[ CAS No. 1239908-20-3 ] {[proInfo.proName]}

Name: 1239908-20-3|(R)-2,2'-(2-(1-(2-(2,5-Dichlorobenzamido)acetamido)-3-methylbutyl)-5-oxo-1,3,2-dioxaborolane-4,4-diyl)diacetic acid|98%
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SKU: A183051
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Quality Control of [ 1239908-20-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1239908-20-3 ]

Product Details of [ 1239908-20-3 ]

CAS No. :	1239908-20-3	MDL No. :	MFCD29767859
Formula :	C₂₀H₂₃BCl₂N₂O₉	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MBOMYENWWXQSNW-AWEZNQCLSA-N
M.W :	517.12	Pubchem ID :	56844015
Synonyms :	MLN9708;Ninlaro	Chemical Name :	(R)-2,2'-(2-(1-(2-(2,5-Dichlorobenzamido)acetamido)-3-methylbutyl)-5-oxo-1,3,2-dioxaborolane-4,4-diyl)diacetic acid

Calculated chemistry of [ 1239908-20-3 ]

Physicochemical Properties

Num. heavy atoms :	34
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.45
Num. rotatable bonds :	13
Num. H-bond acceptors :	9.0
Num. H-bond donors :	4.0
Molar Refractivity :	120.79
TPSA :	168.33 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.85 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.26
Log Po/w (WLOGP) :	1.54
Log Po/w (MLOGP) :	0.53
Log Po/w (SILICOS-IT) :	1.33
Consensus Log Po/w :	1.13

Druglikeness

Lipinski :	2.0
Ghose :	None
Veber :	2.0
Egan :	1.0
Muegge :	1.0
Bioavailability Score :	0.11

Water Solubility

Log S (ESOL) :	-3.74
Solubility :	0.0936 mg/ml ; 0.000181 mol/l
Class :	Soluble
Log S (Ali) :	-5.43
Solubility :	0.00192 mg/ml ; 0.0000037 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.62
Solubility :	0.0124 mg/ml ; 0.0000239 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	4.06

Safety of [ 1239908-20-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1239908-20-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1239908-20-3 ]

