[ CAS No. 127199-45-5 ] {[proInfo.proName]}

Name: 127199-45-5|(S)-tert-Butyl 5-azaspiro[2.4]heptan-7-ylcarbamate|98%
Brand: Ambeed
SKU: A124184
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Quality Control of [ 127199-45-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 127199-45-5 ]

SDS Specification

Alternatived Products of [ 127199-45-5 ]

Product Details of [ 127199-45-5 ]

CAS No. :	127199-45-5	MDL No. :	MFCD09955395
Formula :	C₁₁H₂₀N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CGEBPOMWRHSMLI-MRVPVSSYSA-N
M.W :	212.29	Pubchem ID :	10353141
Synonyms :

Calculated chemistry of [ 127199-45-5 ]

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 :	50.36 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.93 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.37
Log Po/w (XLOGP3) :	0.94
Log Po/w (WLOGP) :	0.82
Log Po/w (MLOGP) :	1.15
Log Po/w (SILICOS-IT) :	1.09
Consensus Log Po/w :	1.27

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.48
Solubility :	6.96 mg/ml ; 0.0328 mol/l
Class :	Very soluble
Log S (Ali) :	-1.58
Solubility :	5.53 mg/ml ; 0.026 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.31
Solubility :	1.04 mg/ml ; 0.00492 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.21

Safety of [ 127199-45-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 127199-45-5 ]

* 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 [ 127199-45-5 ]

[ 127199-45-5 ] Synthesis Path-Downstream 1~87

1
[ 101987-89-7 ]
[ 127199-45-5 ]
[ 129321-52-4 ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine In acetonitrile for 7.5h; Heating;

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

2
[ 127199-45-5 ]
[ 127199-27-3 ]
7-[7-(s)-tert-butoxycarbonylamino-5-azaspiro[2,4]-hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.5%	With triethylamine; In acetonitrile; at 80℃; for 2.0h;	II 100.0g, III 80.0g was dissolved in 2000 ml acetonitrile. Add 41.0g triethylamine. Raise the temperature to 80 C. After reacting 2h, TLC detection reaction finishes. Lowering the temperature to 0 C, after stirring 2h filtration, filtration cake 45 C hot air drying 6h yellow product obtained after IV 147.0g. Yield: 91.5%.

Reference： [1]Patent: CN106349218,2017,A .Location in patent: Paragraph 0028
[2]Journal of Medicinal Chemistry,1994,vol. 37,p. 3344 - 3352

3
[ 127199-45-5 ]
[ 127199-26-2 ]
7-((S)-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 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In acetonitrile for 5h; Heating;

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

4
[ 127199-45-5 ]
8-Chloro-6,7-difluoro-1-((1R,2R)-2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]
7-((S)-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 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylamine 1.) CH₃CN, reflux, 5 h, 2.) RT, 15 min.; Yield given. Multistep reaction;

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

5
[ 127199-45-5 ]
8-Chloro-6,7-difluoro-1-((1R,2R)-2-fluoro-cyclopropyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]
7-((S)-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 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylamine 1.) CH₃CN, reflux, 5 h, 2.) RT, 15 min.; Yield given. Multistep reaction;

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

6
[ 127199-42-2 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 5%-palladium/activated carbon; ammonium formate In ethanol for 4h; Reflux;	2 Intermediate product of Preparation 4 5-phenylethyl Removal 0.37 g of intermediate 4 described above with 20 ml of 95% ethanol solution was added 4 equivalents of solid ammonium formate and 0.5 g of 5% palladium - carbon. Then heated at reflux for 4 hours, after cooling the solid was removed by filtration, washed once with a small amount of ethanol. Then solvent was distilled off under reduced pressure. The final product obtained 0.28 g of crude product. The crude product was dissolved in 20 ml of ethyl acetate, then treated with 20 ml of 10% aqueous citric acid solution three times, the aqueous phase with 20% sodium hydroxide aqueous solution was adjusted to alkaline, then extracted three times with 40 ml of dichloromethane, with was washed once with saturated brine, dried over anhydrous magnesium sulfate after filtration, the solvent was distilled off to give the desired final product 0.245 g, 99% yield.
46%	With hydrogen In ethanol for 6h;

Reference： [1]Current Patent Assignee: GUANGZHOU YINGYA PHARMACEUTICAL; SHENZHEN LANGQI PHARMACEUTICAL - CN105330590, 2016, A Location in patent: Paragraph 0047; 0048; 0049
[2]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

7
[ 127199-45-5 ]
[ 167888-38-2 ]
[ 167888-06-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine In dimethyl sulfoxide at 100℃; for 87h;
	With dimethyl sulfoxide In (2S)-N-methyl-1-phenylpropan-2-amine hydrate	30 5-Amino-7-((S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid Example 30 5-Amino-7-((S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid A mixture of 20.0 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, 28.9 g of (S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane ([α]D20 -47.2° (c=1, MeOH)) and 80 ml of dimethyl sulfoxide was heated at 100° C. for 36 hours. The reaction mixture was poured into 500 ml of ice water. The deposited crystals were collected by filtration, washed with water and isopropanol, and then recrystallized from a mixture of methylene chloride and methanol to give 14.7 g of the desired compound, which was identified as the compound of Example 19.

