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Use of Lipase Catalytic Resolution in the Preparation of ethyl (2S,5R)-5-((benzyloxy)amino) piperidine-2-carboxylate, a Key Intermediate of the #-lactamase Inhibitor Avibactam tao wang, Liang-dong Du, Ding-jian Wan, Xiang Li, Xinzhi Chen, and Guofeng Wu Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00173 • Publication Date (Web): 05 Nov 2018 Downloaded from http://pubs.acs.org on November 6, 2018

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Organic Process Research & Development

Use of Lipase Catalytic Resolution in the Preparation of ethyl (2S,5R)-5-((benzyloxy)amino) piperidine-2-carboxylate, a Key Intermediate of the -lactamase Inhibitor Avibactam

Tao Wanga,c, Liang-Dong Du b, Ding-jian Wan b, Xiang Li b, Xin-Zhi Chen c*, Guo-Feng Wu a*

a Research

&Development Center, Zhejiang Medicine CO., Ltd, 59 East Huangcheng Road, Xinchang, Zhejiang, 312500, P. R. China

b Shanghai

Laiyi Center for Biopharmaceuticals R&D, 5B, Building 8 200 Niudun Road Pudong District, Shanghai, 201203, P. R. China

c Key

Laboratory of Biomass Chemical Engineering of Ministry of Education, Zhejiang

University, 38 Zhejiang University Road, Xihu District, Hangzhou, 310007, P. R. China *E-mail:[email protected]

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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For Table of Contents Only HO HO N

HCl

1) Rh/C , H2

CO2Et

2) Lipozyme CALB

N CO2Et H single enantiomer dr > 99:1 HO

HO

N H

HO

(R) (R) CO2

CO2H

OBn HN

+ H N

THF

+

lipase catalytic resolution

N CO2Et Boc

(Boc)2O, TEA

O (S)

H2N

N N H

CO2Et

O

(R)

N

OSO3Na

Avibactam The total yield : 23.9%

N Boc water-soluble


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ABSTRACT Here we describe an efficient and cost-effective chemoenzymatic synthesis of the -lactamase

inhibitor

avibactam

starting

from

commercially

available

ethyl-5-hydroxypicolinatehydrochloride. Avibactam was synthesized in 10 steps with an overall yield of 23.9%. The synthetic route features a novel lipase-catalyzed resolution

step

during

the

preparation

of

(2S,5S)-ethyl

5-hydroxypiperidine-2-carboxylate, a valuable precursor of the key intermediateethyl (2S,5R)-5-((benzyloxy)amino) piperidine-2-carboxylate. Oursynthetic route was used to produce 400 grams of avibactam sodium salt.

KEYWORDS avibactam,lipozyme CALB,lipase-catalyzed resolution, chiral isomers



Page 4 of 22

INTRODUCTION The production of β-lactamases by pathogenic bacteria is a common mechanism of intrinsic and acquired immunity to β-lactam antibiotics. β-Lactamase inhibitors can bind to β-lactamases and inactivate them, which can significantly improve the efficacy of β-lactam antibiotics in the treatment of penicillin- and penicillin derivative-resistant bacterial infections. Avibactam (1, Figure 1), sodium (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo [3.2.1]octan-6-yl sulfonate, is a novel non-β-lactam β-lactamase inhibitor that contains a diazabicyclo[3.2.1]octane (DBO) heterocyclic core structure

1–4.

The

clinical use of avibactam in combination with ceftazidime, a cephalosporin antibiotic, was approved by the European Medicines Agency (EMA) in 2015 (sold as Zavicefta) and the Food and Drug Administration (FDA) in 2016 (sold as Avycaz). Ceftazidime/avibactam has been used for the successful treatment of multidrug Gram-negative bacterial infections including complicated intra-abdominal infections (CIAI), complicated urinary tract infections (CUTI), and hospital acquired pneumonia (HAP) 5,6. Furthermore, compared with the other three currently available β-lactamase inhibitors, clavulanic acid, sulbactam, and tazobactam, avibactam is more potent and has a broader spectrum of activity. Avibactam is active against class Aβ-lactamases including Klebsiella pneumoniaecarbapenemases (KPCs) and extended-spectrum β-lactamases(ESBLs),

class

C

β-lactamases,

and

some

class

D

β-lactamases1,7,8.Additionally, avibactam acts as a reversible covalent inhibitor, which is a unique mechanism of inhibition among β-lactamase inhibitors 2,9.

