127199-44-4|(R)-tert-Butyl 5-azaspiro[2.4]heptan-7-ylcarbamate| Ambeed

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Quality Control of [ 127199-44-4 ] Purity: 95% SDS Specification

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Product Details of [ 127199-44-4 ]

CAS No. :	127199-44-4
Formula :	C₁₁H₂₀N₂O₂
M.W :	212.29
SMILES Code :	O=C(OC(C)(C)C)N[C@H]1CNCC21CC2
MDL No. :	MFCD11519122
InChI Key :	CGEBPOMWRHSMLI-QMMMGPOBSA-N
Pubchem ID :	10104620

Safety of [ 127199-44-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 127199-44-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	0
Fraction Csp3	0.91
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	61.73
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	50.36 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.57
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.94
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.82
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.15
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.09
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.31

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.48
Solubility	6.96 mg/ml ; 0.0328 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.58
Solubility	5.53 mg/ml ; 0.026 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.31
Solubility	1.04 mg/ml ; 0.00492 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.93 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.21

Application In Synthesis of [ 127199-44-4 ]

* 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 [ 127199-44-4 ]

[ 127199-44-4 ] Synthesis Path-Downstream 1~32

1
[ 101987-89-7 ]
[ 127199-44-4 ]
[ 129321-51-3 ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

2
[ 127199-44-4 ]
[ 127199-27-3 ]
7-((R)-7-tert-Butoxycarbonylamino-5-aza-spiro[2.4]hept-5-yl)-8-chloro-6-fluoro-1-((1R,2S)-2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

3
[ 127199-44-4 ]
[ 127199-26-2 ]
7-((R)-7-tert-Butoxycarbonylamino-5-aza-spiro[2.4]hept-5-yl)-8-chloro-6-fluoro-1-((1S,2R)-2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

4
[ 127199-44-4 ]
8-Chloro-6,7-difluoro-1-((1R,2R)-2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]
7-((R)-7-Amino-5-aza-spiro[2.4]hept-5-yl)-8-chloro-6-fluoro-1-(2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

5
[ 127199-44-4 ]
8-Chloro-6,7-difluoro-1-((1R,2R)-2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]
7-((R)-7-Amino-5-aza-spiro[2.4]hept-5-yl)-8-chloro-6-fluoro-1-(2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

6
[ 127199-43-3 ]
[ 127199-44-4 ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

7
[ 127199-44-4 ]
[ 167888-38-2 ]
5-Amino-7-((R)-7-tert-butoxycarbonylamino-5-aza-spiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,1996,vol. 44,p. 1376 - 1386.

8
[ 129306-33-8 ]
[ 127199-44-4 ]
9-(7-tert-butoxycarbonylamino-5-aza-spiro[2.4]hept-5-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,1998,vol. 46,p. 1710 - 1715.

9
[ 127199-44-4 ]
[ 767306-94-5 ]
7-(7-tert-butoxycarbonylamino-5-aza-spiro[2.4]hept-5-yl)-6-fluoro-1-(4-hydroxy-phenyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4693 - 4709.

10
[ 127199-44-4 ]
[ 103995-00-2 ]
7-(7-tert-butoxycarbonylamino-5-aza-spiro[2.4]hept-5-yl)-6-fluoro-1-(4-hydroxy-phenyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4693 - 4709.

11
[ 127199-44-4 ]
(S)-9-((R)-7-Amino-5-aza-spiro[2.4]hept-5-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,1998,vol. 46,p. 1710 - 1715.

12
[ 127199-44-4 ]
5-Amino-7-((R)-7-amino-5-aza-spiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,1996,vol. 44,p. 1376 - 1386.

13
[ 58632-95-4 ]
[ 127199-44-4 ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

14
7-(hydroxyimino)-5-<1(R)-phenylethyl>-4-oxo-5-azaspiro<2.4>heptane [ No CAS ]
[ 127199-44-4 ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

15
[ 127199-40-0 ]
[ 127199-44-4 ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

16
[ 127199-44-4 ]
7-((R)-7-Amino-5-aza-spiro[2.4]hept-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

17
[ 127199-44-4 ]
7-((R)-7-Amino-5-aza-spiro[2.4]hept-5-yl)-8-chloro-6-fluoro-1-((1R,2S)-2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

18
[ 127199-44-4 ]
7-((R)-7-Amino-5-aza-spiro[2.4]hept-5-yl)-8-chloro-6-fluoro-1-((1S,2R)-2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

19
[ 127199-39-7 ]
[ 127199-44-4 ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352.

