Name: 101968-85-8|(S)-2-(3-(tert-Butyl)ureido)-3,3-dimethylbutanoic acid|98%
Brand: Ambeed
SKU: A224873
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Yield	Reaction Conditions	Operation in experiment
		206.b Step 1b: Step 1b: Preparation of (S)-2-(3-tert-Butyl-ureido)-3,3-dimethyl-butyric acid This material was prepared by the same procedure as described in Example 205 step 1b except using (S)-2-(3-tert-Butyl-ureido)-3,3-dimethyl-butyric acid methyl ester instead of (S)-2-(3-Adamantan-1-yl-ureido)-3,3-dimethyl-butyric acid methyl ester 1H-NMR (CDCl3-d) C1.00 (s, 9H), 1.56 (s, 9H), 3.49 (s, 1H); LCMS RT=0.96 min, [M+H]+=231.3.

2
methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride salt [ No CAS ]
[ 101968-85-8 ]
[ 394735-27-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 4-methyl-morpholine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide; toluene at 0 - 10℃;
75%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃;	1 [0496] Methyl (1R,2S,5S)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (54c) [0497] To a solution of 54a (4 mmol, 0.92 g) and 54b (4 mmol, 0.82 mg) in anhydrous DMF (20 mL) was added DIPEA (10 mmol, 1.29 g) and was cooled to 0 °C. HATU (4.4 mmol, 1.67 g) was added to the solution under 0 °C and then stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 solution (250 mL), 1 M HCl solution (250 mL), and saturated brine solution (250 mL) sequentially. The organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was then purified with flash chromatography (15-50% EtOAc in hexanes as the eluent) to afford 54c as colorless oil (1.14 g, 75%).
75%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃;	1 [0496] Methyl (1R,2S,5S)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (54c) [0497] To a solution of 54a (4 mmol, 0.92 g) and 54b (4 mmol, 0.82 mg) in anhydrous DMF (20 mL) was added DIPEA (10 mmol, 1.29 g) and was cooled to 0 °C. HATU (4.4 mmol, 1.67 g) was added to the solution under 0 °C and then stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 solution (250 mL), 1 M HCl solution (250 mL), and saturated brine solution (250 mL) sequentially. The organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was then purified with flash chromatography (15-50% EtOAc in hexanes as the eluent) to afford 54c as colorless oil (1.14 g, 75%).