[ 1239908-20-3 ] Synthesis Path-Downstream 1~29

1
[ CAS Unavailable ]
[ 77-92-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With boric acid In acetone at 20℃; for 22h;	3 Synthesis of ixazomib citrate 3.00 g (6.06 mmol) of 2,5-dichloro-N-[2-({( R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5- trimethyihexahydro-4,6-methano-1 ,3,2-benzodioxaborol-2-yl]butyl}amino)-2- oxoethy]benzamide of formula V, 0.41 g (6.67 mmol) of boric acid and 1.28 g (6.67 mmo) of citric acid are weighed into a flask. The mixture is stirred in 15 ml of acetone at the room temperature for 22 h. 50 ml of ethyl acetate is added to the mixture. After removal of a part of the solvent (15 ml) by distillation and spontaneous cooling of the reaction mixture, Ixazomib citrate of formula I is obtained by aspiration. After drying in a vacuum drier (16 h at 40°C) the yield of the reaction is 91 % and HPLC purity of the product is 98.9%. 1H NMR (DMSO, 500.13 MHz, 25°C): 12.15 (br.s., 2H), 10.71 (br.s., 1 H), 9.13 (t, 1 H, J - 5.7 Hz), 7.66 (s, 1H), 7.57 (d, 2H, J = 1.4 Hz), 4.27 (br, 2H), 2.92 - 2.87 (m, 1H), 2.77 - 2.73 (m, 1 H), 2.66 - 2.59 (m, 1H), 2.53 (br, 2H), 1.69 (br, 1H), 1.38 - 1.18 (m, 2H), 0.88 (d, 6H, J = 6.4 Hz); 1H NMR (DMSO, 250.13 MHz, 80 °C): 10.29 (br.s., 1H), 8.82 (t, 1 H, J = 5.7 Hz), 7.62 (t, 1H, J = 1.5 Hz), 7.53 (d, 2H, J = 1.5 Hz), 4.27 (d, 2H, J - 5.6 Hz), 2.76 - 2.62 (m, 5H), 1.79 - 1.63 (m, 1H), 1.44 - 1.20 (m, 2H), 0.897 (d, 3H, J = 6.5 Hz), 0.892 (d, 3H, J - 6.4 Hz); The XRPD pattern is shown in Fig. , the characteristics peaks are presented in Table 1. We refer to this novel form of Ixazomib citrate as Form 3; The DSC record contains an endotherm that corresponds to the melting point Tonset= 22.2°C. The record is shown in Fig. 2 in the Appendix; The TGA record indicates a weight loss in the temperature range of 20 to 200°C of about 1.3%. The record is shown in Fig. 3 in the Appendix.
84%	In ethyl acetate at 50 - 70℃; for 24h;	2.2 Step 2: Citric acid (6.4 g, 33 mM, 1.2 eq)Was dissolved in 70 ° C ethyl acetate (400 mL)Then add the product on the step,After stirring at 50 ° C for 24 hours,Cooled to room temperature, filtered, washed with ethyl acetate,Dried to give the desired product 11.9g, yield 84%Its purity was 97.4% by HPLC.
1908 g	With hydrogenchloride In water; acetone at 45 - 50℃; for 4.5h; Large scale;	6 Example 6. Preparation of form 2 of Ixazomib Citrate having high levels of residual solvents A double jacket glass reactor was charged with 2,5-dichloro-N-[2- [[(1 R)- 1 -[(3aS,4S,6S,7aR)-hexahydro-3 a,5,5-trimethyl-4,6-methano-1 ,3,2-benzodioxaborol-2-ylj-3-methylbutylj aminoj-2-oxoethylj benzamide (2000 g), citric acid monohydrate (1103 g), conc. aqueous HC1 (51 mL) and acetone (20 L). Obtained solution was warmed to about 45 °C and stirred at 45 - 50 °C for about 4.5 hours. The solution was concentrated under reduced pressure (about 30 kPa, process temperature 25 - 40 °C, internal temperature about 55 °C) to about one third of the original volume (about 7 L) and the residue was diluted with ethyl acetate (10 L). Obtained mixture was concentrated to about 10 L and diluted again with ethyl acetate (10 L). Obtained mixture was concentrated to about 16 L and diluted again with ethyl acetate (14.8 L). Obtained mixture was concentrated to about 23 L and then it was warmed to 45 -50 °C. After about 2 hours treatment at 45 - 50 °C, the mixture was cooled to about 25 °C during about 1.5 hour and stirred at about 25 °C for additional 1 hour. Insoluble solid was separated by filtration, washed with ethyl acetate (3 x 5 L) and dried in vacuum oven at temperature about 50 °C and pressure below 100 mbars to give Ixazomib citrate Form 2 (1908 g, 727 ppm of acetone, 1 % of ethyl acetate), as identified by XRPD.

5.3 g

With Dihydroxy-isobutyl-boran In methanol; toluene at 25 - 75℃; for 5h;

3 Example-3: Preparation of Ixazomib citrate. The compound of formula-V (10 gms) was added to toluene (150 ml) at 25-30°C. Methanol (50 ml) was added to the reaction mixture at 25-30°C. Isobutyl boronic acid (2.47 gms) and citric acid (4.65 gms) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 70-75°C and filtered the reaction mixture through hiflow bed, washed with methanol. Stined the obtained filtrate for 5 hours at 70-75°C. Distilled off the solvent completely from the reaction mixture under reduced pressure, co-distilled with methanol and again co-distilled with ethyl acetate. Ethyl acetate (100 ml) was added to the obtained compound at 25-30°C and stined for 3 hours at same temperature. Filtered the precipitated solid, washed with ethyl acetate and then dried to afford the title compound. (Yield: 5.3 gms).