Figure 1 Structure of Avibactam (Sodium Salt) (1). O H2N

S N

N R O O O S 1 O O- Na+


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In recent years, considerable research has focused on the synthesis of avibactam10–22(Scheme 1);and in particular, on the preparation of a key intermediate, ethyl

(2S,5R)-5-((benzyloxy)amino)

piperidine-2-carboxylate

10–22

and

its

derivatives(Scheme 1). In the early stages of β-lactamase inhibitor research, Sanofi-Aventis developed route A for the synthesis of avibactam 13, 15. In this process, piperidine derivatives with two chiral centers were used as starting materials to synthesizeavibactam via inversion of configuration. Miller and colleagues also prepared avibactam analogue using an approach based on route A19.However, the raw materials for these synthetic routes are expensive and the processes require the use of several environmentally undesirable reagents and solvents. Later, route B was developed to synthesizeavibactam from L-glutamate acid or L-pyroglutamic

acid

14.

In

this

route,

ethyl

(2S,5R)-5-((benzyloxy)amino)

piperidine-2-carboxylate was constructed via multiple synthetic steps including ring-opening, ring-closing,reduction, and deprotection. Recently, AstraZeneca and Forest Laboratories optimized this process using commercially available Boc-benzyl glutamate as a starting material (achieving a 55 %overall yield) 22. The final established route to synthesize the ethyl (2S,5R)-5-((benzyloxy)amino) piperidine-2-carboxylateanalogue is based on the olefin metathesis reaction, which is promoted by transition metal-based catalysts

20

(Route C).However, there are

disadvantages to this route, including substrate instability that leads to a lower yield, the requirement for chiral ligand participation, and lower stereoselectivity. The limitations of the current routes result in difficulties industrial scale.


implementing them on an


Page 6 of 22

Scheme 1. Reported Synthetic Routes to the Avibactam Key Intermediate Route A

R

R OH O

R O

N H

R

O

TFA anhydride

OBn NH

OH O

N O

O

R

S N H

O

CF3

(2R,5S)-vinyl 5-((benzyloxy)amino) piperidine-2-carboxylate Route B

NH2

HOOC

O

S

S COOH

COOEt

N H

O

COOEt HN Boc

N2C

OBn HN R

OBn N

S

S N H

COOEt

N H

COOEt

(2S,5R)-ethyl 5-((benzyloxy)amino) piperidine-2-carboxylate

Route C TBSO O

Hoveyda-Grubbs Catalyst

Boc

N

S

TBSO Boc

O

N

O

S TBSO HN

R

NH OBn O-benzyl-N-((3R,6S)-6-(((tert-butyldimethylsilyl)oxy) methyl)piperidin-3-yl)hydroxylamine

Here, we report the use oflipase catalyticresolution as a central step to construct ethyl (2S,5R)-5-((benzyloxy)amino) piperidine-2-carboxylate, the key intermediate of avibactam (Scheme 2). Scheme 2.Use of Lipase Catalytic Resolution to Construct the Avibactam Key Intermediate HO

HO HCl N

N H

1) Rh/C , H2

CO2Et

4

2) lipase catalytic resolution

2

CO2Et

+ HO N H

4'

RESULTS AND DISCUSSION


CO2H

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In this study, we developed an optimized approach to synthesize avibactam based on previously published protocols were

made:

first,

12-16

the

(Scheme 3, route D). Two fundamental changes commercially

available

and

affordable

ethyl-5-hydroxypicolinatehydrochloridewas used as the starting material, which avoids the Complex construction process of piperidine ringused in previously reported routes; second, a novel lipase-catalyzed resolution step was used to synthesize (2S,5S)-ethyl 5-hydroxypiperidine-2-carboxylate (4), the valuable precursor of the key intermediate ethyl (2S,5R)-5-((benzyloxy)amino) piperidine-2-carboxylate (7).

Scheme 3. Route D: Our Approach to the Synthesis of Avibactam Route D HO

HO N

2

Rh/C H2 EtOH

HCl CO2Et

HCl N H

CO2Et

3

OBn HN

7

CO2Et

Toluene

N H

Phosphate solution

CO2Et

4

O

O H2N

NH3,MeOH H2N N H

HO

Lipozyme CALB

HN

9

NH OBn

N O

1

N

OSO3Na

To start, ethyl 5-hydroxypicolinatehydrochloride (2) was converted into ethyl 5-hydroxypiperidine-2-carboxylatehydrochloride