	With 2,6-dimethylpyridine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In acetonitrile at 10 - 30℃; for 3 - 5h;	1 1.0 equivalent of the compound of formula 11 was charged to vessel A, followed by 3 volumes of acetonitrile and 2.25 eq of 2, 6-LUTIDINE WHILE the temperature was maintained between 20 °C and 30 °C. Then 1.0 eq of the compound of formula 111, 0.5 eq of 1-hydroxybezotriazole hydrate, 1.2 eq of EDCI hydrochloride and 4 volumes of acetonitrile were charged to vessel B between 10 °C and 20 °C. The solution containing the compound of formula 11 was then immediately added to the slurry containing the compound of formula Ill. The reaction was complete in about 3 to 5 hours. The reaction mixture was then diluted with 6 volumes of MTBE and the pH was adjusted with 3N hydrochloric acid, extracted, washed with sodium bicarbonate solution and concentrated. After addition of 6X of acetonitrile and reconcentration to about 7 volumes of a 10% aqueous lithium hydroxide solution (2 equiv) were charged. The batch was agitated for 3 hours between 20 °C and 25 °C. Dilution of the batch with 4 volumes of isopropyl acetate was followed by pH adjustment with 3N hydrochloric acid, extraction and sodium chloride wash. Concentration with additional isopropyl acetate prepared the batch for the salt formation step. L (-)-A-METHYLBENZYLAMINE (1. 1 EQUIV) was charged to the free acid solution (6 to 6.5 volumes) at 70 °C to 80 °C. The temperature was maintained for about 30 minutes and then the batch was cooled to 20 °C to 25 °C. The salt product was filtered and washed with 3 volumes of I-PROPYL acetate. The wet cake was dried under vacuum at 40 °C to 50 °C for 3 hours and then at 75 °C to 85 °C for at least 10 hours to provide the compound of formula IV in about 85-95% molar yield. 'H-NMR (400 MHz, CD30D) : 8 7.45 (m, 5H), 4.92 (s, broad, 5H), 4.39 (q, 3H), 4.33 (dd, 1 H), 4.28 (s, 1 H), 4.03 (d, 1 H), 3.96 (dd, 1 H), 1.63 (d, 3H), 1.45 (m, 2H), 1.28 (s, 9H), . 1.05 (s, 3H), 1.04 (s, 9H), 0.91 (s, 3H); 13C-NMR (100.6 MHz, CD30D) : 8179. 3,173. 3,160. 1,140. 7,130. 6,130. 4, 128. 0,63. 9,59. 2, 52.6, 51.1, 49.3, 36.4, 33.3, 30.1, 28.8, 27.5, 27.2, 21.5, 20.5, 13.6
	Stage #1: methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride salt; (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With 2,6-dimethylpyridine In acetonitrile at 0 - 15℃; Industry scale; Stage #2: With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In acetonitrile at 5 - 30℃; for 4h; Industry scale;	1 Into a reactor (FM) was charged 351 kg of compound Ia, 314 kg of compound Ib, and 807 L of acetonitrile. Batch temperature was adjusted to 0 to 100C. 323kg of 2,6-lutidine followed by 123 L of acetonitrile was charged to R-1 , while maintaining temperature at 0 to 15 0C. 351 kg of EDCI-HCI followed by 123 L of acetonitrile was charged to between 5 to 250C. The mixture was stirred at 20 to 30 0C for 4 h. Reaction completion was checked by HPLC to show less than 0.75% of un-reacted compound Ia. 1755L of MTBE followed by 807 kg of 9.9% HCI was charged to R-1 between 150C to 25 0C. The batch was stirred for 15 minutes and settled for at least 30 minutes, and the aqueous layer was split to HOLD TANK. 807 kg of 9.9% HCI was charged to R-1 at 15 to 25 0C. The batch was stirred for 15 minutes and settled for 30 minutes, and the aqueous layer was split to HOLD TANK. 211 kg of sodium bicarbonate followed by 4001 L of water was charged to R-2, and the whole was agitated until all solid dissolved. 1404 L of the NaHCOe solution in R-2 was transferred to R-1 at 15 to 25 0C. The mixture was stirred for 15 minutes and settled for at least 30 minutes. The aqueous layer was split to HOLD TANK. 140 kg of sodium chloride was charged to the NaHCθ3 solution in R-2. Half of the NaHCOa/ NaCI solution in R-2 was transferred to R-1. The whole in R-1 was agitated for 15 minutes and settles for at lest 30 minutes. The aqueous layer was split to HOLD TANK. The remainder of the NaHCOa/ NaCI solution in R-2 was transferred to R-1. The whole in R-1 was agitated for 15 minutes and settled for at lest 30 minutes. The aqueous layer was split to HOLD TANK. The batch in R-1 was concentrated to about 1053 L under vacuum. 97 kg of lithium hydroxide Monohydrate followed by 1404 L of water was charged to R-2, and the mixture was stirred at 20 to 30 0C until all solids dissolved. The lithium hydroxide solution in R-2 was transferred to R-1. The whole was stirred at 20 to 300C for 3h. Hydrolysis completion was checked by HPLC to show 100% conversion. 1053 L of MTBE followed by 1404 L of water was charged to R-1. The mixture was stirred for 20 minutes and settles for at least 30 minutes. The aqueous layer was split to R-2. The organic layer was transferred to HOLD TANK. 1053 L of MTBE was charged to R-2. The mixture was stirred for about 10 minutes and settled for at least 30 minutes. The aqueous layer was transferred to R- 1. The organic layer was transferred to HOLD TANK. 293 kg of 9.9% HCI followed by 1530 kg of isopropyl acetate and 660 kg of 9.9 % HCI was charged to R-1 at 20 to 30 0C. The mixture in R-1 was stirred for 30 minutes and settled for at least 30 minutes. The aqueous layer was split to HOLD TANK. 35 kg of Sodium Chloride followed by 702 L of water was charged to R-2. The NaCI solution in R-2 was transferred to R-1. The mixture was stirred for 15 minutes at 15 to 25 0C and settled for at least 30 minutes. The aqueous layer was split to HOLD TANK. The batch in R-I followed by 306 kg of isopropyl acetate rinse was transferred to R-2 via 1 μm inline filter. The batch in R-2 was concentrated to about 1404 L under vacuum at 35 to 60 0C. 918 kg of isopropyl acetate was charged to to R-2, and the batch was concentrated to about 1404 L under vacuum at 35 to 60 0C. Water content in the batch was <0.5% w/w. 1530 kg of isopropyl acetate was charged to R-2. The batch temperature was adjusted to 43 to 48 0C, and 109 kg of N1N- dimethylcyclohexylamine (DMCA) was charged to R-2. 4 kg of compound Ic' seed inI 1 L of isopropyl acetate was charged to R-2. The batch was stirred for 5 h at 43 to 48 0C for 1 h. 130 kg of DMCA was charged to R-2 over 2 h at 43 to 48 0C. 153 kg of isopropyl acetate rinse was charged to R-2. The batch was cooled to 5 to 100C over a period of 3 hours. The batch was filtered in portions with a centrifuge. The wet cake was washed with cold isopropyl acetate and was dried under vacuum at 25 0C for 4 h followed by at 45 0C for at least 8 h. 706 kg of Compound Ic' was obtained (90% yield). 1H NMR (DMSO-d6), δ 0.80 (s, 3H), 0.91 (s, 9H), 0.99 (s, 3H), 1.02-1.25 (m, 5H), 1.17 (s, 9H), 1.35 (d, J = 8 Hz, 1H), 1.43 (dd, J = 5 and 8 Hz, 1H), 1.54-1.58 (m, 1H), 1.68-1.78 (m, 3H), 2.23 (s, 6H), 2.28 (m, 1 H), 3.73 (dd, J = 5 and 10 Hz, 1 H), 3.96 (d, J = 10 Hz, 1H), 4.08 (s, 1 H)1 4.15 (d, J = 10 Hz, 1 H), 5.87 (d, J = 10 Hz1 1 H), 5.95 (brs, 1 H).
	Stage #1: methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride salt; (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 5℃; for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 25 - 30℃; for 6h;	41 Example-41: Preparation of (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Formula-29) A mixture of (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-27 (50 g), (lR,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride compound of formula-53a (49.1 g), 1 -hydroxybenzotriazole (5.8 g) and dichloromethane (500 ml) was cooled to 0-5°C. Diisopropylethylamine (45.3 ml) was added to the reaction mixture and stirred for 10 minutes at 0-5°C. A solution of Ν,Ν'- Dicyclohexylcarbodiimide (49.2 g) in dichloromethane (150 ml) was added to the reaction mixture. Temperature of the reaction mixture was raised to 25-30°C and stirred for 6 hours at the same temperature. After completion of the reaction, filtered the un-wanted solid and washed the bed with dichloromethane. The filtrate was washed with hydrochloric acid solution followed by sodium bicarbonate solution and sodium chloride solution. Distilled of the solvent from the organic layer to get (lR,2S,5S)-methyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylate compound of formula-54 as a residue. The residue was dissolved in tetrahydrofuran (250 ml). A solution of lithium hydroxide monohydrate „ (14.5 g) and water (250 ml) was added to the reaction mixture and stirred for 6 hours at 25-30°C. Water followed by ethyl acetate were added to the reaction mixture and stirred for 15 minutes. Both the organic and aqueous layers were separated; dichloromethane was added to the aqueous -: layer and pH of the reaction mixture was adjusted to below 3 by using dilute hydrochloric acid solution. Both the organic and aqueous layers were separated; the aqueous layer was extracted with dichloromethane. All the organic layers were combined and washed with sodium chloride solution. Distilled off the solvent from the organic layer and then co-distilled with cyclohexane. The obtained residue was cooled to 25-30°C, cyclohexane (375 ml) was added to the reaction mixture and stirred for 20 minutes. Filtered the solid and washed with cyclohexane. The obtained wet solid was added to a mixture of methyl tertiary butyl ether (250 ml) and cyclohexane (250 ml). The reaction mixture was heated to 65-70°C and stirred for 30 minutes at the same temperature. The reaction mixture was cooled to 10-15°C. Filtered the precipitated solid, washed with cyclohexane and then dried to get title compound as a solid. Yield: 60 gms.

Reference： [1]Bhalerao, Dinesh S.; Arkala, Anil Kumar Reddy; Madhavi; Nagaraju; Gade, Srinivas Reddy; Kumar, U. K. Syam; Bandichhor, Rakeshwar; Dahanukar, Vilas H. [Organic Process Research and Development, 2015, vol. 19, # 11, p. 1559 - 1567]
[2]Current Patent Assignee: TEXAS A&M UNIVERSITY SYSTEM - WO2022/20711, 2022, A1 Location in patent: Paragraph 0495-0497
[3]Current Patent Assignee: TEXAS A&M UNIVERSITY SYSTEM - WO2022/20711, 2022, A1 Location in patent: Paragraph 0495-0497
[4]Current Patent Assignee: MERCK & CO INC - WO2004/113294, 2004, A1 Location in patent: Page/Page column 20-21
[5]Current Patent Assignee: MERCK & CO INC - WO2008/79216, 2008, A1 Location in patent: Page/Page column 18-20
[6]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1 Location in patent: Page/Page column 49-50

3
None [ No CAS ]
[ 101968-85-8 ]
None [ No CAS ]

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2004/113294, 2004, A1 Location in patent: Page/Page column 25

4
[ 101968-85-8 ]
[ 1175058-34-0 ]
[ 1175058-33-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h;	11.5 To the above crude compound was added 4.0 M HCl in dioxane (10 mL). After 1 h, the reaction mixture was concentrated and dried to give the corresponding HCl salt as a white solid. To the above amine HCl salt in DCM/DMF (10:3, 13 mL) was added 2S-(3-tert-Butyl- ureido)-3,3-dimethyl-butyric acid (64 mgs, 0.28 mmol), HATU (128 mg, 0.34 mmol) and DIPEA (0.15 mL, 0.84 mmol). After 1 h at rt, the reaction mixture was diluted with ethyl acetate and washed with IN HCl (2x), NaHCO3 (Ix), and brine (Ix). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to dryness.