Reference： [1]Yoshida, Toshihiko; Yamamoto, Yoichi; Orita, Hitomi; Kakiuchi, Masato; Takahashi, Yoshie; Itakura, Masakazu; Kado, Noriyuki; Yasuda, Shingo; Kato, Hideo; Itoh, Yasuo [Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 7, p. 1376 - 1386]
[2]Current Patent Assignee: ABBVIE INC - US5547962, 1996, A

8
((S)-5-Benzyl-4-oxo-5-aza-spiro[2.4]hept-7-yl)-carbamic acid tert-butyl ester [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogen In ethanol at 60℃; for 5h;

Reference： [1]Satoh, Koji; Imura, Akihiro; Miyadera, Akihiko; Kanai, Kazuaki; Yukimoto, Yusuke [Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 587 - 590]

9
[ 129306-33-8 ]
[ 127199-45-5 ]
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 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine 1.) DMSO, RT, 72 h, 2.) aq. EtOH, reflux, 6 h; Multistep reaction;

Reference： [1]Kawakami, Katsuhiro; Atarashi, Shohgo; Kimura, Youichi; Takemura, Makoto; Hayakawa, Isao [Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 11, p. 1710 - 1715]

10
[ 127199-45-5 ]
[ 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 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In N,N-dimethyl-formamide at 65℃; for 12h;

Reference： [1]Baker, William R.; Cai, Shaopei; Dimitroff, Martin; Fang, Liming; Huh, Kay K.; Ryckman, David R.; Shang, Xiao; Shawar, Ribhi M.; Therrien, Joseph H. [Journal of Medicinal Chemistry, 2004, vol. 47, # 19, p. 4693 - 4709]

11
[ 127199-45-5 ]
[ 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 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In N,N-dimethyl-formamide at 65℃; for 48h;

12
[ 127199-45-5 ]
C₁₉H₁₂BF₄NO₅ [ No CAS ]
7-(7-tert-butoxycarbonylamino-5-aza-spiro[2.4]hept-5-yl)-6-fluoro-1-(4-hydroxy-phenyl)-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (7S)-5-azaspiro[2.4]heptan-7-ylcarbamic acid tert-butyl ester; C₁₉H₁₂BF₄NO₅ With sodium hydrogencarbonate In acetonitrile at 65℃; for 12h; Stage #2: With triethylamine In ethanol at 65℃; for 3h;

13
[ 127199-45-5 ]
(S)-9-((S)-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 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1.) Et₃N, 2.) Et₃N / 1.) DMSO, RT, 72 h, 2.) aq. EtOH, reflux, 6 h 2: concd. HCl / 0.08 h / Ambient temperature

Reference： [1]Kawakami, Katsuhiro; Atarashi, Shohgo; Kimura, Youichi; Takemura, Makoto; Hayakawa, Isao [Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 11, p. 1710 - 1715]

14
[ 24424-99-5 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 92 percent / toluene / 18 h / Ambient temperature 2: 90 percent / H₂ / 5percent Pd/C / ethanol / 5 h / 60 °C / 15200 - 19000 Torr

Reference： [1]Satoh, Koji; Imura, Akihiro; Miyadera, Akihiko; Kanai, Kazuaki; Yukimoto, Yusuke [Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 587 - 590]

15
[ 180506-32-5 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) Ph₃P, diethylazodicarboxylate, diphenylphosphoryl azide, 2.) LiAlH₄ / 1.) THF, RT, 24 h, 2.) THF, reflux, 1 h 2: 92 percent / toluene / 18 h / Ambient temperature 3: 90 percent / H₂ / 5percent Pd/C / ethanol / 5 h / 60 °C / 15200 - 19000 Torr
	Multi-step reaction with 4 steps 1: triphenylphosphine; diphenyl phosphoryl azide; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Inert atmosphere; Cooling with ice 2: lithium aluminium tetrahydride / tetrahydrofuran / Cooling with ice; Reflux 3: triethylamine / ethanol / 20 °C 4: palladium on activated charcoal; hydrogen / ethanol / 20 °C

Reference： [1]Satoh, Koji; Imura, Akihiro; Miyadera, Akihiko; Kanai, Kazuaki; Yukimoto, Yusuke [Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 587 - 590]
[2]Current Patent Assignee: SUZHOU DAWNRAYS PHARMACEUTICAL - CN109232530, 2019, A

16
[ 144282-41-7 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 92 percent / toluene / 18 h / Ambient temperature 2: 90 percent / H₂ / 5percent Pd/C / ethanol / 5 h / 60 °C / 15200 - 19000 Torr

Reference： [1]Satoh, Koji; Imura, Akihiro; Miyadera, Akihiko; Kanai, Kazuaki; Yukimoto, Yusuke [Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 587 - 590]

17
[ 129306-04-3 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 65 percent / 0.1percent aq. K₂HPO₄/KH₂PO₄ buffer pH=6.0 / 240 h / 30 °C / Phaeocreopsis sp. JSM 1880 2: 1.) Ph₃P, diethylazodicarboxylate, diphenylphosphoryl azide, 2.) LiAlH₄ / 1.) THF, RT, 24 h, 2.) THF, reflux, 1 h 3: 92 percent / toluene / 18 h / Ambient temperature 4: 90 percent / H₂ / 5percent Pd/C / ethanol / 5 h / 60 °C / 15200 - 19000 Torr

Reference： [1]Satoh, Koji; Imura, Akihiro; Miyadera, Akihiko; Kanai, Kazuaki; Yukimoto, Yusuke [Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 587 - 590]

18
[ 220969-69-7 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: toluene / 0.5 h / Heating 2: 65 percent / 0.1percent aq. K₂HPO₄/KH₂PO₄ buffer pH=6.0 / 240 h / 30 °C / Phaeocreopsis sp. JSM 1880 3: 1.) Ph₃P, diethylazodicarboxylate, diphenylphosphoryl azide, 2.) LiAlH₄ / 1.) THF, RT, 24 h, 2.) THF, reflux, 1 h 4: 92 percent / toluene / 18 h / Ambient temperature 5: 90 percent / H₂ / 5percent Pd/C / ethanol / 5 h / 60 °C / 15200 - 19000 Torr