(3;cis/trans

=

97:3)

via

a

hydrogenation reaction in ethanol. Trans isomers can be easily removed by reslurrying in ethyl acetate at 35 ℃ and isolation by filtration.Next, we screened a series of lipases for one suitable

to catalyze the resolution of (2S,5S)-ethyl

5-hydroxypiperidine-2-carboxylate(4) from compound 3 (Table 1). When porcine pancreas lipase, porcine liver esterase, lipase AS “Amano” lipase AK “Amano”, and lipase PS “Amano” SD were separately used to catalyze this reaction, we were unable to detect any formation of the target product in each case. (entry 1–entry 5). However, when Chiralzyme IM-100 lipase and Lipozyme CALB were screened as potential catalysts, we detected formation of 4 (entries 6 and 7). Further investigation revealed that crude 3 underwent Chiralzyme IM-100 lipase and Lipozyme CALB17-catalyzed resolution to yield enantiomerically pure compound 4 with a diastereomeric ratio (dr) of ≥99:1. Although Chiralzyme IM-100 lipase and Lipozyme CALB gave equivalent



Page 8 of 22

products and yields, we selected Lipozyme CALB as the catalyst, because it was difficult to remove the Chiralzyme IM-100 lipase from the system following the completion of the reaction.

Table 1 Screening of a Series of Lipases for the Lipase-Catalyzed Resolution Step HO HCl N H

lipase

HO (S)

CO2Et

HO (R) (S) CO2Et

N H

3

+

4

N H

(R) CO2H

4'

entry

lipase

solventa

Time

Yieldb

1

Porcine pancreas

isopropyl ether solution

24h

none


24h

none

lipase 2

Porcine liver esterase

3

Lipase AS “Amano”


24h

none

4

Lipase AK “Amano”


24h

none

5

Lipase PS “Amano”


24h

none


24h

30%


24h

34%

SD 6

Chiralzyme IM-100 lipase

7 a

Lypozyme CALB

isopropyl ether solution: isopropyl ether:water (99.5:0.5, v/v). bYield after purification with silica gel

chromatography.

To optimize the Lipozyme CALB-catalyzed resolution step, we then investigated the effect of a range of pH values on the reaction (Table 2)17. We found that compound 3 was almost completely hydrolyzed at pH 8 or pH 10 (entry 1, 2). However, we were able to detect product 4 at lower pH values (pH 7.5, pH 7, and pH 6.8) following 12h


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incubation (entries 3, 4, and 5, respectively), with the highest yield of 4 obtained at pH 6.8. When the reaction buffer was below pH 6.8, the reaction progressed very slowly, and a longer incubation time (up to 30 h) was required to obtain a satisfactory product yield. Additionally, in buffer solutions below pH 7,Lipozyme CALB is efficient

to

identify

its

substrate:

we

obtained

(2S,5S)-ethyl

5-hydroxypiperidine-2-carboxylate(4) with nearly 100% chiral purity as the R,R configuration was almost completely hydrolyzed.

Table 2 Optimization of pH Conditions for theLipozyme CALB-catalyzed Resolution Step HO HCl N H

Lypozyme CALB

HO (S)

CO2Et KH2PO4 Buffer

(S) CO2Et

N H

3

+

N H

4

entry 1 2 3 4 5 a

HO (R)

PH 10 8 7.5 7 6.8

(R) CO2H

4'

time 12 h 12 h 12 h 12 h 12 h

Yiela Trace Trace 12% 34% 48%

Yield after purification with silica gel chromatography.

Synthesis of the Key Intermediate 7 and Avibactam An efficient and cost-effective synthesis of intermediate 7 was crucial for the viability of our proposed synthetic route (route D). Starting from commercially available ethyl-5-hydroxypicolinatehydrochloride (2) (Scheme 4),compound 3, with an isomeric ratio of 97:3 (cis/trans), was synthesized via a hydrogenation reaction.Trans isomers can be easily removed by reslurrying in ethyl acetate at 35℃ and isolation by filtration23. the pure product 3 underwent lipase (Lipozyme CALB17)-catalyzed resolution to yield compound 4 as a single enantiomer with dr ≥99:1, together with the side product 4' 11b. Subsequently, a mixture of di-tert-butyl carbonate (Boc2O) and triethylamine was added dropwise to the aqueous solution of 4 and 4', and the mixture



was

stirred

at

room

temperature

for

Page 10 of 22

18h

to

(2S,5S)-1-tert-butyl-2-ethyl-5-hydroxy-piperidine-1,2-dicarboxylate(5)

form

and

the

byproduct 5'11b. As compound 5' is water-soluble, it was easy to yield the pure product 5 by extraction with EtOAc. Overall, compound 5 was obtained using relatively environment-friendly methods and the average total yield for the three-step process was 42.9%. Next, compound 5 was dissolved in acetonitrile and stirred at −30°C for 30 min, followed by the successive dropwise addition of 2,6-dimethylpyridine and trifluoromethanesulfonic anhydride. A solution of O-benzylhydroxylamine in 2,6-dimethylpyridine was subsequently added and the mixture was stirred at room temperature for 12h to yield compound 6. The key intermediate 7 was prepared by treating compound 6 with trifluoroacetic acid to remove the tert-butyloxycarbonyl (Boc) protecting group. The total yield for the final two steps was 75.2%.