20
[ 1400809-02-0 ]
[ 127199-44-4 ]
[ 35231-56-2 ]
[ 1400808-34-5 ]

Yield	Reaction Conditions	Operation in experiment
75%		Preparation of D17:The bis-sulfone 2 (11.80 g, 17.23 mmol) was dissolved in NMP (60 mL), followed by adding 2-methylpyrimidin-5-ol 1 (7.59 g, 68.93 mmol). The homogeneous solution was obtained. K2CO3 (9.53 g, 68.93 mmol) was added and the resulting suspension was heated to 100 C for 1 hr, then Boc protected amine (7.32 g, 34.46 mmol) was added and the resulting mixture was heated to 100 C for one more hour, cooled to the room temperature and water (450 mL) was poured into the mixture with stirring. The mixture was cooled to 0 C, filtered and washed the precipitates with water (2×25 mL), dried to give about 12 g of the white solid crude product. The crude solid was dissolved in dichloromethane and silica gel was added. Solvents were removed. Flash chromatography of the residue over silica gel (EtOAc/hexane: 20% to 50% to 90%) to give the pure D17 as a white solid (7.76 g, 75%). LC-MS: M+1: 635.30.
75%		General procedure: Example 9 Synthesis of Formula 1 compounds where L=Q and R8 is NHalkyl General Scheme for the bis-sulfone Route: D14 D15 D16 [0518] Tert-buty 2-amino-3-cyano-5-fluoro-lH-indol-7-yl(methyl)carbamate (D13): Crude tert-butyl 3,5-difluoro-2-nitrophenyl(methyl)carbamate (C3) (46.12 g, 0.162 mol) was dissolved in DMF (80 ml) and cooled in an ice-water bath. To it was added malononitrile (1 1.8 g, 179 mmol) followed by the addition of the NaOH solution (12.98 g, 325 mmol) in water (20 ml). After the exothermic reaction mixture was stirred for one hour, the ice-water bath was removed and the reaction was stirred for another one hour. It was then diluted with DMF (80 ml) and water (80 ml), and the atmosphere was displaced with argon. Sodium bicarbonate (109 g, 1.3 mol) followed by sodium hydrosulfite (123 g, 649 mmol) was added. The mixture was well stirred under argon at 40 C for 12 hours (Additional sodium hydrosulfite could be added if the reaction took longer time to complete). After the reaction was cooled down to room temperature, it was diluted with EtOAc (100 ml) and then filtered through a fritted glass funnel. The solids were washed with EtOAc/hexane (1 : 1, 400 ml). The aqueous layer was separated, and the organic layer was extracted with 10% buffer 7 solution (3x 100 ml). The combined aqueous layers were back extracted with EtOAc/hexane (1 : 1, 200ml). The combined organic phases was washed with 5% K2CO3 solution (300 ml). The extractions were then dried over sodium sulfate and concentrated by rotary evaporation to afford the crude compound (D13) as brown color solid (32.6 g, 66 %). LC-MS : M+l : 305.16. [0519] 1H NMR (DMSO, 300 MHz): delta = 10.77 (s, 1H), 6.84-6.80 (m, 1H), 6.69 (s, 2H), 6.69-6.66 (m, 1H), 3.14 (s, 3H), 1.33 (s, 9H). [0520] Tert-buty 2,4-bis(benzylthio)-6-fluoro-9H-pyrimido[4,5-Z>]indol-8- yl(methyl)carbamate (D15): Crude /er/-butyl 2-amino-3-cyano-5-fluoro-lH-indol-7- yl(methyl)carbamate (D13) (4 g, 13.14 