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2016/155684, 2016, A1 Location in patent: Page/Page column 4; 9; 10
[2]Current Patent Assignee: CHENGDU BEISIKAIRUI BIOTECHNOLOGY - CN106986884, 2017, A Location in patent: Paragraph 0052; 0054
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/222819, 2017, A2 Location in patent: Paragraph 00141; 00146; 00147; 00148; 00149
[4]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/173071, 2018, A1 Location in patent: Page/Page column 17

2
[ 2020087-10-7 ]
[ 77-92-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	In ethyl acetate at 50℃; for 24h;	1.4 Step 4: (R) -2,2'- (2- (1- (2- (2,5-Dichlorobenzamido) acetamido) -3-methylbutyl) 1,3,2-dioxaborolane-4,4-dicarboxylic acid) diacetic acid Citric acid (58 g, 302 mM, 1.2 eq)Was dissolved in ethyl acetate (2 L) at 70 ° C,After adding 111 g (252 mM) of the product from Step 3,After stirring at 50 ° C for 24 hours,Cooled to room temperature, filtered, washed with ethyl acetate,Dried to give the desired product 120g, yield 93%, by HPLC, purity greater than 99%
85%	In ethyl acetate at 70℃; for 0.5h;	4.4.1-4.4.6 preparation example 4.6: anhydrous citric acid (3.97 g, 20.7mmol) was added into 30 mL of ethyl acetate, heat at 70 °C; dissolve C (8.72 g, 19.7mmol) in 20 mL of ethyl acetate, added the drops of citric acid into ethyl acetate solution. Reacting at 70 ° C for 0.5 hours and then produced a white solid, cool to room temperature and continue to stir the reaction overnight. Filtering, the filter cake was washed with a small amount of ethyl acetate and diethyl ether, drying and then obtained a white solid as final product D 8.63g, yield 85%, and melting point: 208-210 ° C. The nuclear magnetic and mass spectral data are basically the same as in Preparation Example 4.1.
72%	With boric acid In acetone at 20℃; for 20h;	6 Synthesis of ixazomib citrate 224 mg (0.5 mmol) of (R)-2,5-dichloro-N-(2-((3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)amino)-2-oxoethyl)benzamide of formula VIII, 34 mg (1.1 equivalent) of boric acid and 107 mg (1.1 equivalent) of citric acid are weighed into a flask. The mixture is stirred in 1.5 ml of acetone at the room temperature for 20 h. 4.5 ml of ethyl acetate is added to the mixture. After stirring at the room temperature for 3 hours, Ixazomib citrate of formula I is obtained by aspiration. After drying in a vacuum drier (16 h at 40°C) the yield of the reaction is 72% and HPLC purity of the product is 99.5%. The 1H NMR and XRPD records correspond to Form 2 as published in the patent WO 2009/15437.

Reference： [1]Current Patent Assignee: CHENGDU BEISIKAIRUI BIOTECHNOLOGY - CN106986884, 2017, A Location in patent: Paragraph 0037; 0047-0050
[2]Current Patent Assignee: PEKING UNIVERSITY - CN108794520, 2018, A Location in patent: Paragraph 0015; 0069-0088
[3]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2016/155684, 2016, A1 Location in patent: Page/Page column 2; 4; 11

3
[ 2905-61-5 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium hydroxide / Alkaline conditions 2: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 5 °C / Cooling with ice 3: boric acid / acetone / 20 h / 20 °C
	Multi-step reaction with 3 steps 1: sodium hydroxide / Alkaline conditions 2: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 5 °C 3: boric acid / acetone / 22 h / 20 °C
	Multi-step reaction with 3 steps 1.1: sodium hydroxide / water; tetrahydrofuran / 3 h / 0 - 5 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 0.17 h / 0 - 5 °C 2.2: 0.17 h / 0 - 5 °C 2.3: 2 h / 0 - 5 °C 3.1: Dihydroxy-isobutyl-boran / toluene; methanol / 5 h / 25 - 75 °C