Scheme 4. Synthesis of the Key Intermediate 7 HO

HO

Rh/C , H2

N

HCl reslurrying in EA CO2Et

N H

HO

N H

(S) CO2Et

OBn (R) HN 1) Tf 2O, 2,6-Dimethylpyridine 2)

NH2OBn, CH3CN

5 total yield for the three steps: 42.9% HO

HO (R)

+ (R) N Boc

(R) CO2

5' water soluble

+

N H

4 (a single enantiomer, dr >99 :1)

(S) (S) N CO2Et Boc

THF

HO (S)

3

2

(Boc)2O, TEA

Lipozyme CALB HCl CO2Et Phosphate solution

(S)

TFA

N CO2Et Boc

DCM

6

(R) CO2H

4'

OBn(R) HN N H 7

(S) CO2Et

the yield for the last two steps : 75.2%

H N

Route D

Finally, we use compound 7 as the key intermediate to complete the synthesis of avibactam. Because subsequent reactions are relatively simple and do not involve the construction of complex chiral centers. So we synthesized avibactam on the basis of previously published routes12,

14–16, 19, 21

and refered to the detailed experiments


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reported by Michael Golden et al22(Scheme 5). That is, Amminolysis of esters (compound 7) with NH3 in MeOH leads to amide (compound 8) ,which upon protection with Fmoc-Cl in the presence of DIEA in chlorobenzene, followed by cyclization of the piperidine with CDI and subsequent deprotection with Et2NH affords bicyclic compound 9. simultaneous debenzylation and sulfonylation of compound 9 with H2 over Pd/C and SO3-Me3N in the presence of Et3N in i-PrOH/H2O. Treatment of sulfonic acid (compund10) with Bu4NOAc, gives rise to the corresponding quaternary ammonium salts (compound 11) which upon sodium exchange reaction with BuCH(Et)COONa in EtOH/H2Ofurnishes the target avibactam sodium. Thus,An efficient synthesis of pure, crystalline avibactam was completed in 10 steps with a 23.9% overall yield from 5-hydroxypicolinatehydrochloride (2). This route was efficient, cost-effective, used environment-friendly reagents, and we were able to successfully perform the synthesis on a 400-gram scale. Scheme 5. Conversion of 7 to Avibactam (1)

N H

O

O (S)

OBn (R) HN

96.5% yield

(S) CO2Et

H2N HN

NH3, MeOH Toluene

8

7

O

(R)

N

1) FMOC-Cl,DIPEA,PhCl 2) CDI 3) Diethylamine 4) HCl (aq)

N

O

9

N

(R) N

O O S 10 O OH

1)nBu4NOAc 2) Swap to MIBK

aq IPA,NEt3

O (S) H2N

H2N

(R)

N O

H2,Pd/C, SO3.NMe3

OBn

O (S)

(S)

H2N O

(R) NH OBn

(S)

H2N

89.0% yield

N

O 11 O S OO Bu N+

H2O/EtOH

(R)

N

Sodium 2-ethylhexanoate O

N

O O S O 1 O- Na+ yield 96.2%

4

yield 89.6%

CONCLUSION In summary, we have developed an efficient and cost-effective process for the synthesis of avibactam (1) from commercially available and affordable ethyl 5-hydroxypicolinatehydrochloride (2). A lipase-catalyzed (Lipozyme CALB) step to achieve kinetic resolution of (2S,5S)-5-hydroxypiperidine-2-carboxylate acid (4), the valuable precursor of the key intermediate ethyl (2S,5R)-5-((benzyloxy)amino)



Page 12 of 22

piperidine-2-carboxylate (7) was successfully accomplished, and this reaction achieved excellent stereoselectivity. Finally, we finished the synthesis of avibactam from 7 based on previously published protocols. This enzyme resolution method not only provides us a rapid ,mild, and efficient synthesis of avibactam , but also provides a potential tool for rapidly building a family of chiral piperidine-2-carboxylate with other substituting groups. EXPERIMENTAL SECTION General. Unless otherwise mentioned, all commercial reagents and solvents were used directly as purchased. Flash chromatography was performed using silica gel with petroleum ether/ethyl acetate or dichloromethane/methanol as the eluent. Melting points were uncorrected. Optical rotations were measured with a sodium lamp. NMR spectra were recorded on a spectrometer at 500 MHz (1H NMR), 101 MHz or 126 MHz (13C NMR). Mass spectrometry data were recorded on a high-resolution mass spectrometer in the electrospray ionization (ESI) mode. Chemical shifts (δ) are reported in parts per million and referenced to the residual solvent peak, and J values are given in hertz (Hz).