Reference： [1]Satoh, Koji; Imura, Akihiro; Miyadera, Akihiko; Kanai, Kazuaki; Yukimoto, Yusuke [Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 587 - 590]

19
[ 207554-17-4 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: trifluoroacetic acid / CH₂Cl₂ / 1.5 h / Ambient temperature 2: toluene / 0.5 h / Heating 3: 65 percent / 0.1percent aq. K₂HPO₄/KH₂PO₄ buffer pH=6.0 / 240 h / 30 °C / Phaeocreopsis sp. JSM 1880 4: 1.) Ph₃P, diethylazodicarboxylate, diphenylphosphoryl azide, 2.) LiAlH₄ / 1.) THF, RT, 24 h, 2.) THF, reflux, 1 h 5: 92 percent / toluene / 18 h / Ambient temperature 6: 90 percent / H₂ / 5percent Pd/C / ethanol / 5 h / 60 °C / 15200 - 19000 Torr

Reference： [1]Satoh, Koji; Imura, Akihiro; Miyadera, Akihiko; Kanai, Kazuaki; Yukimoto, Yusuke [Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 587 - 590]

20
[ 127199-45-5 ]
5-amino-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 74 percent / NEt₃ / dimethylsulfoxide / 87 h / 100 °C 2: conc. HCl / 0.08 h

21
[ 58632-95-4 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 67 percent / tetrahydrofuran / 4 h 2: 46 percent / H₂ / 50percent aq. 5percent Pd/C / ethanol / 6 h / 3192 Torr

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

22
7-(hydroxyimino)-5-<1(R)-phenylethyl>-4-oxo-5-azaspiro<2.4>heptane [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 30 percent / H₂ / Raney nickel / methanol / 12 h 2: 80 percent / lithium aluminium hydride / tetrahydrofuran / 17 h / Heating 3: 67 percent / tetrahydrofuran / 4 h 4: 46 percent / H₂ / 50percent aq. 5percent Pd/C / ethanol / 6 h / 3192 Torr

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

23
[ 127199-41-1 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 67 percent / tetrahydrofuran / 4 h 2: 46 percent / H₂ / 50percent aq. 5percent Pd/C / ethanol / 6 h / 3192 Torr

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

24
[ 127199-45-5 ]
DU-6668 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 76 percent / Et₃N / acetonitrile / 7.5 h / Heating 2: 35percent HCl / 0.25 h / Ambient temperature

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

25
[ 127199-45-5 ]
[ 127254-12-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / acetonitrile / 5 h / Heating 2: 35percent HCl / 0.25 h / Ambient temperature

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

26
[ 127199-45-5 ]
7-((S)-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 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / acetonitrile / 5 h / Heating 2: 35percent HCl / 0.25 h / Ambient temperature

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]

27
[ 127199-38-6 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 80 percent / lithium aluminium hydride / tetrahydrofuran / 17 h / Heating 2: 67 percent / tetrahydrofuran / 4 h 3: 46 percent / H₂ / 50percent aq. 5percent Pd/C / ethanol / 6 h / 3192 Torr
	Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 12 h / 0 - 20 °C 2: triethylamine; dmap / dichloromethane / 3 h / 20 °C 3: ammonium formate; 5%-palladium/activated carbon / ethanol / 4 h / Reflux

Reference： [1]Kimura; Atarashi; Kawakami; Sato; Hayakawa [Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3344 - 3352]
[2]Current Patent Assignee: GUANGZHOU YINGYA PHARMACEUTICAL; SHENZHEN LANGQI PHARMACEUTICAL - CN105330590, 2016, A

28
7-(S)-[tert-butoxycarbonylamino]-5-N-acetylazaspiro[2.4]heptane [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydroxide In ethanol; chloroform; water	[Example 25] 7-(S)-[tert-Butoxycarbonylamino]-5-azaspiro[2.4]heptane [Example 25] 7-(S)-[tert-Butoxycarbonylamino]-5-azaspiro[2.4]heptane In ethanol (4.0 ml) was dissolved 7-(S)-[tert-butoxycarbonylamino]-5-N-acetylazaspiro[2.4]heptane (386 mg, 1.5 mmol). At room temperature, a 1 mol/l aqueous solution (4.0 ml) of sodium hydroxide was added to the resulting solution. After stirring the mixture at 50ØC for 3 hours, a 5 mol/l aqueous solution (2.2 ml) of sodium hydroxide was added thereto, followed by stirring at 70ØC for 20 hours. Ethanol was evaporated under reduced pressure. The residue was separated by the addition of chloroform and water. The organic layer was dried over sodium sulfate, filtered, and then evaporated under reduced pressure, whereby the title compound (231 mg, 72%) was obtained as a crystalline residue. The 1H-NMR spectrum of the compound coincided with that of the standard product.
72%	With sodium hydroxide In ethanol; water at 20 - 70℃; for 23h;	25 EXAMPLE 25; 7-(S)-[tert-Butoxycarbonylamino]-5-[2.4]heptane In ethanol (4.0 ml) was dissolved 7-(S)-[tert-butoxycarbonylamino]-5-N-acetylazaspiro[2.4]heptane (386 mg, 1.5 mmol). At room temperature, a 1 mol/l aqueous solution (4.0 ml) of sodium hydroxide was added to the resulting solution. After stirring the mixture at 50° C. for 3 hours, a 5 mol/l aqueous solution (2.2 ml) of sodium hydroxide was added thereto, followed by stirring at 70° C. for 20 hours. Ethanol was evaporated under reduced pressure. The residue was separated by the addition of chloroform and water. The organic layer was dried over sodium sulfate, filtered, and then evaporated under reduced pressure, whereby the title compound (231 mg, 72%) was obtained as a crystalline residue. The 1H-NMR spectrum of the compound coincided with that of the standard product.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1310487, 2003, A1
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2004/19223, 2004, A1 Location in patent: Page 33