Reference： [1]Current Patent Assignee: QUEST DIAGNOSTICS INC - WO2007/5838, 2007, A2 Location in patent: Page/Page column 61

5
[ 101968-85-8 ]
[ 1175058-37-3 ]
[ 1175058-36-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h;	12.2 To the above crude compound was added 4.0 M HCl in dioxane (10 mL). After 1 h, the reaction mixture was concentrated and dried to give the corresponding HCl salt as a white solid. To the above amine HCl salt in DCM/DMF (10:3, 13 mL) was added 25'-(3-tert-Butyl- ureido)-3,3-dimethyl-butyric acid (60 mgs, 0.26 mmol), HATU (128 mg, 0.34 mmol) and DIPEA (0.15 mL, 0.84 mmol). After 1 h at rt, the reaction mixture was diluted with ethyl acetate and washed with IN HCl (2x), NaHCO3 (Ix), and brine (Ix). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to dryness.

Reference： [1]Current Patent Assignee: QUEST DIAGNOSTICS INC - WO2007/5838, 2007, A2 Location in patent: Page/Page column 63

6
[ 101968-85-8 ]
[ 1175058-39-5 ]
[ 1175058-38-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h;	13.2 To the above crude compound was added 4.0 M HCl in dioxane (10 mL). After 1 h at rt, the reaction mixture was concentrated and dried to give the corresponding HCl salt as a white solid. To the above amine HCl salt in DCM/DMF (10:3, 13 mL) was added 2S-(3-tert- Butyl-ureido)-3,3-dimethyl-butyric acid (93 mgs, 0.40 mmol), HATU (200 mg, 0.53 mmol) and DIPEA (0.35 mL, 2.0 mmol). After 1 h at rt reaction mixture was diluted with ethyl EPO acetate and washed with IN HCl (2x), NaHCO3 (Ix), and brine (Ix). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to dryness. MS m/z 683 (M++H), 705 (M+^-Na), 681 (M+-H).

Reference： [1]Current Patent Assignee: QUEST DIAGNOSTICS INC - WO2007/5838, 2007, A2 Location in patent: Page/Page column 64-65

7
[ 101968-85-8 ]
C₂₇H₃₆N₄O₅*ClH [ No CAS ]
[ 1175058-42-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide	14.4 Compound 37 was dissolved in 4N HCl in 1,4-dioxane (2 mL) and stirred 1 h at RT. The reaction mixture was concentrated in vacuo and the residue (compound 38) was dissolved in DMF (2 mL). The solution was treated with (S)-2-(3-tert- butylureido)-3,3-dimethylbutyric acid (C; 100 mg; 440 μmol), HATU (200 mg; 520 μmol), and DIPEA (800 mL). The reaction mixture was diluted with water and the resulting precipitate was filtered, washed with water and dried to give 250 mg (80%) of the corresponding 2-hydroxycarboxamide 39. The solid was dissolved in dichloromethane (20 mL) and treated with l,l,l-tris(acetyloxy)-l,l-dihydro-l,2-benziodoxol-3-(lH)-one (D; 220 mg; 660 μmol). The reaction mixture was stirred for 2h at RT. The solution was diluted with diethyl ether (40 mL) followed by the addition of saturated aq. Na2S2O3 (10 mL) and 10 mL of aq. NaHCO3 (10 mL). The biphasic mixture was stirred for 10 min and the layers were separated. The organic phase was washed with saturated aq. NaCl, dried and concentrated in vacuo. The residue was purified by chromatography (SiO2; Hexane/EtOAc, 1:1) then the isolated material was lyophilized from acetonitrile and 0.01% aq. HCl to give 150 mg (46%) of the title compound (40) as the HCl salt. Mass Spec (M + Na) 705.

Reference： [1]Current Patent Assignee: QUEST DIAGNOSTICS INC - WO2007/5838, 2007, A2 Location in patent: Page/Page column 68

8
[ 101968-85-8 ]
[ 918662-54-1 ]
[ 918662-55-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h;	16.5 To the above compound was added 4.0 M HCl in dioxane (15 mL). After 1 h, the reaction mixture was concentrated and dried to give the corresponding HCl salt as a white solid. To the above amine HCl salt in DCM/DMF (3:1, 60 mL) was added 2S-(3-tert-BvLtyl- ureido)-3,3-dimethyl-butyric acid (848 mg, 3.67 mmol), HATU (1.67 g, 4.40 mmol) and DIPEA (2.6 mL, 14.08 mmol). After 1 h at rt, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with IN HCl (2 x 50 mL), NaHCO3 (1 x 100 mL), and brine (Ix). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to dryness. This material was used in the next step as crude without further purification.

Reference： [1]Current Patent Assignee: QUEST DIAGNOSTICS INC - WO2007/5838, 2007, A2 Location in patent: Page/Page column 73

9
[ 101968-85-8 ]
C₂₄H₃₂N₄O₅*ClH [ No CAS ]
[ 1175058-29-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 16h;	9.5 To the above crude compound was added 4.0 M HCl in dioxane (10 mL). After 1 h, the reaction mixture was concentrated and dried to give the corresponding HCl salt as a white solid. To the above amine HCl salt in DCM/DMF (8:3. 11.0 mL) was added 2S-(3-tert- Butyl-ureido)-3,3-dimethyl-butyric acid (81.0 mg, 0.35 mmol), HATU (160 mg, 0.42 mmol) and DIPEA (0.2 mL, 1.05 mmol). After 16 h at rt, the reaction mixture was diluted with ethyl acetate and washed with IN HCl (2x), NaHCO3 (Ix), and brine (Ix). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to dryness.

Reference： [1]Current Patent Assignee: QUEST DIAGNOSTICS INC - WO2007/5838, 2007, A2 Location in patent: Page/Page column 57

10
[ 101968-85-8 ]
C₂₅H₃₂N₄O₅*ClH [ No CAS ]
[ 1175058-31-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 3h;	10.2 To the above crude compound was added 4.0 M HCl in dioxane (5.0 mL). After 1 h, the reaction mixture was concentrated and dried to give the corresponding HCl salt as a white solid. To the above amine HCl salt in DCM/DMF (7:3. 10.0 mL) was added 2£'-(3-tert-Butyl- ureido)-3,3-dimethyl-butyric acid (46 mg, 0.2 mmol), HATU (91 mg, 0.24 mmol) and EPO DIPEA (0.1 mL, 0.6 mmol). After 3 h at it, the reaction mixture was diluted with ethyl acetate and washed with IN HCl (2x), NaHCO3 (Ix), and brine (Ix). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to dryness.