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2016/155684, 2016, A1
[2]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2016/155684, 2016, A1
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/173071, 2018, A1

4
[ 667403-46-5 ]
2,2’-{2-[(1R)-1-([(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid [ No CAS ]

Reference： [1]Patent: WO2016/155684,2016,A1
[2]Patent: CN106608883,2017,A
[3]Patent: CN106478701,2017,A
[4]Patent: CN106478701,2017,A
[5]Patent: CN106478701,2017,A
[6]Patent: CN106478701,2017,A
[7]Patent: CN106478701,2017,A
[8]Patent: CN106478701,2017,A
[9]Patent: CN106478701,2017,A
[10]Patent: CN106478701,2017,A
[11]Patent: WO2018/158697,2018,A1
[12]Patent: US10118937,2018,B1

5
[ 1201903-03-8 ]
[ 77-92-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
	In acetone at 25 - 60℃; for 5h;	1 Example 1: Preparation of amorphous ixazomib citrate A solution of citric acid (2.77 g) in acetone (50 mL) was added to a solution of Ν,Ν',Ν"- [boroxin-2,4,6-triyltris[[(lR)-3-methylbutane-l, l-diyl]imino(2-oxoethane-2,l-diyl)]]tris(2,5- dichlorobenzamide) (5 g) in acetone (50 mL) at 30 ± 5 °C. The mixture was heated and maintained at 60 °C for 5 hours. The obtained mixture was distilled under vacuum at 60 °C. Diisopropyl ether (DIPE, 100 mL) was added to the obtained foamy solid and the mixture was distilled to remove the DIPE solvent. This process was repeated once more to yield amorphous ixazomib citrate.

Reference： [1]Current Patent Assignee: VIATRIS INC - WO2017/46815, 2017, A1 Location in patent: Page/Page column 20; 21

6
[ 2020087-10-7 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: ethyl acetate / 12 h / 120 °C 2: hydrogenchloride; water / ethyl acetate / 0.5 h / 20 °C 3: ethyl acetate / 0.5 h / 60 °C
	Multi-step reaction with 2 steps 1: ethyl acetate / 20 °C 2: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 2 steps 1: ethyl acetate / 20 °C 2: formic acid ethyl ester / 20 - 70 °C

Reference： [1]Current Patent Assignee: PEKING UNIVERSITY - CN106608883, 2017, A
[2]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A
[3]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A

7
[ 1072833-77-2 ]
[ 77-92-9 ]
2,2’-{2-[(1R)-1-([(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	In acetone; at 20℃; for 0.5h;	The Txazomib (5 g) was added in a solution of citric acid (2.93 g) in acetone (100 mL) at ambient temperature. The reaction mixture was stirred for 30 minutes andfiltered. The filtrate was stirred for 4-5 hours. The solid was collected by filtration and dried to give <strong>[1072833-77-2]Ixazomib</strong> citrate. (Yield- 95 percent)
	In ethyl acetate; at 60℃; for 0.5h;	Aqueous citric acid (398 mg, 2.07 mmol)Was added to 4 ml of ethyl acetate,Heated to 60 ° C. V (680 mg, 1.88 mmol) was dissolved in 3 ml of ethyl acetate,Was added dropwise to the citric acid in ethyl acetate solution and after reaction for 30 min,Cooled to room temperature,Filter,Ethyl acetate,Dried to a white solid product I,Yield 85-95percent

Reference： [1]Patent: WO2018/158697,2018,A1 .Location in patent: Page/Page column 25; 26
[2]Patent: CN106608883,2017,A .Location in patent: Paragraph 0047; 0061; 0062; 0063