29
[ 577775-46-3 ]
[ 127199-45-5 ]
1-[(7S)-(tertiary-butoxycarbonyl)amino-5-azaspiro[2,4]hept-5-yl]-3-methyl-2-phenylpyrido[1,2-a]benzimidazole-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine In dimethyl sulfoxide at 90℃; for 3h;	175 Reference Example 175; 1-[(7S)-(tertiary-butoxycarbonyl)amino-5-azaspiro[2,4]hept-5-yl]-3-methyl-2-phenylpyrido[1,2-a]benzimidazole-4-carbonitrile (I-175) To dimethylsulfoxide (8ml) solution of 750 mg (2.36mmol) of 1-chloro-3-methyl-2-phenylpyrido[1,2-a]benzimidazole-4-carbonitrile (I-8) were added 551 mg (2.60 mmol) of (7S)-(tertiary-butoxycarbonyl)amino-5-azaspiro[2,4]heptane and 658 µl (4.72 mmol) of triethylamine, and the resultingmixture was heated at 90°C for 3 hours. After cooling, water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography. This was eluted with a mixed solvent of chloroform/acetone (10/1, v/v) to obtain 1.11 g (95 %) of the entitled compound as a yellow crystal. MS(ESI)m/z:494 (M+1)+.1H-NMR(CDCl3)δ: 0.41-1.04 (4H, m), 1.48(9H, s), 2.34(3H, s), 2.70-4.03(5H, m), 7.36-7.42(2H, m) , 7.53-7.67(5H, m), 8.06(1H, d, J=8.3Hz), 8.12-8.26(1H, m).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1479681, 2004, A1 Location in patent: Page 109

30
[ 127199-45-5 ]
[ 112811-68-4 ]
[ 627532-31-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine In acetonitrile at 25 - 50℃; for 76h;	1 Example 1: Ethyl 4-[7-(S)-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-2,5-difluoro-3-methoxybenzoylacetate; 7-(S)-tert-Butoxycarbonylamino-5-azaspiro[2.4]heptane (3.84 g, 1.0 eq.) was added to a solution containing ethyl 2,4,5-trifluoro-3-methoxybenzoylacetate (5.00 g, 18.10 mmol), acetonitrile (50 mL), and triethylamine (5.1 mL, 2.0 eq.), and the mixture was sequentially stirred at 25°C for three days and at 50°C for four hours. After the reaction mixture had been allowed to cool, the solvent was removed under reduced pressure. Toluene (50 mL) was added to the residue, and the resultant organic solution (organic layer) was washed with water (30 mL) and saturated saline (30 mL). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate = 3/1), and several fractions were combined. The solvent of the combined fraction was removed under reduced pressure, to thereby yield 6.30 g of the title compound as yellow-green oil (74%). 1H-NMR (270 MHz, CDCl3) δ: 0.64-0.90 (4H, m), 1.29 (3H, t, J = 7.2 Hz), 1.35 (9H, s), 3.28-4.25 (5H, m), 3.81 (3H, s), 3.89 (2H, d, J = 3.5 Hz), 4.23 (2H, q, J = 7.2 Hz, 14.3 Hz), 7.34(1H, m) MASS: m/e = 469 (EIMS)

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1518856, 2005, A1 Location in patent: Page/Page column 13

31
[ 98349-24-7 ]
[ 127199-45-5 ]
[ 627532-39-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In acetonitrile; at 40℃; for 23h;	Example 5: Ethyl 4-[7-(S)-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-2,5-difluorobenzoylacetate;-(S)-[tert-Butoxycarbonylamino]-5-azaspiro[2.4]heptane (3.11 g, 1.2 eq.) was added to a solution containing <strong>[98349-24-7]ethyl 2,4,5-trifluorobenzoylacetate</strong> (3.00 g, 12.19 mmol), acetonitrile (60 mL), and triethylamine (3.4 mL, 2.0 eq.), and the mixture was stirred for 23 hours at 40C. After the reaction mixture had been allowed to cool, the solvent was removed under reduced pressure. Ethyl acetate (90 mL) was added to the residue, and the mixture was heated to 40C for dissolution. The organic solution (organic layer) was washed with water (30 mL * 2) and dried over sodium sulfate, and the solvent was removed under reduced pressure. Hexane (60 mL) was added to the residue, and the mixture was stirred for one hour at 25C. The formed precipitates were collected through filtration and dried, to thereby yield 5.10 g of the title compound as yellow-orange crystals (95%). 1H-NMR (270 MHz, CDCl3) delta: 0.64-0.94 (4H, m), 1.27 (3H, t, J = 7.0 Hz), 1.45 (9H, s), 3.24-3.91 (5H, m), 3.85 (3H, s), 3.88(2H, s), 4.21 (2H, q, J = 7.0 Hz, 14.3 Hz), 6.27 (1H, dd, J = 7.0 Hz, 14.0 Hz), 7.57 (1H, dd, J = 7.0 Hz, 14.0 Hz) MASS: m/e = 439 (EIMS)

Reference： [1]Patent: EP1518856,2005,A1 .Location in patent: Page/Page column 14-15