Preparation of ethyl 5-hydroxypiperidine-2-carboxylatehydrochloride (3) Rh/C

(25.0

g,

10%)

was

added

to

a

mixture

of

ethyl-5-hydroxypicolinatehydrochloride(2) (250.0 g, 1.496 mol) and ethanol(1.5 L) in a vessel. The reaction mixture was stirred under the atmosphere of hydrogen (200.0 psi) at room temperaturefor 12h until completion of the reaction (by TLC analysis). Then, the mixture was filtered and the solvent was removed under reduced pressure to obtain the crude product, The reaction mass was treated with ethyl acetate (1.00 L) at 35 ℃ which leads to precipitation of the solid. The precipitated solid was filtered, washed

with

the

ethyl

acetate

and

dried

in

oven

to

give

ethyl5-hydroxypiperidine-2-carboxylate hydrochloride (3) (253.0 g,94%).1H NMR (500 MHz, DMSO) δ 5.37 (d, J = 2.5 Hz, 1H), 4.22 (dq, J = 7.0,1.0 Hz, 2H), 4.10 (dd, J = 9.5, 4.5 Hz, 1H), 3.94 (s, 1H), 3.11– 3.08 (m, 2H), 2.00 – 1.94 (m, 2H), 1.76 – 1.67 (m, 2H), 1.25 (t, J = 7.0 Hz, 1H),. 13C NMR (126 MHz, DMSO) δ 168.05 (s),


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61.72(s), 60.60 (s), 54.59 (s), 48.04 (s),28.32 (s), 20.08 (s), 13.89 (s).IR (cm−1): 3397, 2959,1747, 1415, 1374, 1169, 1135, 1077, 1031. MS (ESI) m/z: 174.1 [M + H]+ Preparation of (2S, 5S)-ethyl 5-hydroxypiperidine-2-carboxylate (4) Ethyl 5-hydroxypiperidine-2-carboxylate hydrochloride3 (253.0 g, 1.460 mol) was dissolved in a potassium phosphate buffer solution(8.53 L, 0.1 M, pH = 8). The pH of the solution was adjusted to 6.8 with dipotassium hydrogen phosphate followed by the addition ofLipozyme CALB (253.0 g, 5000 LU/g ). The reaction mixturewas stirred at room temperature for 12 h until completion of the reaction (chiral HPLC,detected by BOC derivatization of 4 ). The aqueous solution of 4 (8.53 L) was obtained by filtration

and directly used for the next step. Preparation of (2S, 5S)-1-tert-butyl-2-ethyl-5-hydroxypiperidine-1,2-dicarboxylate (5) Triethylamine(407 mL, 2.92mol) wasadded to a mixture of the aqueous solution of 4 (8.53 L) and THF(8.00 L) at room temperature. Then (Boc)2O(101.0 g,1.752 mol) was added dropwise to the mixture at 0oC. The reaction mixture was stirred at room temperature for 18 h until completion of the reaction (by TLC analysis). Then, the reaction mixture was extracted three times with ethyl acetate (3.00 L × 3). The by-product 5' is water-soluble and remained in the aqueous solution. The combined organic layers were dried over anhydrous MgSO4. Evaporation of the solvent under vacuum, followed by flash column chromatography on silica gel(petroleum ether/ethyl acetate = 4/1), gave the corresponding product 5, as a pale yellow liquid 1 (74.73g, the two step total yields :42.9%), [α]20 D = −101.59 (c = 0.62, CHCl3); H NMR

(500 MHz, CDCl3) δ 4.73 (d, J = 87.9 Hz, 1H), 4.21 (s, 2H), 4.10 (d, J = 9.0 Hz, 1H), 3.64 (s, 1H), 2.72 (dt, J = 50.3, 11.5 Hz, 1H), 2.29 (s, 1H), 1.98 (d, J = 10.3 Hz, 1H), 1.81 – 1.67 (m, 1H), 1.64 (s, 1H), 1.60 (s, 1H), 1.46 (d, J = 17.5 Hz, 9H), 1.28 (t, J = 6.9 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 171.47 (s), 155.55 (s), 80.55 (s), 66.57 (d, J = 22.1 Hz), 61.27 (s), 53.35 (d, J = 119.3 Hz), 48.00 (d, J = 84.9 Hz), 30.12 (d, J = 58.6 Hz), 28.29 (s), 24.91 (d, J = 22.5 Hz), 14.22 (s).IR (cm−1): 2979, 1741, 1699, 1403, 1370, 1149, 1073, 1024.MS (ESI) m/z: 296.1[M+Na]+ Preparation of (2S, 5R)-1-tert-butyl-2-ethyl 5-((benzyloxy)amino) piperidine-1, 2-