8
[ 50-79-3 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide / dichloromethane / 0.5 h 1.2: 12 h / 20 °C 2.1: lithium hydroxide; water / tetrahydrofuran / 0.5 h / 20 °C 3.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide; N-ethyl-N,N-diisopropylamine / 20 °C 4.1: ethyl acetate / 12 h / 120 °C 5.1: hydrogenchloride; water / ethyl acetate / 0.5 h / 20 °C 6.1: ethyl acetate / 0.5 h / 60 °C
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / tetrahydrofuran / 0 - 20 °C 2: lithium hydroxide; water / 0 - 30 °C 3: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0 - 20 °C 4: ethyl acetate / 24 h / 50 °C
	Multi-step reaction with 5 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / tetrahydrofuran / 0.5 h / 0 °C 1.2: 20 °C 2.1: lithium hydroxide / acetone; water / 0 - 20 °C 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 3.2: 20 °C 4.1: ethyl acetate / 20 °C 5.1: ethyl acetate / 0.33 h / 20 - 70 °C

	Multi-step reaction with 5 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / tetrahydrofuran / 0.5 h / 0 °C 1.2: 20 °C 2.1: lithium hydroxide / acetone; water / 0 - 20 °C 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 3.2: 20 °C 4.1: 20 °C 5.1: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 5 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / tetrahydrofuran / 0.5 h / 0 °C 1.2: 20 °C 2.1: lithium hydroxide / acetone; water / 0 - 20 °C 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 3.2: 20 °C 4.1: 20 °C 5.1: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 5 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / tetrahydrofuran / 0.5 h / 0 °C 1.2: 20 °C 2.1: lithium hydroxide / acetone; water / 0 - 20 °C 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 3.2: 20 °C 4.1: 20 °C 5.1: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 5 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / tetrahydrofuran / 0.5 h / 0 °C 1.2: 20 °C 2.1: lithium hydroxide / acetone; water / 0 - 20 °C 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 3.2: 20 °C 4.1: 20 °C 5.1: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 5 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / tetrahydrofuran / 0.5 h / 0 °C 1.2: 20 °C 2.1: lithium hydroxide / acetone; water / 0 - 20 °C 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 3.2: 20 °C 4.1: 20 °C 5.1: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 5 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / tetrahydrofuran / 0.5 h / 0 °C 1.2: 20 °C 2.1: lithium hydroxide / acetone; water / 0 - 20 °C 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 3.2: 20 °C 4.1: formic acid ethyl ester / 20 °C 5.1: ethyl acetate / 20 - 70 °C
	Multi-step reaction with 5 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / tetrahydrofuran / 0.5 h / 0 °C 1.2: 20 °C 2.1: lithium hydroxide / acetone; water / 0 - 20 °C 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 3.2: 20 °C 4.1: ethyl acetate / 20 °C 5.1: formic acid ethyl ester / 20 - 70 °C
	Multi-step reaction with 6 steps 1: acetonitrile / 1 h / 20 °C / Inert atmosphere 2: sodium hydroxide; water / 1 h / 0 - 10 °C 3: acetonitrile / 20 - 30 °C 4: 1 h / 0 - 10 °C 5: hydrogenchloride / di-isopropyl ether / 5 h / 20 °C 6: acetone / 0.5 h / 20 °C
	Multi-step reaction with 4 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.5 h / 20 °C 1.2: 2 h 2.1: lithium hydroxide / water; tetrahydrofuran / 0.5 h / 20 °C 3.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide / dichloromethane / 0.67 h 3.2: 20 °C 4.1: ethyl acetate / 0.5 h / 70 °C

Reference： [1]Current Patent Assignee: PEKING UNIVERSITY - CN106608883, 2017, A
[2]Current Patent Assignee: CHENGDU BEISIKAIRUI BIOTECHNOLOGY - CN106986884, 2017, A
[3]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A
[4]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A
[5]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A
[6]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A
[7]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A
[8]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A
[9]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A
[10]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A
[11]Current Patent Assignee: FRESENIUS SE & CO. KGAA - WO2018/158697, 2018, A1
[12]Current Patent Assignee: PEKING UNIVERSITY - CN108794520, 2018, A