mmol), sodium hydroxide (756 mg, 18.9 mmol), and EtOH (40 ml) were added in a 350ml seal tube. The mixture was stirred at 50 C for 15mins to dissolve all NaOH and then cooled down to room temperature. After the atmosphere was displaced with argon, the solution was added with carbon disulfide (10 ml) and dimethyl sulfoxide (1 ml). The reaction was stirred at room temperature for lhour then refluxed at 80 C for 42 hours. It was then cooled down to room temperature and placed in an ice-water bath. Water (20 ml) was added followed by the addition of benzyl chloride (3.33 g, 26.27 mmol). The ice-water bath was removed, and the reaction was stirred at ambient temperature for 5 hours. An additional of benzyl chloride (1.66 g, 13.13 mmol) was added, and the resulting solution was stirred at room temperature overnight. It was diluted with EtOAc (60 ml) and water (100 ml). The resulting solution was partitioned into two layers, and the aqueous phase was removed through an extraction funnel and back extracted with 50 ml of ethyl acetate. The combined organic layers were concentrated by rotary evaporation, and the residue was purified through silica gel column chromatography (15 % EtOAc in hexane) to afford the tile compound (D15) as yellow foam (2.65 g, 36%). LC-MS : M+l : 561.05. [0521] 1H NMR (CDC13, 300 MHz): delta = 8.72 (s, 1H), 7.66-7.62 (dd, J = 8.37, 2.28 Hz, 1H), 7.48-7.27 (m, 10H), 7.05-7.01 (dd, J = 10.14, 2.28 Hz, 1H), 4.69 (s, 2H), 4.55 (s, 2H), 3.37 (s, 3H), 1.48 (s, 9H). [0522] Tert-buty 2,4-bis(benzylsulfonyl)-6-fluoro-9H-pyrimido[4,5-Z>]indol-8- yl(methyl)carbamate (D16): The solution of tert-bu yl 2,4-bis(benzylthio)-6-fluoro-9H- pyrimido[4,5-6]indol-8-yl(methyl)carbamate (D15) (2.28 g, 4.07 mmol) in DCM (50 ml) was cooled in an ice-water bath and added with 3-chloroperoxybenzoic acid 77 % (2.01 g, 8.95 mmol). After the reaction was stirred for 1 hour, the ice-water bath was removed and an additional mCPBA (2.01 g) was added. The resulting solution was stirred at ambient temperature for 7 hours. It was then extract with 5% K2CO3 solution (100 ml), and the aqueous layer was back extracted with DCM (100ml). The combined organic layers were washed first with 5% K2C03 (100 ml) then with 5% NaCl solution (50 ml). It was dried over sodium sulfate and concentrated by rotary evaporation to afford the crude title compound (D16) as bright yellow solid (2.54 g, quantitative yield). LC-MS : M+l : 625.05. [0523] 1H NMR (CDCI3, 300 MHz): delta = 10.07 (s, 1H), 8.49-8.46 (dd, J = 8.64, 2.22 Hz, 1H), 7.54-7.51 (m, 1H), 7.38-7.27 (m, 10H), 4.95 (s, 2H), 4.84 (s, 2H), 3.40 (s, 3H), 1.52 (s, 9H). Scheme: D16 D17 D18 (4.069) [0524] Preparation of D17: The bis-sulfone 2 (1 1.80 g, 17.23 mmol) was dissolved in NMP (60 mL), followed by adding 2-methylpyrimidin-5-ol 1 (7.59 g, 68.93 mmol). The homogeneous solution was obtained. K2CO3 (9.53 g, 68.93 mmol) was added and the resulting suspension was heated to 100 C for 1 hr, then Boc protected amine (7.32 g, 34.46 mmol) was added and ...