Reference： [1]Current Patent Assignee: QUEST DIAGNOSTICS INC - WO2007/5838, 2007, A2 Location in patent: Page/Page column 58-59

11
[ 101968-85-8 ]
[ 1035377-49-1 ]
[ 1035377-50-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: (2S,4R)-tert-butyl 2-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(5-(pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)pyrrolidine-1-carboxylate With hydrogenchloride; methanol In 1,4-dioxane at 20℃; for 1.5h; Stage #2: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 16h;	5.7 Step 7: Preparation of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-4-(5-(pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)pyrrolidine-2-carboxamide.; A mixture of (2S,4R)-tert-butyl 2-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(5-(pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)pyrrolidine 1-carboxylate (max 340 μmol) in 4M HCl/dioxane (4 mL) and MeOH (2 mL) was stirred at room temperature for 90 min, then concentrated under reduced pressure and further concentrated from toluene (2×). To a mixture of this product, 2S-(3-tert-butylureido)-3,3-dimethylbutyric acid (78 mg, 1 equiv.) and HATU (155 mg, 408,mol, 1.2 equiv.) in CH2Cl2 (8 mL) and DMF (3 mL) was added iPr2NEt (0.24 mL, 1.39 mmol, 4 equiv.). After 16 h at room temperature the reaction mixture was diluted with EtOAc (50 mL) and washed with 1M HCl (2×), sat. aqueous NaHCO3 and brine. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give a buff solid foam (180 mg, 73%, three steps).

Reference： [1]Current Patent Assignee: VIROBAY - US2008/161254, 2008, A1 Location in patent: Page/Page column 15

12
[ 101968-85-8 ]
[ 1035377-53-7 ]
[ 1035377-29-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: (2S,4R)-tert-butyl 2-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylate With hydrogenchloride; methanol In 1,4-dioxane at 20℃; for 1.5h; Stage #2: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 16h;	6.5 Step 5: Preparation of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-4-(2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidine-2-carboxamide Prepared according to Example 5, Step 7, using (2S,4R)-tert-butyl 2-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylate (420 mg, 688 mmol); the product was obtained as a buff solid (265 mg, 73%).

Reference： [1]Current Patent Assignee: VIROBAY - US2008/161254, 2008, A1 Location in patent: Page/Page column 17

13
(S)-trimethylsilyl 2-amino-3,3-dimethylbutanoate [ No CAS ]
[ 1609-86-5 ]
[ 101968-85-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (S)-trimethylsilyl 2-amino-3,3-dimethylbutanoate; Tert-butyl isocyanate In dichloromethane at 20 - 30℃; for 14 - 16.5h; Heating / reflux; Stage #2: With hydrogenchloride; water In dichloromethane at 15 - 20℃; for 0.333333 - 1h;	A; B (S)-2-(3-te^Butylureido)-3,3-dimethyIbutanoic acid (3) - Method A[0025] A 20-L glass flask was charged with dichloromethane (7.00 L) under a nitrogen atmosphere at 25-35 0C followed by tert-butyl-L-glycine (1.00 kg; 7.62 mol) with stirring. To the suspension was added triethylamine (0.94 kg; 9.29 mol; 122 mole %) at 25-35 0C. The reaction mixture was then treated with chlorotrimethylsilane (1.15 L; 9.00 mol; 118 mole %) with stirring at 25-35 0C. The reaction mixture was then heated to reflux temperature (39- 41 0C) and maintained under reflux for 3 h. The reaction mixture was cooled to 20-25 0C and tert-butyl isocyanate (0.76 kg; 7.67 mol; 101 mole %) was added to the reaction mass at 20- 25 0C The reaction temperature was adjusted to 25-30 0C and the resulting mixture stirred for 14-15 hours at 25-30 0C. The reaction mixture was monitored by thin layer chromatography (TLC) for the complete disappearance of tert-butyl-L-glycine. Once TLC confirmed the absence of the starting material, the reaction mixture was treated with water (4 L) at 25-30 °C. The reaction was cooled to 15-20 0C and the reaction mixture was acidified to a pH of 1.0 to 2.0 by the addition of 6N aqueous hydrochloric acid (1.0 L; 6.0 mol) at 15-20 0C. Precipitation of the product was observed after the addition of the acid was complete. The mixture was stirred for 20-30 minutes and the slurry was filtered. The filter cake was washed with water (1.00 L) and allowed to dry under vacuum on the filter until no additional solvent was collected in the receiver. The solid was transferred to polypropylene trays and dried at 60-70 0C until loss on drying was below 0.50%. Yields of compound 3 (see Figure 1) were 1.30-1.56 kg (73.9-88.6%) for three runs. HPLC Purity of these lots ranged from 99.00 to 99.78%.; (S)-2-(3-te^-ButyIureido)-3,3-dimethyIbutanoic acid (3) - Method BSynthetic Scheme - Use of Hexamethyldisilazane and Catalytic ChlorotrimethylsilaneH H 4) (-Bu-N=C=O, 20-250C ^ XNV N^CO2H5) H2O O6) 5N aq HCI7) Filter and dry (50-600C) 3[0026] tert-Butyl-L-leucine (100 g, 0.76 mol) and dichloromethane (DCM; 1000 mL) were charged to a clean, dry round-bottom flask at ambient temperature. Hexamethyldisilazane (HMDS; 319.6 mL, 1.52 mol; 200 mole%) was added slowly to the flask with stirring at room temperature over 10 to 15 minutes followed by a catalytic amount of chlorotrimethylsilane (2.4 mL; 0.018 mol; 2 mole%). The contents were reflux ed for 3 h, and then cooled to RT. tert-Butylisocyanate (86.76 mL; 0.76 mol; 100 mole%) was added at ambient temperature over 30 min. and then stirred at ambient temperature for about 16 h, monitoring the progress of the reaction by TLC (elution solvent: 20% methanol in DCM; visualization by dipping the dry plate in a ninhydrin solution, then heating until the spots appear). Once the TLC assay indicated that the reaction was complete, water (1.0 L) was added and the reaction mass was acidified to pH = 2 with 5 N aqueous hydrochloric acid. The reaction mass was stirred for 1 h at ambient temperature then the DCM was distilled under vacuum. The reaction mass was cooled to 10-15 0C and stirred for 30 minutes. The precipitated solids were filtered, washed with hexanes and dried at 50-60 0C under vacuum for 4-5 h to provide 120 g (68%) of (5)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid. HPLC: 98.8%; Chiral HPLC: 97.8%; 1H NMR (DMSO-D6, 200 MHz): δ 12.3 (br s, IH), 5.9- 5.95 (d, J= 10 Hz, 2NH), 3.85-3.9 (d, J= 10 Hz, IH), 1.2 (s, 9H), 0.84 (s, 9H).