9
[ 338965-44-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: lithium hydroxide; water / tetrahydrofuran / 0.5 h / 20 °C 2: benzotriazol-1-ol; dicyclohexyl-carbodiimide; N-ethyl-N,N-diisopropylamine / 20 °C 3: ethyl acetate / 12 h / 120 °C 4: hydrogenchloride; water / ethyl acetate / 0.5 h / 20 °C 5: ethyl acetate / 0.5 h / 60 °C
	Multi-step reaction with 3 steps 1: lithium hydroxide; water / 0 - 30 °C 2: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0 - 20 °C 3: ethyl acetate / 24 h / 50 °C
	Multi-step reaction with 4 steps 1.1: lithium hydroxide / acetone; water / 0 - 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 2.2: 20 °C 3.1: ethyl acetate / 20 °C 4.1: ethyl acetate / 0.33 h / 20 - 70 °C

	Multi-step reaction with 4 steps 1.1: lithium hydroxide / acetone; water / 0 - 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 2.2: 20 °C 3.1: 20 °C 4.1: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 4 steps 1.1: lithium hydroxide / acetone; water / 0 - 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 2.2: 20 °C 3.1: 20 °C 4.1: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 4 steps 1.1: lithium hydroxide / acetone; water / 0 - 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 2.2: 20 °C 3.1: 20 °C 4.1: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 4 steps 1.1: lithium hydroxide / acetone; water / 0 - 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 2.2: 20 °C 3.1: 20 °C 4.1: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 4 steps 1.1: lithium hydroxide / acetone; water / 0 - 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 2.2: 20 °C 3.1: 20 °C 4.1: ethyl acetate / 0.33 h / 20 - 70 °C
	Multi-step reaction with 4 steps 1.1: lithium hydroxide / acetone; water / 0 - 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 2.2: 20 °C 3.1: formic acid ethyl ester / 20 °C 4.1: ethyl acetate / 20 - 70 °C
	Multi-step reaction with 4 steps 1.1: lithium hydroxide / acetone; water / 0 - 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 0.5 h / 0 °C 2.2: 20 °C 3.1: ethyl acetate / 20 °C 4.1: formic acid ethyl ester / 20 - 70 °C
	Multi-step reaction with 3 steps 1.1: lithium hydroxide / water; tetrahydrofuran / 0.5 h / 20 °C 2.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide / dichloromethane / 0.67 h 2.2: 20 °C 3.1: ethyl acetate / 0.5 h / 70 °C

10
[ 2088749-42-0 ]
[ 77-92-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	In ethyl acetate at 50 - 70℃; for 24h;	3.2 Step 2: Citric acid (6.4g, 33mM, 1.2eq) was dissolved in ethyl acetate (400mL) at 70 ° C and the product from the previous step was added andstirred at 50 ° C for 24 hours, cooled to room temperature, filtered, Ethyl acetate and dried to give 12.6 g of the target product in a yield of 89%.Its purity byHPLCwas 98.3%.

Reference： [1]Current Patent Assignee: CHENGDU BEISIKAIRUI BIOTECHNOLOGY - CN106986884, 2017, A Location in patent: Paragraph 0056; 0058

11
[ CAS Unavailable ]
[ 77-92-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	In ethyl acetate at 50 - 70℃; for 24h;	4.2 Step 2: Citric acid (6.4g, 33mM, 1.2eq) was dissolved in ethyl acetate (400mL) at 70 ° C and the product from the previous step was added andstirred at 50 ° C for 24 hours, cooled to room temperature, filtered, Ethyl acetate and dried to give 12.9 g of the target product in 91% yield. The purity was 95.6% byHPLC.