dicarboxylate (6) 2, 6-dimethylpyridine (95.0 mL, 805.0 mmol) and Tf2O (131 mL, 778 mmol) wereadded successively, dropwise, to a mixture of 5 (202.0 g, 741.0 mmol) in CH3CN (2.00L) at -30 oC, and the reaction mixture was stirred at this temperature for 15 min.NH2OBn and 2, 6-dimethylpyridine (95 mL , 805.0 mmol) was slowly added to the reaction solution at -30 oC. Then, the reaction mixture was stirred at 0oC for 30 min and at room temperature for 12 h. The reaction mixture was extracted with ethyl acetate (600 mL × 3), and the combined organic layers were dried over anhydrous MgSO4. Evaporation of the solvent under vacuum gave the corresponding crude product 6 (280.2 g).The crude product 6 was directly used to next step without further purification.The pure product 6 is a white solid, m.p. 122.3−125.2 °C; [α]20 D = −81.59 (c = 0.63, CHCl3);1H NMR (500 MHz, CDCl3) δ 7.39 – 7.32 (m, 4H), 7.32 – 7.27 (m, 1H), 5.47 (s, 1H), 4.72 (dd, J = 25.9, 11.5 Hz, 3H), 4.19 (dd, J = 14.0, 7.0 Hz, 3H), 3.14 (t, J = 36.2 Hz, 2H), 1.96 (s, 2H), 1.69 (d, J = 13.9 Hz, 1H), 1.46 (s, 10H), 1.29 – 1.24 (m, 3H).13C NMR (126 MHz, CDCl3) δ 137.92 (s), 128.53 (s), 128.37 (s), 127.80 (s),80.19 (s), 76.66 (s), 61.07 (s), 53.68 (s),53.26 (s), 42.76 (s), 28.37 (s), 22.98 (s), 21.26 (s), 14.28 (s). IR (cm−1): 3242, 2947, 1738, 1674, 1427, 1152, 1195, 1030,701.MS (ESI) m/z: 379.2 [M+H]+ Preperation of ethyl (2S, 5R)-5-((benzyloxy) amino) piperidine-2-carboxylate (7) Trifluoroacetate acid (124.0 mL, 1.665 mol) was added dropwise to the solution of the crude product 6 (280.2 g) in CH2Cl2 (1.50 L) at 0 oC. The mixture was stirred at r.t.for 15h. The pH of reaction solution was adjusted to 10 with saturated sodium bicarbonate solution. Then, the reaction mixture was extracted with DCM (600 mL × 3), and the combined organic layers were dried over anhydrous MgSO4. Evaporation of the solvent under vacuum, followed by flash column chromatography on silica gel(DCM/MeOH = 20/1)), gave the corresponding crude product 7,as a pale yellow 1 liquid(155.4g, the two step total yields :75.2% ),[α]20 D = -10.40 (c = 0.92, CHCl3); H

NMR (500 MHz, CDCl3) δ 7.41 – 7.32 (m, 4H), 7.33 – 7.21 (m, 1H), 4.89 – 4.42 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.38 (ddd, J = 11.9, 4.0, 1.8 Hz, 1H), 3.27 (dd, J = 11.0, 3.1 Hz, 1H), 2.99 (tt, J = 10.5, 4.0 Hz, 1H), 2.44 (dd, J = 11.9, 9.8 Hz, 1H), 2.07 (ddd,