32
[ 351354-45-5 ]
[ 127199-45-5 ]
[ 627532-50-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In acetonitrile for 6h; Heating / reflux;	4 Referential Example 4: Ethyl 4-[7-(S)-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-2,5-difluoro-3-methoxybenzoate; Potassium carbonate (4.70 g, 2.0 eq.) and 7-(S)-[tert-butoxycarbonylamino]-5-azaspiro[2.4]heptane (4.34 g, 1.2 eq.) were added to a solution of ethyl 2,4,5-trifluoro-3-methoxybenzoate (4.00 g, 17.00 mmol) in acetonitrile (40 mL), and the mixture was stirred for six hours under reflux. After the reaction mixture was allowed to cool down, the formed inorganic product was removed through filtration, and the solvent of the filtrate was removed under reduced pressure. Ethyl acetate (80 mL) was added to the residue, and the formed organic solution (organic layer) was washed with water (20 mL). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure, followed by co-boiling with hexane. Hexane (80 mL) was added to the residue, and the mixture was stirred for one hour at 25°C. The formed precipitates were collected through filtration and dried, to thereby yield 5.32 g of the title compound as colorless crystals (73%). The solvent of the crystallization mother liquor was removed under reduced pressure, and isopropyl alcohol (20 mL) and water (10 mL) were added to the residue, followed by stirring for one hour under ice-cooling. The formed precipitates were collected through filtration and dried, to thereby further yield 0.55 g of the title compound as colorless crystals (8%, total 81%). The solvent of the crystallization mother liquor was removed under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate = 5/1), and several fractions were combined. The solvent of the combined fraction was removed under reduced pressure, to thereby further yield 0.40 g of the title compound as colorless crystals (5%, total 86%).1H-NMR (270 MHz, DMSO-d6) δ: 0.43-0.91 (4H,, m), 1.28 (3H, t, J = 7.2 Hz), 1.38 (9H, s), 3.38-4.06 (5H, m), 3.73 (3H, s), 4.25 (2H, q, J = 7.2 Hz, 14.3 Hz), 7.20 (1H, m), 7.25 (1H, q, J = 7.0 Hz, 15.0 Hz) MASS: m/e = 427 (FABMS)

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1518856, 2005, A1 Location in patent: Page/Page column 18

Yield	Reaction Conditions	Operation in experiment
		Step 1b Scheme 1) 7(S)-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]heptane (Compound 1. The title compound was prepared in 10 steps from 1-acetylcyclopropanecarboxylic acid as described in J. Med. Chem. 1994, 37, 3344-3352 (Examples 17-27b).

34
[5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylato-O₃,O₄ ]difluoroboron [ No CAS ]
[ 107-06-2 ]
[ 127199-45-5 ]
[ 167888-06-4 ]

Yield	Reaction Conditions	Operation in experiment
	With dimethyl sulfoxide; triethylamine; N-ethyl-N,N-diisopropylamine In methanol; diethyl ether; dichloromethane	19 5-Amino-7-((S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid Example 19 5-Amino-7-((S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid A mixture of 6.0 g of [5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylato-O3,O4 ]difluoroboron, 5.59 g of (S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane ([α]D20 -46.6° (c=1, MeOH)), 3.06 ml of N,N-diisopropylethylamine and 24 ml of dimethyl sulfoxide was stirred at 30° C. for 3 days. The reaction mixture was diluted with water, neutralized with 10% hydrochloric acid to pH 7 and extracted with methylene chloride. The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, methylene chloride-methanol (100:1)) to give yellow crystals, which were washed with a mixture of methylene chloride and diethyl ether. 3.17 g of pale yellow crystals were obtained. A mixture of 3.14 g of the crystals, 3.09 ml of triethylamine, 62 ml of methanol and 31 ml of 1,2-dichloroethane was heated at reflux for 14 hours and then evaporated. The residue was diluted with water and neutralized with 10% hydrochloric acid to pH 7. The deposited crystals were collected by filtration and washed with water, isopropanol and diethyl ether to give 2.79 g of the desired compound as pale yellow crystals, which were recrystallized from a mixture of methylene chloride and methanol to give pale yellow needles, m.p. 217.5°-219° C. Analysis for C25 H31 FN4 O5 Calculated %: C, 61.72; H, 6.42; N, 11.52 Found %: C, 61.71; H, 6.48; N, 11.39

Reference： [1]Current Patent Assignee: ABBVIE INC - US5547962, 1996, A

35
[ 853029-57-9 ]
[ 127199-45-5 ]
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%).

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

36
[ 127199-37-5 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: ammonium acetate; sodium cyanoborohydride; acetic acid / ethanol / 14 h / 0 °C / pH 5.5 2: lithium aluminium tetrahydride / tetrahydrofuran / 12 h / 0 - 20 °C 3: triethylamine; dmap / dichloromethane / 3 h / 20 °C 4: ammonium formate; 5%-palladium/activated carbon / ethanol / 4 h / Reflux

Reference： [1]Current Patent Assignee: GUANGZHOU YINGYA PHARMACEUTICAL; SHENZHEN LANGQI PHARMACEUTICAL - CN105330590, 2016, A

37
[ 32933-03-2 ]
[ 127199-45-5 ]

Reference： [1]Patent: CN105330590,2016,A

38
[ 129306-05-4 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: triethylamine / tetrahydrofuran / 2 h / 0 - 20 °C 2: ammonium acetate; sodium cyanoborohydride; acetic acid / ethanol / 14 h / 0 °C / pH 5.5 3: lithium aluminium tetrahydride / tetrahydrofuran / 12 h / 0 - 20 °C 4: triethylamine; dmap / dichloromethane / 3 h / 20 °C 5: ammonium formate; 5%-palladium/activated carbon / ethanol / 4 h / Reflux
	Multi-step reaction with 6 steps 1: NADPH; D-glucose / tert-butyl methyl ether / 56 h / 40 °C 2: caesium carbonate / N,N-dimethyl-formamide / 100 °C 3: triphenylphosphine; diphenyl phosphoryl azide; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Inert atmosphere; Cooling with ice 4: lithium aluminium tetrahydride / tetrahydrofuran / Cooling with ice; Reflux 5: triethylamine / ethanol / 20 °C 6: palladium on activated charcoal; hydrogen / ethanol / 20 °C