Reference： [1]Current Patent Assignee: VIROBAY - WO2009/39361, 2009, A2 Location in patent: Page/Page column 7-8

14
[ 101968-85-8 ]
[ 1187162-83-9 ]
[ 1187162-87-3 ]

Yield	Reaction Conditions	Operation in experiment
71.6%	With N-ethyl-N,N-diisopropylamine; HATU In dimethyl sulfoxide at 20℃; for 3h; Inert atmosphere;	12; II To a solution of (2S,4R)-2-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidinium chloride (6.3 g, 11.2 mmol) in dimethylsulfoxide (20 mL) was added (R)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid (2.33 g, 10.2 mmol), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 4.74 g, 12.1 mmol) followed by diisopropylethylamine (4.95 g, 38.4 mmol), and the reaction mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. Completion of the reaction was monitored by TLC analysis. The reaction mixture was diluted with water and the resulting solid was filtered and dried under reduced pressure to yield 6.3 g (71.6%) of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxamide (HPLC purity: 99.2% by area; HPLC retention time: 15.06 minutes)

Reference： [1]Current Patent Assignee: VIROBAY - US2009/234127, 2009, A1 Location in patent: Page/Page column 5-6; 13

15
[ 20859-02-3 ]
[ 1609-86-5 ]
[ 101968-85-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: L-tert-Leucine With sodium hydroxide In water Stage #2: Tert-butyl isocyanate In water Cooling with ice;	2 The pH of a stirred aqueous solution (1150 g) containing L-tert-leucine (100 g, 762 mmol) was adjusted to 11.5 using a 48% by weight aqueous sodium hydroxide solution. Thereafter, tert-butyl isocyanate (75.5 g, 762 mmol) was slowly added thereto in an ice bath. The reaction was completed in 6 hours after the addition. The reaction mixture was analyzed with HPLC; as a result, it was found that 172 g of an N-tert-butylcarbamoyl-L-tert-leucine was generated (yield: 98%), and 0.02% of a dipeptide-like compound and 0.07% of N,N'-di(tert-butyl)urea were generated. The amount of the enantiomer was below measurable limits, i.e., 0.01%. The pH of the reaction mixture after the reaction was 9.3.

Reference： [1]Current Patent Assignee: KANEKA CORPORATION - EP2221294, 2010, A1 Location in patent: Page/Page column 6-7

16
[ 101968-85-8 ]
[ 1606175-06-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2: thionyl chloride / 0 - 30 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1

17
[ 101968-85-8 ]
3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2: water; hydrogenchloride / 10 h / 25 - 30 °C
	Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2: thionyl chloride / 0 - 30 °C 3: water; lithium hydroxide monohydrate / tetrahydrofuran / 6 h / 25 - 30 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1

18
[ 101968-85-8 ]
[ 816444-90-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / dichloromethane / 0.17 h / 0 - 5 °C 1.2: 6 h / 25 - 30 °C 2.1: water monomer; lithium hydroxyde monohydrate / tetrahydrofuran / 6 h / 25 - 30 °C
	Multi-step reaction with 3 steps 1.1: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2.1: water monomer; hydrogenchloride / 10 h / 25 - 30 °C 3.1: (S)-1,2,3,4-tetrahydronapht-1-yl-amine / ethyl acetate / 30 h / 25 - 30 °C 3.2: 0.33 h / 25 - 30 °C
	Multi-step reaction with 4 steps 1.1: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2.1: thionyl chloride / 0 - 30 °C 3.1: water monomer; lithium hydroxyde monohydrate / tetrahydrofuran / 6 h / 25 - 30 °C 4.1: (S)-1,2,3,4-tetrahydronapht-1-yl-amine / ethyl acetate / 30 h / 25 - 30 °C 4.2: 0.33 h / 25 - 30 °C

	Multi-step reaction with 2 steps 1: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; 4-methyl-morpholine / toluene; N,N-dimethyl-formamide / 0 - 10 °C 2: water monomer; sodium hydroxide / toluene; methanol / 0 - 30 °C
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 20 °C 2: lithium hydroxyde monohydrate / tetrahydrofuran; water monomer / 3 h / 20 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[4]Bhalerao, Dinesh S.; Arkala, Anil Kumar Reddy; Madhavi; Nagaraju; Gade, Srinivas Reddy; Kumar, U. K. Syam; Bandichhor, Rakeshwar; Dahanukar, Vilas H. [Organic Process Research and Development, 2015, vol. 19, # 11, p. 1559 - 1567]
[5]Current Patent Assignee: TEXAS A&M UNIVERSITY SYSTEM - WO2022/20711, 2022, A1

19
[ 101968-85-8 ]
[ 1606172-12-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2: water; hydrogenchloride / 10 h / 25 - 30 °C 3: ethyl acetate / 30 h / 25 - 30 °C
	Multi-step reaction with 4 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2: thionyl chloride / 0 - 30 °C 3: water; lithium hydroxide monohydrate / tetrahydrofuran / 6 h / 25 - 30 °C 4: ethyl acetate / 30 h / 25 - 30 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1

20
[ 101968-85-8 ]
[ 394735-28-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / dichloromethane / 0.17 h / 0 - 5 °C 1.2: 6 h / 25 - 30 °C 2.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 6 h / 25 - 30 °C 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; dicyclohexyl-carbodiimide / dichloromethane / 5 h / 0 - 30 °C
	Multi-step reaction with 4 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2.1: water; hydrogenchloride / 10 h / 25 - 30 °C 3.1: (S)-1,2,3,4-tetrahydronapht-1-yl-amine / ethyl acetate / 30 h / 25 - 30 °C 3.2: 0.33 h / 25 - 30 °C 4.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; dicyclohexyl-carbodiimide / dichloromethane / 5 h / 0 - 30 °C
	Multi-step reaction with 5 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2.1: thionyl chloride / 0 - 30 °C 3.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 6 h / 25 - 30 °C 4.1: (S)-1,2,3,4-tetrahydronapht-1-yl-amine / ethyl acetate / 30 h / 25 - 30 °C 4.2: 0.33 h / 25 - 30 °C 5.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; dicyclohexyl-carbodiimide / dichloromethane / 5 h / 0 - 30 °C

Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / toluene; N,N-dimethyl-formamide / 0 - 10 °C 2: water; sodium hydroxide / toluene; methanol / 0 - 30 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / N,N-dimethyl-formamide; ethyl acetate / 0 - 10 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[4]Bhalerao, Dinesh S.; Arkala, Anil Kumar Reddy; Madhavi; Nagaraju; Gade, Srinivas Reddy; Kumar, U. K. Syam; Bandichhor, Rakeshwar; Dahanukar, Vilas H. [Organic Process Research and Development, 2015, vol. 19, # 11, p. 1559 - 1567]

21
[ 101968-85-8 ]
[ 394730-60-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / dichloromethane / 0.17 h / 0 - 5 °C 1.2: 6 h / 25 - 30 °C 2.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 6 h / 25 - 30 °C 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; dicyclohexyl-carbodiimide / dichloromethane / 5 h / 0 - 30 °C 4.1: Dess-Martin periodane / dichloromethane / 0 - 30 °C
	Multi-step reaction with 5 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2.1: water; hydrogenchloride / 10 h / 25 - 30 °C 3.1: (S)-1,2,3,4-tetrahydronapht-1-yl-amine / ethyl acetate / 30 h / 25 - 30 °C 3.2: 0.33 h / 25 - 30 °C 4.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; dicyclohexyl-carbodiimide / dichloromethane / 5 h / 0 - 30 °C 5.1: Dess-Martin periodane / dichloromethane / 0 - 30 °C
	Multi-step reaction with 6 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 2,6-dimethylpyridine / toluene / 5 h / 0 - 35 °C 2.1: thionyl chloride / 0 - 30 °C 3.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 6 h / 25 - 30 °C 4.1: (S)-1,2,3,4-tetrahydronapht-1-yl-amine / ethyl acetate / 30 h / 25 - 30 °C 4.2: 0.33 h / 25 - 30 °C 5.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; dicyclohexyl-carbodiimide / dichloromethane / 5 h / 0 - 30 °C 6.1: Dess-Martin periodane / dichloromethane / 0 - 30 °C