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J = 17.0, 8.5, 4.6 Hz, 1H), 2.01 – 1.89 (m, 1H), 1.53 (tdd, J = 13.0, 11.1, 3.8 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ173.07 (s), 137.78 (s), 128.37 (s), 127.84 (s), 76.78 (s), 60.84 (s),58.41 (s), 57.10 (s), 49.44 (s), 28.10 (s), 28.01 (s), 14.20 (s).IR (cm−1): 3270, 2930, 1736, 1453, 1191, 1033, 746, 695. MS (ESI) m/z: 279.0 [M + H]+. Preperation of (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxamide (8) Ethyl(2S, 5R)-5-((benzyloxy) amino) piperidine-2-carboxylate7(593.0g, 2.130 mol) was mixed with a solution of 7M ammonia in methanol (2.00 L).The reaction mixture was stirred at r.t for 8 h until completion of the reaction (by TLC analysis). The solid was removed by filtration andthe obtained cake was washed withmethanol (2 x 500mL). The filtrateswerecombined and concentrated under vacuum to 1.50 L (Cautiouly, warming from 0oC) followed by the addition of toluene (3.00 L). This operation is repeated twice in succession. The obtained solution was stirred at 80 oC for 0.5 h.Thenit was cooled to 0oC. The crude product 9precipitated and was obtained by filtration and washed with methyl tert-butyl ether(1.00 L× 3) and dried in vacuum to give the pure 8as a white solid (510.1 g, 96.5%),m.p. 148.2−150.9 °C; [α]20 D = −19.20. (c = 0.36, CHCl3);1H NMR (400 MHz, DMSO) δ 7.58 – 7.17 (m, 5H), 7.10 (s, 1H), 6.92 (s, 1H), 6.48 (d, J = 6.0 Hz, 1H), 4.57 (s, 2H), 3.13 (dd, J = 11.9, 2.4 Hz, 1H), 2.87 (dd, J = 11.0, 2.7 Hz, 1H), 2.81 – 2.68 (m, 1H), 2.21 (dd, J = 11.8, 10.2 Hz, 1H), 1.88 – 1.76 (m, 2H), 1.34 – 1.20 (m, 1H), 1.11 (ddd, J = 17.5, 12.9, 4.0 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 176.31 (s), 137.69 (s), 128.45 (s), 128.43 (s), 127.94 (s), 76.90 (s), 59.74 (s), 57.01 (s), 49.25 (s), 28.17 (s), 27.76 (s).IR (cm−1): 3378, 2946, 1624, 1438, 1323, 1122, 824, 698. MS (ESI) m/z: 250.2 [M + H]+. Preperation

of

(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-

carboxamide (9) (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide 8 (510.1 g, 2.045 mol) was mixed with di-isopropylethylamine (381 mL, 2.188mol) and chlorobenzene (3.00 L) at 20 °C. The solution of 9-Fluorenylmethyl chloroformate (540.2 g, 2.086mol) in chlorobenzene (3.10 L) was added to the reaction mixture.The mixture was stirred at 30 °C until completion of the reaction. Then carbonyl diimidazole (331.3 g, 2.658



mol,dropwisely) was added and agitation was continued at 15 °Cfor 11 h until completion of the reation. Diethylamine (529 mL , 5.112 mol) was added and agitation was continued at r.t. for 2 h Aqueous 3 M hydrochloric acid (3.20L, 9.600 mol) was added (to achieve a pH of 2 to 6) and the mixture was cooled to 0 °C. The solid was isolated by filtration, washed with water (1.50 L × 2.0) and 1-chlorobutane (1.50 L × 2.0), and dried to give the title compound as a white crystalline solid (495.0 1 g, 89%), m.p. 154.2−156.1 °C; [α]20 D = −23.57 (c = 0.65, CHCl3); H NMR (400

MHz, DMSO) δ 7.45 (dd, J = 7.8, 1.6 Hz, 2H), 7.43 – 7.33 (m, 4H), 7.30 (s, 1H), 4.93 (q, J = 11.3 Hz, 2H), 3.69 (d, J = 6.9 Hz, 1H), 3.62 (s, 1H), 2.90 (s, 2H), 2.22 – 1.94 (m, 1H), 1.93 – 1.76 (m, 1H), 1.75 – 1.50 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 172.27 (s), 167.70 (s), 135.60 (s), 129.24 (s), 128.84 (s), 128.59 (s), 78.30 (s), 59.18 (d, J = 253.0 Hz), 57.92 (s), 47.80 (s), 20.86 (s), 17.31 (s). IR (cm−1): 3406, 2991, 1761, 1663, 1455, 1386, 1022, 755. MS (ESI) m/z: 298.1[M + Na]+. Preparation of Tetrabutylammonium [(2S, 5R)-2-Carbamoyl-7-oxo-1, 6-diazabicyclo[3.2.1]octan-6-yl] Sulfate (11) (2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide9(495.0 g, 1.792mol) was mixed with sulfur trioxide trimethylamine complex (301.0 g, 2.150 mol), triethylamine (65 mL, 890 mmol), 10%w/w Pd/C (40 g, 0.025 wt), isopropanol (2.50L), and water (2.50 L). This mixture was then held in a hydrogenation vessel and flushed with nitrogen at ambient pressure. Hydrogen was then fed into the vessel at 0.4 mol equiv per hour until the debenzylation reaction was completed. The catalyst was removed by filtration and washed with water. The combined filtrates were washed with n-butyl acetate (2.00 L). A solution of tetrabutylammonium acetate (812.0 g, 2.698 mol), acetic acid (11 g, 180 mmol) in water (1.00 L) was prepared. 72% of the tetrabutylammonium acetate solution was added to the reaction mixture, which was then extracted with DCM (2.00 L). The remaining 28% of the tetrabutylammonium acetate solution was added to the reaction mixture which was then extracted with DCM (1.50 L). The organic extracts were combined and concentrated to 1.50 L followed by the addition of 4-methyl-2-pentanone (1.25 L). The reaction mixture was cooled to 0 °C to precipitate the desired product