Reference： [1]Current Patent Assignee: GUANGZHOU YINGYA PHARMACEUTICAL; SHENZHEN LANGQI PHARMACEUTICAL - CN105330590, 2016, A
[2]Current Patent Assignee: SUZHOU DAWNRAYS PHARMACEUTICAL - CN109232530, 2019, A

39
[ 127199-45-5 ]
[ 127199-25-1 ]
7-[7-(s)-tert-butoxycarbonylamino-5-azaspiro[2,4]-hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester With hydrogenchloride In water for 3h; Reflux; Stage #2: (7S)-5-azaspiro[2.4]heptan-7-ylcarbamic acid tert-butyl ester With triethylamine In water; acetonitrile at 80℃; for 2h;	7 preparation of 7-[7-(s)-tert-butoxycarbonylamino-5-azaspiro[2,4]-hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (0.5 g) was dissolved300 ml of concentrated hydrochloric acid,Heated to reflux under stirring,Reaction 3h, TLC monitoring to the reaction completely,Cooling to room temperature, adding 30% sodium hydroxide solution adjusted PH value of 3 to 4, and then extracted twice with dichloromethane,The organic phases were combined,Dried over anhydrous sodium sulfate,Filtering, concentrating the filtrate to obtain solid, then recrystallizing from ethanol and directly for the next step. The above solid was reacted with 7- (s) -tert-butoxycarbonylamino-azaspiro [2,4] heptane 4. 3 gMixed into 500ml of acetonitrile solution,Dropping triethylamine 8. 8ml,Stirring heated to 80 ° C reflux reaction 2h,TLC was followed until the reaction was complete.The solvent was removed under reduced pressure. To the residue was added 200 ml of dichloromethane,And then washed with water and saturated brine, respectively.The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the product, 0.62g, 81% yield,

Reference： [1]Current Patent Assignee: SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD. - CN103360310, 2016, B Location in patent: Paragraph 0024; 0057-0059

40
5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
99.3%	With palladium on activated charcoal; hydrogen In ethanol at 20℃;	1.7; 2.7 Step 7 5.00 g of Compound VI was added to the reaction flask, then 0.5 g of Pd/C and 50 mL of ethanol were added, and the hydrogen was replaced three times.Stir at room temperature for 10-12 hours under hydrogen atmosphere, and filter.Concentrated and dried to give 3.25 g of Compound VII, yield 99.3%.
94.7%	With palladium 10% on activated carbon; ammonium formate In ethanol; water at 5 - 10℃;	2 Example 2 (1) Will (7S)-tert-butoxycarbonylamino-5-N-benzylazaspiro[2.4]heptane(raw material) 20 g and 10% by weight of palladium carbon (containing water, dry weight)2.3g added to ethanol 250g,Added 12g ammonium formate,After adding 5~10°C reaction,TLC detected the end of the reaction.The mixture was suction filtered, and the filtrate was concentrated under reduced pressure at 40 to 45°C and concentrated until no condensation occurred.(2) Add 180 g of methylene chloride and 70 g of purified water to the concentrate and dissolve it with 15% sodium hydroxide at 0 to 5°C.The liquid was adjusted to a pH of about 13 (pH paper), and the layers were separated. The aqueous layer was extracted three times with dichloromethane (25 g each) and the organic layers were combined. The organic layer was washed twice with saturated sodium chloride solution (30 g each), the brine layers were combined, the brine layer was extracted with dichloromethane three times (12 g each time), and the organic layers were combined.The organic layer was dried over anhydrous sodium sulfate (9 g) for 1 h, suction filtered, and the filtrate was concentrated under reduced pressure at 30-35[deg.] C. and concentrated until no condensation occurred.(3) 60 g of n-hexane was added to the concentrated residue, stirred at 510° C. for 3 h, suction-filtered, and the filter cake was vacuum dried at 35 4040° C. for 3 h to obtain 13.3 g of a white solid, ie, (7S)-tert-butoxycarbonylamino-. 5-Azaspiro[2.4]heptane (Compound 1), yield 94.7%, GC purity 99.4%.

Reference： [1]Current Patent Assignee: SUZHOU DAWNRAYS PHARMACEUTICAL - CN109232530, 2019, A Location in patent: Paragraph 0026; 0040; 0041; 0047; 0061; 0062
[2]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN107879966, 2018, A Location in patent: Paragraph 0061-0066; 0070

41
6-chloro-2-[4-(2-pyrrolidin-1-yl-ethyl)-phenylamino]-nicotinamide [ No CAS ]
[ 127199-45-5 ]
C₂₉H₄₀N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine at 125℃; for 24h;

Reference： [1]Caldwell, Richard; Liu-Bujalski, Lesley; Qiu, Hui; Mochalkin, Igor; Jones, Reinaldo; Neagu, Constantin; Goutopoulos, Andreas; Grenningloh, Roland; Johnson, Theresa; Sherer, Brian; Gardberg, Anna; Follis, Ariele Viacava; Morandi, Federica; Head, Jared [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 21, p. 3419 - 3424]

42
C₁₃H₁₄N₄O [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / Cooling with ice; Reflux 2: triethylamine / ethanol / 20 °C 3: palladium on activated charcoal; hydrogen / ethanol / 20 °C