Reference： [1]Current Patent Assignee: CHENGDU BEISIKAIRUI BIOTECHNOLOGY - CN106986884, 2017, A Location in patent: Paragraph 0060; 0062

12
[ 2088749-44-2 ]
[ 77-92-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	In ethyl acetate at 50 - 70℃; for 24h;	5.2 Step 2: Citric acid (6.4g, 33mM, 1.2eq) was dissolved in ethyl acetate (400mL) at 70 ° C and the product from the previous step was added andstirred at 50 ° C for 24 hours, cooled to room temperature, filtered, Ethyl acetate, and dried to give 13.3 g of the target product in 94% yield. Its purity byHPLCwas 96.2%.

Reference： [1]Current Patent Assignee: CHENGDU BEISIKAIRUI BIOTECHNOLOGY - CN106986884, 2017, A Location in patent: Paragraph 0064; 0066

13
[ 2088749-45-3 ]
[ 77-92-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	In ethyl acetate at 50 - 70℃; for 24h;	6.2 Step 2: Citric acid (6.4g, 33mM, 1.2eq) was dissolved in ethyl acetate (400mL) at 70 ° C and the product from the previous step was added andstirred at 50 ° C for 24 hours, cooled to room temperature, filtered, Ethyl acetate and dried to give 12.3 g of the target product in 87% yield. The purity was 95.1% byHPLC.

Reference： [1]Current Patent Assignee: CHENGDU BEISIKAIRUI BIOTECHNOLOGY - CN106986884, 2017, A Location in patent: Paragraph 0068; 0070

14
[ CAS Unavailable ]
[ 77-92-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	In ethyl acetate at 20 - 70℃; for 0.333333h;	1.5 Step 5: 4-(R,S)-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetylamino)-3-Methylbutyl)-6-oxo-1,3,2-dioxaborolane-4-carboxylic acid Citric acid monohydrate (51.3 g, 244.1 mM, 1.0 eq) was dissolved in ethyl acetate (2 L) at 70°C.The product obtained in Step 4 was slowly added thereto, stirred at 70° C. for 20 minutes, transferred to room temperature (20-30° C.), and stirred overnight, ie, there was a lot of solids.The resulting product was filtered, washed with ethyl acetate and n-hexane, and dried to obtain 110 g of the desired product in a yield of 87%.

Reference： [1]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A Location in patent: Paragraph 0053; 0066-0068; 0081; 0086; 0091; 0096; 0101

15
[ CAS Unavailable ]
[ 77-92-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	In ethyl acetate at 20 - 70℃;	2 Example 2 Dissolve citric acid monohydrate (6.87 g, 32.7 mM, 1.0 eq) in 70 °C ethyl acetate (400 mL) and slowlyThe product obtained in the above step was added, stirred at 70° C. for 20 min, transferred to room temperature (20-30° C.), stirred overnight, filtered, washed with ethyl acetate and n-hexane, and dried to obtain the target product 14.1 g, yield 83%.

Reference： [1]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A Location in patent: Paragraph 0069; 0072

16
[ CAS Unavailable ]
[ 77-92-9 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
74%	With formic acid ethyl ester at 20 - 70℃;	3 Example 3 Dissolve citric acid monohydrate (5.74 g, 27.3 mM, 1.0 eq) in ethyl formate (350 mL) at 70 °C and slowlyThe product obtained in the above step was added, stirred at 70° C. for 20 min, transferred to room temperature (20-30° C.), stirred overnight, filtered, washed with ethyl acetate and n-hexane, and dried to obtain the target product 10.5 g, yield 74%.

Reference： [1]Current Patent Assignee: CHENGDU BEISI KAIRUI BIOLOGICAL TECH - CN106478701, 2017, A Location in patent: Paragraph 0073; 0074; 0076

17
[ 2088749-42-0 ]
[ 1239908-20-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 20 °C 2: ethyl acetate / 0.33 h / 20 - 70 °C