References: [1]Patent: US2012/238751,2012,A1 .Location in patent: Page/Page column 63.
[2]Patent: WO2014/43272,2014,A1 .Location in patent: Paragraph 0523; 0524.

21
[ 1400809-02-0 ]
[ 127199-44-4 ]
[ 35231-56-2 ]
[ 1400802-17-6 ]

References: [1]Patent: US2012/238751,2012,A1 .

22
[ 1400808-67-4 ]
[ 127199-44-4 ]
[ 35231-56-2 ]
[ 1400809-72-4 ]

Yield	Reaction Conditions	Operation in experiment
0.182 g		EXAMPLE 12: Synthesis of Prodrugs at R (5)-2-Amino-A^-(4-((R)-7-amino-5-azaspiro[2.4]heptaii-5-yl)-6-fluoro-2-(2- methylpyrimidiii-5-yloxy)-9H-pyrimido[4.5-Z>]indol-8-yl)-A7-methylpropanamide D16 D77 D78 D79 D80 (4.423) [0576] The mixture of D16 (1.00 g, 1.46 mmol) in trifluoroacetic acid (3.0 mL) was stirred for 30 min at 23 C. Trifluoroacetic acid was evaporated by reduced pressure to provide D77 (quantitative yield) as deep orange solid. This crude material was used for next reaction without further purification. LC/MS (ESI, M+H+) = 585. The mixture of D77 (0.292 g, 0.50 mmol), 2-methylpyrimidin-5-ol (0.165 g, 1.50 mmol) and K2C03 (0.276 g, 2.00 mmol) in NMP (5.0 mL) was stirred for 2 hr at 100 C. After being stirred for 2 hr, the reaction was checked by LC/MS. (R)-tert-bu yl 5-azaspiro[2.4]hepten-7-ylcarbamate (0.318 g, 1.50 mmol) was added at once, the mixture was allowed to stir for 1 hr 30 min at 100 C. The resulting heterogeneous mixture was cooled to 23 C and purified by HPLC to provide D78 (0.182 g, 0.34 mmol) as yellow solid. LC/MS (ESI, M+H+) = 535. To a solution of D78 (0.182 g, 0.34 mmol) and K2C03 (0.094 g, 0.68 mmol) in CH2C12 (10.0 mL) was added (5)-2-(l,3-dioxoisoindolin-2-yl)propanoyl chloride (0.161 g, 0.68 mmol) dissolved in CH2C12 (2.0 mL) at 23 C. The mixture was allowed to stir for 2 hr at 60 C and then cooled to 23 C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to give D79 as yellow solid. LC/MS (ESI, M+H+) = 736. To a solution of D79 in ethanol (7.0 mL) was added hydrazine (1.5 mL, 30 wt. % solution in water) via syringe at 23 C. The mixture was stirred for 1 hr at 23 C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to provide 5 as light yellow solid. LC/MS (ESI, M+H+) = 606. The mixture of 5 in trifluoroacetic acid (1.50 mL) was stirred for 30 min at 23 C. The crude material was purified by HPLC to provide a title compound D80 (0.031 g, 0.061 mmol) as white solid. LC/MS (ESI, M+H+) = 506.

References: [1]Patent: WO2014/43272,2014,A1 .Location in patent: Paragraph 0575; 0576.

23
[ 1581682-46-3 ]
[ 127199-44-4 ]
[ 1581683-55-7 ]

Yield	Reaction Conditions	Operation in experiment
60%		Example lu - Preparation of Compound of Formula I 6-Fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)methyl)-9H-pyrimido[4,5- b]indol-4-ol: [0284] The ethyl 2-amino-7-((tert-butoxycarbonyl)(methyl)amino)-5-fluoro-lH- indole-3-carboxylate (3.5 lg, lOmmol) and 2-(2-methylpyrimidin-5-yl)acetonitrile (1.50g, l lmmol, 1.1 equi.) was added into 50ml 4M dioxane solution, the mixture was stirred at room temperature for24 hours, then removed excess dioxane solvent, the residue was re- dissolved into 50ml 5% NaOH in H20 and 50 ml Methanol, the solution was heated to reflux for 2 hours, then the solution was neutralized with 6M HCl, the resulting solution was concentrated. The residue was purified by reverse phase column to provide the desired product 6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)methyl)-9H-pyrimido[4,5- b]indol-4-ol (680mg, 20% yield in over two steps), MS (ESI) m/z 339 (M + H)+. (R)-4-(7-amino-5-azaspiro[2.4]heptan-5-yl)-6-fluoro-N-methyl-2-((2-methylpyrimidiii- 5-yl)methyl)-9H-pyrimido[4,5-b]indol-8-amine (6) [0285] To a solution of 6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5- yl)methyl)-9H-pyrimido[4,5-b]indol-4-ol (34mg, 0.1 mmol) in 5ml NMP under ice water bath was added into 42mg (0.3 mmol) K2C03, followed 45mg BOP (0.1 mmol), the olution was stirred for 30 min, then <strong>[127199-44-4](R)-tert-butyl 5-azaspiro[2.4]heptan-7-ylcarbamate</strong> (22mg, 0.1 mmol) was added to above solution, then the mixture was warmed to 40 degree and stirred for overnight (12 hours), the reaction mixture was purified by HPLC to provide (R)-tert-butyl (5-(6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)methyl)-9H-pyrimido[4,5-b]indol- 4-yl)-5-azaspiro[2.4]heptan-7-yl)carbamate, 33mg, 60% yield). [0286] The Boc protected compounds 5 (30mg) was dissolved into 2ml 50% TFA in DCM, the mixture was stirred for one 1 hours, then concentrated, the residue was purified by reverse HPLC to provide final compound 6( 12mg, yield 46% ).

