, and then the mixture was extracted with 10 ml of dichloromethane, the organic phases were combined and concentrated to 20 ml. Then, 50 ml of methyl isobutyl ketone was charged, and then the mixture was concentrated to 40 ml and cooled to 0 C., and filtrated. The filter cake was then washed with 10 ml of methyl isobutyl ketone, and then vacuum dried, and finally 4.7 g of ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt (II) was obtained in a yield of 92.7% and a purity of 99.1% in HPLC.

Example 11: Preparation of ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt (II)

(31) To a hydrogenation reaction caldron were charged 15 g of isopropanol, 18 g of water, 4.6 g (0.01 mol) of N,N-di (p-methyl) benzyl-(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-formamide (VI.sub.3) prepared according to Example 8, 1.56 g (0.0112 mol) of sulfur trioxide-trimethylamine, 0.2 g (0.002 mol) of triethylamine, and 0.11 g of palladium-on-carbon (with a water content of 55 wt %) with a palladium mass content of 10%; after the reactor was closed, nitrogen gas protection was applied. The reactor was intermittently introduced with hydrogen to maintain the pressure of hydrogen gas at 0.070.13 MPa; the reactor was insulated at the room temperature for 1 hour, till the raw material VI.sub.3 was completely reacted (at this point, the pressure would rise). After replacement with the nitrogen gas, the reactor continued to be insulated for 1.5 h at the room temperature. After 0.16 g (0.0026 mol) of acetic acid was charged to neutralize, the palladium-on-carbon was filtered out, and the filter cake was washed with 8.6 g of water. The filtrate was washed with 26 ml of n-butyl acetate and separated, and then the aqueous phase was taken.

(32) 3.68 g (0.0122 mol) of tetrabutylammonium acetate and 0.06 g (0.001 mol) of acetic acid were pre-dissolved into 6.5 g of water to prepare a tetrabutylammonium acetate solution. 70 wt % of tetrabutylammonium acetate solution was charged into the washed and separated aqueous phase and salinized at the room temperature for 12 h. 26 ml of dichloromethane was applied to extract organic phases; the solution was then separated to obtain organic phases. The remaining 30 wt % of tetrabutyl ammonium acetate solution was charged into the organic phase and salinized at the room temperature for 12 h, and then the mixture was extracted with 9 ml of dichloromethane, the organic phases were combined and concentrated to 20 ml. Then, 50 ml of methyl isobutyl ketone was charged, and then the mixture was concentrated to 40 ml, cooled to 0 C., and filtrated. Then, the filter cake was washed with 10 ml of methyl isobutyl ketone, and then vacuum dried, finally 4.4 g of ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt (II) was obtained in a yield of 86.8% and a purity of 99.4% in HPLC.