Reference： [1]Current Patent Assignee: SUZHOU DAWNRAYS PHARMACEUTICAL - CN109232530, 2019, A

43
[ 144282-35-9 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / ethanol / 20 °C 2: palladium on activated charcoal; hydrogen / ethanol / 20 °C

Reference： [1]Current Patent Assignee: SUZHOU DAWNRAYS PHARMACEUTICAL - CN109232530, 2019, A

44
[ 127199-45-5 ]
[ 127199-25-1 ]
C₂₆H₃₀ClF₂N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.1%	With sodium hydroxide In butan-1-ol at 50 - 55℃; for 3h;	1.8; 2.8 Step 8 Taking compound VII 3.19g,8-chloro-6,7-difluoro-1-[(1R,2s)-2-fluorocyclopropanyl]Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate3.05g, n-butanol 50mL and anhydrous sodium hydroxide 6g,The mixture was heated to 50-55 ° C under stirring for 3 hours, and the reaction solution was cooled to 45 ° C and concentrated under reduced pressure.50 mL of water and 50 mL of chloroform were added to the residue and stirred.The pH was adjusted to 4 with glacial acetic acid, and the aqueous layer was extracted three times with chloroform.The organic layer was combined, washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered.The filtrate was concentrated under reduced pressure, and 50 mL of ethanol was added to the residue. The mixture was stirred at a temperature of 45 ° C for 30 min, cooled to room temperature, 50 mL of ethyl acetate was added, and stirred at 10 ° C for 1 hour, filtered, filtered, washed with petroleum ether, dried, 30 ° C Drying under reduced pressure for 8 hours gave Compound VIII 4.08 g, yield 97.1%.

Reference： [1]Current Patent Assignee: SUZHOU DAWNRAYS PHARMACEUTICAL - CN109232530, 2019, A Location in patent: Paragraph 0026; 0042; 0043; 0047; 0063; 0064

45
C₈H₁₃BrO₃ [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: caesium carbonate / N,N-dimethyl-formamide / 100 °C 2: triphenylphosphine; diphenyl phosphoryl azide; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Inert atmosphere; Cooling with ice 3: lithium aluminium tetrahydride / tetrahydrofuran / Cooling with ice; Reflux 4: triethylamine / ethanol / 20 °C 5: palladium on activated charcoal; hydrogen / ethanol / 20 °C

Reference： [1]Current Patent Assignee: SUZHOU DAWNRAYS PHARMACEUTICAL - CN109232530, 2019, A

46
C₂₃H₃₁NO₆ [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 25 °C / 775.74 Torr 2: lithium hydroxide monohydrate; water / methanol / 2 h / 30 °C 3: (R)-1-phenyl-ethyl-amine / ethyl acetate; dichloromethane / 1 h / 25 °C 4: triethylamine; diphenylphosphoranyl azide / toluene / 2 h / Molecular sieve 5: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

47
C₁₆H₂₇NO₆ [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: (R)-1-phenyl-ethyl-amine / ethyl acetate; dichloromethane / 1 h / 25 °C 2: triethylamine; diphenylphosphoranyl azide / toluene / 2 h / Molecular sieve 3: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

48
C₁₆H₂₇NO₆ [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine; diphenylphosphoranyl azide / toluene / 2 h / Molecular sieve 2: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

49
[ 1279116-76-5 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
0.35 g	With aluminium In toluene at 70℃; for 3h;	12 Example 12 Preparation of Compound of Formula 14 The compound of formula 13 (0.5 g) was dissolved in 5 mL of toluene, and the temperature of the system was raised to 70 ° C.A toluene solution (2.7 g, 70% in toluene) of red aluminum was added dropwise to the system at this temperature.After the dropwise addition was completed, the reaction was held at 70 ° C for 3 hours.2 mL of 15% aqueous sodium hydroxide solution was added for quenching, 10 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (10 mL * 3), and the organic phases were combined.The organic phase was washed sequentially with saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate.The obtained crude product was subjected to column purification using a dichloromethane / methanol system to finally obtain a compound of formula 14 (0.35 g, white solid).

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A Location in patent: Paragraph 0212-0217

50
C₆H₁₂N₂O₂*2HCl [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1,1,1,3,3,3-hexamethyl-disilazane / acetonitrile / 12 h / 80 °C 2: sodium hydroxide / tetrahydrofuran; water / 2 h / 25 °C 3: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

51
[ 903900-37-8 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydroxide / tetrahydrofuran; water / 2 h / 25 °C 2: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

52
C₂₃H₃₃NO₆ [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate; water / methanol / 2 h / 30 °C 2: (R)-1-phenyl-ethyl-amine / ethyl acetate; dichloromethane / 1 h / 25 °C 3: triethylamine; diphenylphosphoranyl azide / toluene / 2 h / Molecular sieve 4: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

53
tert-butyl 1-cyanocyclopropanecarboxylate [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: zinc; methanesulfonic acid / tetrahydrofuran / 2 h / 60 °C 1.2: 16 h / 20 - 60 °C 2.1: dmap / acetonitrile / 2 h / 25 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 25 °C / 775.74 Torr 4.1: lithium hydroxide monohydrate; water / methanol / 2 h / 30 °C 5.1: (R)-1-phenyl-ethyl-amine / ethyl acetate; dichloromethane / 1 h / 25 °C 6.1: triethylamine; diphenylphosphoranyl azide / toluene / 2 h / Molecular sieve 7.1: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