References: [1]Patent: WO2014/43272,2014,A1 .Location in patent: Paragraph 0284; 0285.

24
[ 127199-44-4 ]
[ 1400802-17-6 ]

References: [1]Patent: WO2014/43272,2014,A1 .

25
[ 127199-44-4 ]
[ 1400808-69-6 ]

References: [1]Patent: WO2014/43272,2014,A1 .

26
[ 127199-44-4 ]
(R)-2-amino-N-(4-(7-(2-aminoacetamido)-5-azaspiro[2.4]heptan-5-yl)-6-fluoro-2-(2-methylpyrimidin-5-yloxy)-9H-pyrimido[4.5-b]ondol-8-yl)-N-methylacetamide [ No CAS ]

References: [1]Patent: WO2014/43272,2014,A1 .

27
[ 853029-57-9 ]
[ 127199-44-4 ]
C₃₁H₃₆N₈O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 6h;	A mixture of 4b (88 mg, 0.2 mmol), (S)-3-(N-Boc-amino)piperidine (44 mg, 0.22 mmol) and K2CO3 (55 mg, 0.4 mmol) in DMF (6 mL) was stirred at 75 C for 6 h. After cooling to r.t., the mixture was poured into water (12 mL) and extracted with DCM (3 * 10 mL). The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the Boc precursor of 1i as a colorless syrup (80 mg, 72%), which was dissolved in DCM (2 mL), and TFA (390 muL) was added. The solution was stirred at room temperature for 3 h and then poured into ice-cold water (4 mL). The organic phase was separated, and the aqueous phase was basified with K2CO3 and extracted with DCM (2 * 10 mL). The organic layers were combined and washed with saturated brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by flash chromatography (DCM/MeOH/TEA, 100:0.5:0.5) to give pure 1i as a white solid (51 mg, 85%).

References: [1]European Journal of Medicinal Chemistry,2014,vol. 83,p. 547 - 560.

28
[ 127199-44-4 ]
7-((R)-7-tert-Butoxycarbonylamino-5-aza-spiro[2.4]hept-5-yl)-8-chloro-6-fluoro-1-((1R,2S)-2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Patent: CN107513053,2017,A .

29
[ 127199-44-4 ]
sitafloxacin [ No CAS ]

References: [1]Patent: CN107513053,2017,A .

30
6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [ No CAS ]
[ 127199-44-4 ]
C₂₄H₂₇F₂N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.7%	With triethylamine; In acetonitrile; at 35℃;	(2) While stirring, add 20.0 mL of acetonitrile, 1.89 g of the compound IV, 2.69 g of triethylamine, and 2.10 g of compound III to the 200 mL reaction flask in this order, and perform the reaction at 35 C. After the reaction is completed, add 100.0 mL thereto. The purified water was stirred well and filtered, and the resulting cake was washed with water and dried in vacuo at 40 C. to give an off-white solid 2.94 g, which was compound V. The yield was 92.7%.

References: [1]Patent: CN107513053,2017,A .Location in patent: Paragraph 0032; 0044; 0050; 0053; 0056.

31
C₁₈H₂₆N₂O₂ [ No CAS ]
[ 127199-44-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; ammonium formate; In isopropyl alcohol; at 20℃;	(1) 3.09 g of Compound II and 30 mL of isopropanol are fed into a 50 ml reaction flask, 0.58 g of 10% Pd/C and 1.09 g of ammonium formate are added under stirring, and the reaction is performed at 20 C. After completion of the reaction, filtration is performed. The filter cake was washed with isopropanol three times, and the filtrate was collected and concentrated under reduced pressure to give an off-white solid 2.17g, which was Compound III, with a yield of 100%;

References: [1]Patent: CN107513053,2017,A .Location in patent: Paragraph 0031; 0043; 0047; 0049; 0055.