Multi-step reaction with 4 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / toluene; N,N-dimethyl-formamide / 0 - 10 °C 2: water; sodium hydroxide / toluene; methanol / 0 - 30 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / N,N-dimethyl-formamide; ethyl acetate / 0 - 10 °C 4: Dess-Martin periodane / ethyl acetate / 5.25 h / 5 - 18 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1
[4]Bhalerao, Dinesh S.; Arkala, Anil Kumar Reddy; Madhavi; Nagaraju; Gade, Srinivas Reddy; Kumar, U. K. Syam; Bandichhor, Rakeshwar; Dahanukar, Vilas H. [Organic Process Research and Development, 2015, vol. 19, # 11, p. 1559 - 1567]

22
[ 101968-85-8 ]
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile [ No CAS ]
[ 1606175-05-6 ]

Yield	Reaction Conditions	Operation in experiment
30 g	With 2,6-dimethylpyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In toluene at 0 - 35℃; for 5h;	10; II Example-10: Preparation of l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo [3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea (F orniuIa-35) Example-10: Preparation of l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo [3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea (F orniuIa-35) The organic layer containing 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-34 which is obtained in example-9 was cooled to 0-5°C. (S)-2-(3-tert- butylureido)-3,3-dimethylbutanoic acid compound of formula-27 (40 g) followed by l-(3- dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (39.8 g), 2,6-lutidine (40.5 ml) were added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was raised to 30- 35°C and stirred for 5 hours at 30-35°C. The reaction mixture was cooled to 0-5°C and treating it with 2N hydrochloric acid followed by 10% sodium bicarbonate and 10% sodium chloride solution. Distilled off the solvent completely from the reaction mixture under reduced pressure to provide title compound as a residue. The obtained compound is purified by column chromatography using cyclohexane:ethyl acetate (8:2) to get title compound as a solid. Yield: 30 gms; Melting range: 140-150°C; DIP-MS (APCI +) m/z = 349.4.

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1 Location in patent: Page/Page column 15; 39

23
[ 101968-85-8 ]
(1R,2S,5S)-N-(4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride [ No CAS ]
[ 394735-28-5 ]

Yield	Reaction Conditions	Operation in experiment
4.5 g	With N-ethyl-N,N-diisopropylamine; HATU In acetonitrile at 25 - 30℃; for 5h;	20; IV Example-20: Preparation of (lR,2S,5S)-N-(4-amino-l-cycIobutyl-3-hydroxy-4-oxobutan-2- yl)-3-((S)-2-(3-tert-butyIureido)-3,3-dimethyIbutanoyl)-6,6-dimethyl-3-azabicycIo[3.1.0] hexane-2-carboxamide (Formula-30) Example-20: Preparation of (lR,2S,5S)-N-(4-amino-l-cycIobutyl-3-hydroxy-4-oxobutan-2- yl)-3-((S)-2-(3-tert-butyIureido)-3,3-dimethyIbutanoyl)-6,6-dimethyl-3-azabicycIo[3.1.0] hexane-2-carboxamide (Formula-30) (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-27 (2 g), followed by 6>-(7-azabenzotriazol-l-yl)-NvN,N',N'-tetramethyluroniumhexafluorophosphate (3.92 g) and diisopropyl ethylamine (4.5 ml) were added to a mixture of (lR,2S,5S)-N-(4-amino-l- cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride compound of formula-46a (3 g) and acetonitrile (60 ml) at 25-30°C and stirred for 5 hours. After completion of the reaction, water followed by ethyl acetate were added to the reaction mixture at 25-30°C and stirred for 10 minutes. Both the organic and aqueous layers were separated; the organic layer was washed with sodium bicarbonate solution followed by sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get residue. Co-distillation of the obtained residue with cyclohexane to get title compound. Yield: 4.5 gms.

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1 Location in patent: Page/Page column 22; 42-43

24
[ 101968-85-8 ]
(1R,2S,5S)-N-(4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride [ No CAS ]
[ 394730-60-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / acetonitrile / 5 h / 25 - 30 °C 2: Dess-Martin periodane / dichloromethane / 0 - 30 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1

25
(S)-trimethylsilyl 2-amino-3,3-dimethylbutanoate [ No CAS ]
[ 10017-37-5 ]
[ 101968-85-8 ]

Yield	Reaction Conditions	Operation in experiment
6 g	Stage #1: (S)-trimethylsilyl 2-amino-3,3-dimethylbutanoate; tert-butylamine hydrochloride With 1,1'-carbonyldiimidazole In tetrahydrofuran; dichloromethane at 25 - 30℃; for 13.5h; Stage #2: With hydrogenchloride In tetrahydrofuran; dichloromethane; water for 0.25h;	8; XIII . Example-8: Preparation of (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid (Formula- 27) Trimethyl silyl chloride (5.0 g) was slowly added to a mixture of (S)-2-amino-3,3- dimethylbutanoic acid compound of formula-25 (5 g), triethylamine (6.42 ml) and dichloromethane (35 ml) at 25-30°C for a period of 30 minutes. The reaction mixture was heated to 40-45°C and stirred for 3 hours. The reaction mixture containing (S)-trimethylsilyl 2-amino- 3,3-dimethylbutanoate compound of formula-25a was cooled to 25-30°C. N,N-carbonyl diimidazole (6.8 g) was added to a mixture of 2-methylpropan-2-amine hydrochloride compound of formula-26a (7.5 g) and tetrahydrofuran (15 ml) at 25-30°C and stirred for 3 hours at 25- 30°C. This reaction mixture was slowly added to the reaction mixture containing compound of formula-26a at 25-30°C for a period of 30 minutes and stirred for 10 hours at 25-30°C. After completion of the reaction, water followed by dichloromethane were added to the reaction mixture and pH of the reaction mixture was adjusted to 2.5 using 6N hydrochloric acid. The reaction mixture stirred for 15 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both the organic layers were combined, washed with 10% sodium chloride solution, dried with sodium sulfate and then distilled under reduced pressure to get title compound. Yield: 6 gms.

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2014/61034, 2014, A1 Location in patent: Page/Page column 33; 38

26
[ 20859-02-3 ]
[ 75-64-9 ]
[ 530-62-1 ]
[ 101968-85-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: <i>tert</i>-butylamine; 1,1'-carbonyldiimidazole In toluene at 0 - 5℃; Stage #2: L-tert-Leucine With sodium hydroxide In water; toluene at 5 - 30℃;

Reference： [1]Bhalerao, Dinesh S.; Arkala, Anil Kumar Reddy; Madhavi; Nagaraju; Gade, Srinivas Reddy; Kumar, U. K. Syam; Bandichhor, Rakeshwar; Dahanukar, Vilas H. [Organic Process Research and Development, 2015, vol. 19, # 11, p. 1559 - 1567]