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13.Compound 13 was collected by filtration and washed with 4-methyl-2-pentanone (1.00 L), and was dried to yield a white crystalline solid 11 (814.0 g, 1 89.6%),m.p.180.3−182.4 °C (decomposition); [α]20 D = −23.20 (c = 0.57, CHCl3); H

NMR (500 MHz, DMSO) δ 7.36 (d, J = 78.9 Hz, 1H), 3.98 (s, 1H), 3.68 (d, J = 6.6 Hz, 1H), 3.33 (s, 1H), 3.27 – 3.12 (m, 4H), 3.01 (d, J = 11.6 Hz, 1H), 2.92 (d, J = 11.7 Hz, 1H), 2.14 – 1.97 (m, 1H), 1.84 (d, J = 6.0 Hz, 1H), 1.66 – 1.47 (m, 5H), 1.44 – 1.18 (m, 4H), 0.94 (t, J = 7.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.29 (s), 166.04 (s), 60.52 (s), 58.69 (s), 57.86 (s), 48.13 (s), 23.95 (s), 20.78 (s), 19.71 (s), 17.24 (s), 13.68 (s).IR (cm−1): 3474, 2964, 1761, 1694, 1488, 1272, 1007, 612.MS (ESI) m/z: 288.0[M + Na]+. Preparation of Avibactam Sodium Salt (1) A solution of sodium 2-ethyl hexanoate (475.0 g, 2.850 mol) in ethanol (2.00 L) was added

to

a

solution

of

tetrabutylammonium

[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo-[3.2.1]octan-6-yl] sulfate 11 (723.0 g) in ethanol (2.50L) and water (50 mL ) over approximately 1 h and the temperature was maintained at r.t. The reaction

mixture was held for 2 h. The product was

filtered, washed with ethanol (2 × 2.00L), and dried to yield a white crystalline solid 1(395.0 g, 96.2%),m.p.259.1−262.4 °C(decomposition); [α]20 D = −46.40 (c = 0.79, MeOH/H2O = 1/1); 1H NMR (500 MHz, D2O) δ 4.15 (dd, J = 5.8, 2.8 Hz, 1H), 4.01 (d, J = 7.5 Hz, 1H), 3.28 (d, J = 12.2 Hz, 1H), 3.06 (d, J = 12.2 Hz, 1H), 2.23 – 2.09 (m, 1H), 2.06 – 1.96 (m, 1H), 1.94 – 1.82 (m, 1H), 1.81 – 1.69 (m, 1H). 13C NMR (126 MHz, D2O) δ 174.72 (s), 169.53 (s), 60.43 (s), 59.93 (s), 47.33 (s), 20.03 (s), 18.31 (s).IR (cm−1): 3459, 1749, 1675, 1361, 1270, 1013, 857, 768. MS (ESI) m/z: 279.0 [M + H]+.

AUTHOR INFORMATION Corresponding Athours *Guo-fengWu

E-mail:[email protected]

*Xin-zhi Chen E-mail:[email protected] ACKNOWLEDGMENT



Page 18 of 22

The authors would like to thank the Research ＆ Development Center, Zhejiang Medicine CO. and Zhejiang University. The research was supported in part by the Postdoctoral Advanced Programs of Zhejiang Province(No. BSH201673) Supporting Information Available.The Supporting Information is available free of charge on the ACS Publications website. Chiral HPLC Report of Compound 5(PDF) Chiral HPLC Report of Compound 7 (PDF) Copies of the1H and 13C NMR spectra of compounds (PDF)

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Process. Res. Dev. 2016, 20(10), 1799-1805. 23)In the process of amplification, we found that under the conditions of enzyme resolution, the crude product containing 3% trans-isomer had no effect on our resolution and no trans-isomer was detected in the resolved product. For the reason, we suspect that the first possibility is that the lipase is unrecognizable to the trans isomers and completely hydrolyzed in buffer solution. Another possibility is that the enzyme can also recognize the trans-isomer. Half of this was hydrolyzed, leaving about 1.5% of the isomers, which, due to their low content, gradually hydrolyzes in our buffer solution as the reaction time increases. This is consistent with the reduction in yield of our main product if it is not treated for a long time during the resolution process.


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Use of Lipase Catalytic Resolution in the ... - ACS Publications

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