32
C₂₀H₁₈ClF₂N₅O₄ [ No CAS ]
[ 127199-44-4 ]
C₃₁H₃₇ClFN₇O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 2h;Inert atmosphere;	To a mixture of compound 36b (120 mg, 0.26 mmol) in NMP (3 mL) was added compound 83a (55 mg, 0.26 mmol) and DIEA (74 mg, 0.57 mmol). The resulting mixture was heated at 100 C for 2 hours. The mixture was purified by C18-flash chromatography, elution gradient from 5%to 70%CH 3CN in water (0.02%FA). Pure fractions were evaporated to dryness to afford compound 83b (120 mg, 70% yield) as a yellow solid. LCMS: R t = 1.19 min in 3 min chromatography (3min-5-95%MeCN in water (0.02%FA), Waters Acquity UPLC BEH C18 1.7um, 2.1*50 mm, 40C), MS (ESI) m/z= 658.1 [M+H] +.

References: [1]Patent: WO2019/149164,2019,A1 .Location in patent: Page/Page column 234; 60.

Historical Records

Technical Information

• Acyl Group Substitution • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chan-Lam Coupling Reaction • Complex Metal Hydride Reductions • Halogenation • Heat of Combustion • Hydride Reductions • Lawesson's Reagent • Leuckart-Wallach Reaction • Mannich Reaction • Petasis Reaction • Preparation of Amines • Reactions of Amines • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes • Specialized Acylation Reagents-Vilsmeier Reagent • Ugi Reaction

Related Functional Groups of
[ 127199-44-4 ]

Amides

A124184 [127199-45-5]

(S)-tert-Butyl 5-azaspiro[2.4]heptan-7-ylcarbamate

Similarity: 1.00

A107521 [127199-54-6]

tert-Butyl ((3S,4S)-4-methylpyrrolidin-3-yl)carbamate

Similarity: 0.94

A321330 [132414-81-4]

5-Boc-hexahydropyrrolo[3,4-b]pyrrole

Similarity: 0.92

A200929 [147459-52-7]

tert-Butyl (3-methylpyrrolidin-3-yl)carbamate

Similarity: 0.92

A862625 [186203-81-6]

tert-Butyl hexahydro-1H-pyrrolo[3,4-b]pyridine-6(2H)-carboxylate

Similarity: 0.91

Amines

A124184 [127199-45-5]

(S)-tert-Butyl 5-azaspiro[2.4]heptan-7-ylcarbamate

Similarity: 1.00

A107521 [127199-54-6]

tert-Butyl ((3S,4S)-4-methylpyrrolidin-3-yl)carbamate

Similarity: 0.94

A200929 [147459-52-7]

tert-Butyl (3-methylpyrrolidin-3-yl)carbamate

Similarity: 0.92

A106626 [149649-58-1]

2-Boc-aminomethyl-pyrrolidine

Similarity: 0.90

A107505 [122536-76-9]

(S)-tert-Butyl pyrrolidin-3-ylcarbamate

Similarity: 0.90

Related Parent Nucleus of
[ 127199-44-4 ]

Pyrrolidines

A124184 [127199-45-5]

(S)-tert-Butyl 5-azaspiro[2.4]heptan-7-ylcarbamate

Similarity: 1.00

A107521 [127199-54-6]

tert-Butyl ((3S,4S)-4-methylpyrrolidin-3-yl)carbamate

Similarity: 0.94

A200929 [147459-52-7]

tert-Butyl (3-methylpyrrolidin-3-yl)carbamate

Similarity: 0.92

A106626 [149649-58-1]

2-Boc-aminomethyl-pyrrolidine

Similarity: 0.90

A107505 [122536-76-9]

(S)-tert-Butyl pyrrolidin-3-ylcarbamate

Similarity: 0.90

Spiroes

A124184 [127199-45-5]

(S)-tert-Butyl 5-azaspiro[2.4]heptan-7-ylcarbamate

Similarity: 1.00

A764534 [1086398-02-8]

tert-Butyl 2,5-diazaspiro[3.4]octane-2-carboxylate

Similarity: 0.87

A325179 [960294-18-2]

1-Boc-1,8-diazaspiro[5.5]undecane

Similarity: 0.85

A197624 [1251005-45-4]

tert-Butyl 1,6-diazaspiro[3.5]nonane-1-carboxylate

Similarity: 0.84

A221123 [674792-08-6]

4-Boc-4,7-diazaspiro[2.5]octane

Similarity: 0.84

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Code	Phrase
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H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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CAS No.: 127199-44-4

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