27
[ 101968-85-8 ]
C₂₃H₃₃N₃O₃*ClH [ No CAS ]
C₃₄H₅₃N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.7%	Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: C₂₃H₃₃N₃O₃*ClH In N,N-dimethyl-formamide at 0℃;	9 Compounds of formula 1 G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) was dissolved in 8ml DMF in an ice water bath, Was addedDIEA (0.18mml, 1.00mmol), stirred for 30min; Compound F-2 (120mg, 0.28mmol) was added To 8ml DMFand the solution was added to the reaction solution of F-2, 0 ° C and stirred overnight; the reaction mixturewas added 50ml of water, The reaction solution was extracted with ethyl acetate, the organic phase was washedsuccessively with 1N hydrochloric acid and saturated sodium bicarbonate solution, then washed with saturatedsaline Brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a yellow oil, 118mgcolumn chromatography to give the compound of Formula 1, as a white Solid, yield 68.7%.
68.7%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; Cooling with ice;	9 Embodiment 9: formula 1 compound preparation G-3 (78 mg, 0 . 34mmol), HATU (128 mg, 0 . 34mmol) dissolved in 8mlDMF in, ice water bath cooling, adding DIEA (0.18mml, 1 . 00mmol), stirring 30 min; compound F-2 (120 mg, 0 . 28mmol) adding to 8mlDMF in, G-2 is added to this solution in the reaction solution, 0 °C stirring sleepovers; added 50 ml water, extracting reaction solution with ethyl acetate, the organic phase in order to sequentially 1N hydrochloric acid and saturated sodium bicarbonate solution, then washed with a saturated salt water, anhydrous sodium sulfate for drying, evaporating solvent to obtain yellow oily matter, column chromatography to obtain 118 mg formula 1 compound, as a white solid, yield 68.7%.
68.7%	Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: C₂₃H₃₃N₃O₃*ClH In N,N-dimethyl-formamide at 0℃;	9 Compounds of formula 1 G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) was dissolved 8mlDMF in an ice water bath, Was added DIEA (0.18mml,1.00mmol), stirred for 30min; Compound F-2 (120mg, 0.28mmol) was added To 8mlDMF and the solution was added to thereaction solution of G-2, 0 ° C and stirred overnight; the reaction mixture was added 50ml of water, The reaction solution wasextracted with ethyl acetate, the organic phase was washed successively with 1N hydrochloric acid and saturated sodiumbicarbonate solution, then washed with saturated saline Brine, dried over anhydrous sodium sulfate, and the solvent wasevaporated to give a yellow oil, 118mg column chromatography to give the compound of Formula 1, as a white Solid, yield68.7%.

68.7%

Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Stage #2: C₂₃H₃₃N₃O₃*ClH In N,N-dimethyl-formamide at 0℃;

9 G-3 (78mg, 0.34mmo 1), HATU (128mg, 0.34mmo 1) was dissolved in 8ml DMF in an ice water bath to cool, added DIEA (0.18mm 1,1.00 mmol), stirred for 30min; Compound F-2 (120 mg, 0.28 mmol) was added to 8 ml of DMF. The reaction solution was added to the reaction solution of G-2 at 0 °C overnight, and 50 ml of water was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate. The organic phase was washed successively with 1N hydrochloric acid and saturated sodium hydrogencarbonate solution. Washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated to give a yellow oil. Column chromatography afforded 118 mg of the compound of formula 1 as a white solid in 68.7% yield.

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936616, 2016, B Location in patent: Paragraph 0093-0095
[2]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936652, 2016, B Location in patent: Paragraph 0055; 0081; 0082; 0083
[3]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936613, 2016, B Location in patent: Paragraph 0101-0103
[4]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936627, 2016, B Location in patent: Paragraph 0099-0101

28
[ 101968-85-8 ]
C₂₄H₃₅N₃O₃*ClH [ No CAS ]
C₃₅H₅₅N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.2%	Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: C₂₄H₃₅N₃O₃*ClH In N,N-dimethyl-formamide at 0℃;	18 Preparation of a compound of formula 1 G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) was dissolved in 8ml DMF in an ice water bath, Was addedDIEA (0.18mml, 1.00mmol), stirred for 30min, Compound F-2 (120mg, 0.27mmol) was added to 8ml DMFand the solution was added to the reaction solution of G-3, 0 ° C and stirred overnight, the reaction mixturewas added 50ml of water, in order to The reaction solution was extracted with ethyl acetate, the organic phasewas washed successively with 1N hydrochloric acid and saturated sodium bicarbonate solution, then withsaturated brine, Dried over anhydrous sodium sulfate, and the solvent was evaporated to give a yellow oil, 102mgcolumn chromatography to give the compound of Formula 1, as a white solid Body, yield 60.2%.
60.2%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; Cooling with ice;	18 Embodiment 18: formula 1 compound preparation G-3 (78 mg, 0 . 34mmol), HATU (128 mg, 0 . 34mmol) dissolved in 8mlDMF in, ice water bath cooling, adding DIEA (0.18mml, 1 . 00mmol), stirring 30 min, compound F-2 (120 mg, 0 . 27mmol) is added to 8mlDMF in, G-3 is added to this solution in the reaction solution, 0 °C stirring overnight, the reaction solution is added in 50 ml water, extracting reaction solution with ethyl acetate, the organic phase in order to sequentially 1N hydrochloric acid and saturated sodium bicarbonate solution, then washed with a saturated salt water, anhydrous sodium sulfate for drying, evaporating solvent to obtain yellow oily matter, column chromatography to obtain 102 mg formula 1 compound, as a white solid, yield is 60.2%.
60.2%	Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: C₂₄H₃₅N₃O₃*ClH In N,N-dimethyl-formamide at 0℃;	18 Compounds of formula 1 G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) was dissolved 8mlDMF in an ice water bath, Was added DIEA (0.18mml,1.00mmol), stirred for 30min, Compound F-2 (120mg, 0.27mmol) was added to 8mlDMF and the solution was added to thereaction solution of G-3, 0 ° C and stirred overnight, the reaction mixture was added 50ml of water, in order to The reactionsolution was extracted with ethyl acetate, the organic phase was washed successively with 1N hydrochloric acid and saturatedsodium bicarbonate solution, then with saturated brine, Dried over anhydrous sodium sulfate, and the solvent was evaporatedto give a yellow oil, 102mg column chromatography to give the compound of Formula 1, as a white solid Body, yield 60.2%.

60.2%

Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Stage #2: C₂₄H₃₅N₃O₃*ClH In N,N-dimethyl-formamide at 0℃;

18 Preparation of compounds of formula I G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) was dissolved in 8ml DMF in an ice water bath, was added DIEA (0.18mml, 1.0Ommol), stirred for 30min, the compound F-2 (120mg, 0.27mmol ) in 8ml DMF was added to the solution was added to the reaction solution of G-3, (TC stirring overnight, the reaction mixture was added 50ml of water, the reaction solution was extracted with ethyl acetate, the organic phase was washed successively with 1N hydrochloric acid and saturated bicarbonate solution was washed with sodium, then washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated to give a yellow oil, 102mg column chromatography to give compound of formula I, as a white solid, a yield of 60.2%.

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936616, 2016, B Location in patent: Paragraph 0121-0123
[2]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936652, 2016, B Location in patent: Paragraph 0109; 0110; 0111
[3]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936613, 2016, B Location in patent: Paragraph 0129-0131
[4]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936627, 2016, B Location in patent: Paragraph 0127-0129

29
[ 101968-85-8 ]
C₂₄H₃₅N₃O₄*ClH [ No CAS ]
C₃₅H₅₅N₅O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.2%	Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: C₂₄H₃₅N₃O₄*ClH In N,N-dimethyl-formamide at 0℃;	27 Preparation of a compound of formula 1 G-3 (30mg, 0.13mmol), HATU (50mg, 0.13mmol) was dissolved in 8ml DMF in an ice-water bath cooling, IntoDIEA (0.1ml, 0.57mmol), stirred for 30min, Compound F-2 (50mg, 0.11mmol) was added to 8ml DMF Andthe solution was added to the reaction solution of G-2, 0 ° C and stirred overnight, the reaction mixture wasadded 50ml of water, ethyl acetate The reaction solution was extracted, the organic phase was washedsuccessively with 1N hydrochloric acid and saturated sodium bicarbonate solution, then washed with saturatedbrine, dried over anhydrous sulfur Sodium sulfate, and the solvent was evaporated to give a yellow oil, 40mgcolumn chromatography to give the compound of Formula 1, as a white solid, yield Rate of 57.2%
57.2%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; Cooling with ice;	27 Embodiment 27: formula 1 compound preparation G-3 (30 mg, 0 . 13mmol), HATU (50 mg, 0 . 13mmol) dissolved in 8mlDMF in, ice water bath cooling, adding DIEA (0.1 ml, 0 . 57mmol), stirring 30 min, compound F-2 (50 mg, 0 . 11mmol) is added to 8mlDMF in, G-2 is added to this solution in the reaction solution, 0 °C stirring overnight, the reaction solution is added in 50 ml water, extracting reaction solution with ethyl acetate, the organic phase in order to sequentially 1N hydrochloric acid and saturated sodium bicarbonate solution, then washed with a saturated salt water, anhydrous sodium sulfate for drying, evaporating solvent to obtain yellow oily matter, column chromatography to obtain 40 mg of formula 1 compound, as a white solid, yield 57.2%
57.2%	Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: C₂₄H₃₅N₃O₄*ClH In N,N-dimethyl-formamide at 0℃;	27 Compounds of formula 1 G-3 (30mg, 0.13mmol), HATU (50mg, 0.13mmol) was dissolved 8mlDMF in an ice-water bath cooling, Into DIEA (0.1ml,0.57mmol), stirred for 30min, Compound F-2 (50mg, 0.11mmol) was added to 8mlDMF And the solution was added to thereaction solution of G-2, 0 ° C and stirred overnight, the reaction mixture was added 50ml of water, ethyl acetate The reactionsolution was extracted, the organic phase was washed successively with 1N hydrochloric acid and saturated sodiumbicarbonate solution, then washed with saturated brine, dried over anhydrous sulfur Sodium sulfate, and the solvent wasevaporated to give a yellow oil, 40mg column chromatography to give the compound of Formula 1, as a white solid, yield Rateof 57.2%

57.2%

Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Stage #2: C₂₄H₃₅N₃O₄*ClH In N,N-dimethyl-formamide at 0℃;

27 Preparation of compounds of formula I G-3 (30mg, 0.13mmol), HATU (50mg, 0.13mmol) was dissolved in 8ml DMF in an ice water bath, was added DIEA (0.1 ml, 0.57 mmol), at 0 °C stirred for 30 min. A solution of F in 8ml DMF was added to the reaction solution of G-2, 0 °C stirring overnight, the reaction mixture was added 50ml of water, the reaction solution was extracted with ethyl acetate, the organic phase was washed successively with 1N hydrochloric acid and saturated sodium bicarbonate solution, then washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated to give a yellow oil, 40mg column chromatography to give the compound of formula I, as a white solid, yield Rate 57.2%.

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936616, 2016, B Location in patent: Paragraph 0149-0151
[2]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936652, 2016, B Location in patent: Paragraph 0137; 0138; 0139
[3]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936613, 2016, B Location in patent: Paragraph 0157-0159
[4]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936627, 2016, B Location in patent: Paragraph 0155-0157

30
[ 101968-85-8 ]
None [ No CAS ]
None [ No CAS ]

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936616, 2016, B Location in patent: Page/Page column 3; 10; 15

31
[ 101968-85-8 ]
None [ No CAS ]
None [ No CAS ]

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936652, 2016, B Location in patent: Paragraph 0021

32
[ 101968-85-8 ]
C₂₃H₃₃N₃O₃*(x)ClH [ No CAS ]
C₃₄H₅₃N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.7%	Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: C₂₃H₃₃N₃O₃*(x)ClH In N,N-dimethyl-formamide at 0℃;	9 Preparation of Compound 9 G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) was dissolved in 8ml DMF in an ice water bath, was added DIEA (0.18mml, 1.00mmol), stirred for 30min; Compound F-2 (120mg, 0.28mmol) in 8ml DMF was added to the solution was added to the reaction solution of G-2, 0 stirred overnight; the reaction mixture was added 50ml of water, the reaction solution was extracted with ethyl acetate, the organic phase was washed successively with 1N hydrochloric acid and saturated bicarbonate sodium washing solution, and then washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a yellow oil, 118mg column chromatography to give the compound of formula 1, as a white solid, a yield of 68.7%.

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936651, 2016, B Location in patent: Paragraph 0081-0083

33
[ 101968-85-8 ]
None [ No CAS ]
None [ No CAS ]

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936651, 2016, B Location in patent: Page/Page column 2

34
[ 101968-85-8 ]
C₂₄H₃₅N₃O₃*(x)ClH [ No CAS ]
C₃₅H₅₅N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.2%	Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: C₂₄H₃₅N₃O₃*(x)ClH In N,N-dimethyl-formamide at 0℃;	18 Preparation of Compound 9 G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) was dissolved in 8ml DMF in an ice water bath, was added DIEA (0.18mml, 1.00mmol), stirred for 30min, Compound F-2 (120mg, 0.27mmol) 8ml DMF was added to the reaction solution, and the solution was added to the G-3, 0 stirring overnight, the reaction mixture was added 50ml of water, the reaction solution was extracted with ethyl acetate, the organic phase was washed successively with 1N hydrochloric acid and saturated sodium bicarbonate washing solution, and then washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a yellow oil, 102mg column chromatography to give the compound of formula 1, as a white solid, a yield of 60.2%.

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936651, 2016, B Location in patent: Paragraph 0109-0111

35
[ 101968-85-8 ]
C₂₄H₃₅N₃O₄*(x)ClH [ No CAS ]
C₃₅H₅₅N₅O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.2%	Stage #1: (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: C₂₄H₃₅N₃O₄*(x)ClH In N,N-dimethyl-formamide at 0℃;	27 Preparation of Compound 9 Compound F-1 (120mg, 0.23mmol) was dissolved in 3ml 4N HCl / dioxane was stirred 1h, the reaction solution was added volatiles evaporated down and 10ml of methylene chloride concentration was continued for 4 times to give 105mg compound F-2 as a white solid, a yield of 100%,

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN103936651, 2016, B Location in patent: Paragraph 0137-0139

36
[ 101968-85-8 ]
methyl (S)-2-((1R,2S,5S)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 20 °C 2: lithium hydroxyde monohydrate / tetrahydrofuran; water monomer / 3 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 20 °C