54
C₁₈H₂₃NO₄ [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: dmap / acetonitrile / 2 h / 25 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 25 °C / 775.74 Torr 3: lithium hydroxide monohydrate; water / methanol / 2 h / 30 °C 4: (R)-1-phenyl-ethyl-amine / ethyl acetate; dichloromethane / 1 h / 25 °C 5: triethylamine; diphenylphosphoranyl azide / toluene / 2 h / Molecular sieve 6: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

55
O1’-tert-butyl O1-methyl cyclopropane-1,1-dicarboxylate [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: lithium hydroxide monohydrate; methanol / 2 h / 0 - 20 °C 2.1: 1,1'-carbonyldiimidazole / acetonitrile / 2 h / 0 - 20 °C 2.2: 9 h / 60 °C 3.1: ammonium acetate; ammonium hydroxide / methanol / 24 h / 60 °C 4.1: dmap / acetonitrile / 2 h / 25 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 25 °C / 775.74 Torr 6.1: lithium hydroxide monohydrate; water / methanol / 2 h / 30 °C 7.1: (R)-1-phenyl-ethyl-amine / ethyl acetate; dichloromethane / 1 h / 25 °C 8.1: triethylamine; diphenylphosphoranyl azide / toluene / 2 h / Molecular sieve 9.1: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

56
[ 1268842-79-0 ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: 1,1'-carbonyldiimidazole / acetonitrile / 2 h / 0 - 20 °C 1.2: 9 h / 60 °C 2.1: ammonium acetate; ammonium hydroxide / methanol / 24 h / 60 °C 3.1: dmap / acetonitrile / 2 h / 25 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 25 °C / 775.74 Torr 5.1: lithium hydroxide monohydrate; water / methanol / 2 h / 30 °C 6.1: (R)-1-phenyl-ethyl-amine / ethyl acetate; dichloromethane / 1 h / 25 °C 7.1: triethylamine; diphenylphosphoranyl azide / toluene / 2 h / Molecular sieve 8.1: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

57
C₁₈H₂₂O₅ [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: ammonium acetate; ammonium hydroxide / methanol / 24 h / 60 °C 2: dmap / acetonitrile / 2 h / 25 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 25 °C / 775.74 Torr 4: lithium hydroxide monohydrate; water / methanol / 2 h / 30 °C 5: (R)-1-phenyl-ethyl-amine / ethyl acetate; dichloromethane / 1 h / 25 °C 6: triethylamine; diphenylphosphoranyl azide / toluene / 2 h / Molecular sieve 7: aluminium / toluene / 3 h / 70 °C

Reference： [1]Current Patent Assignee: CHEMSTONE - CN110483369, 2019, A

58
(2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholine-2-carboxylic acid [ No CAS ]
[ 127199-45-5 ]
{(S)-5-[(2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholine-2-carbonyl]-5-azaspiro[2.4]hept-7-yl}carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: (2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholine-2-carboxylic acid With 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 25℃; for 0.166667h; Inert atmosphere; Stage #2: (7S)-5-azaspiro[2.4]heptan-7-ylcarbamic acid tert-butyl ester With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere;	288 {(S)-5-[(2R,6R)-4-(8-Cyano-qumoxalm-5-yl)-6-methyl-morpholme-2-carbonyl]- 5-aza-spiro[2.4]hept-7-yl}-carbamic acid tert-butyl ester: Into a 50 mL round-bottom flask, was placed (2R,6R)-4-(8-Cyano-quinoxalin-5-yl)-6-methyl-morpholine-2-carboxylic acid (80.0 mg; 0.27 mmol; 1.0 eq.) in DMF (2.0 ml), hatu (203.95 mg; 0.54 mmol; 2.0 eq.) was added and the resulting solution stirred for 10 minutes at rt after which (S)-(5-Aza-spiro[2.4]hept-7-yl)- carbamic acid tert-butyl ester (68.32 mg; 0.32 mmol; 1.20 eq.) and DIPEA (0.14 ml; 0.80 mmol; 3.0 eq.) were respectively added. The resulting mixture was stirred at room temperature for 2 h. The volatils were evaporated and the residue dissolved in DCM (2 mL). The solution was absorbed on a PuriFlash 12 g column and purified by chromatography (Hexane -Ethyl acetate, gradient 80- 20% for 5 minutes then 30-70% for 25 minutes to yield the title compound (75.0 mg; 56%) as a yellow oil. MS:493 [M+H]+.

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2020/25517, 2020, A1 Location in patent: Paragraph 00229; 00602

59
(R)-5-(4-cyclopentyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)-1-(p-tolyl)-1H-1,2,4-triazole-3-carboxylic acid [ No CAS ]
[ 127199-45-5 ]
tert-butyl ((S)-5-(5-((R)-4-cyclopentyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)-1-(p-tolyl)-1H-1,2,4-triazole-3-carbonyl)-5-azaspiro[2.4]heptan-7-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: (R)-5-(4-cyclopentyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)-1-(p-tolyl)-1H-1,2,4-triazole-3-carboxylic acid With 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 20℃; for 0.5h; Stage #2: (7S)-5-azaspiro[2.4]heptan-7-ylcarbamic acid tert-butyl ester With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-d<SUB>6</SUB>-formamide at 20℃;

Reference： [1]Cao, Danyan; Chen, Danqi; Chen, Lin; Damaneh, Mohammadali Soleimani; Hu, Jianping; Huan, Xia-Juan; Li, Jian; Li, Yanlian; Lv, Kaikai; Meng, Tao; Miao, Ze-Hong; Qin, Lihuai; Shen, Jingkang; Song, Shan-Shan; Tian, Chang-Qing; Wang, Xin; Wang, Ying-Qing; Xiong, Bing; Yu, Ting [Journal of Medicinal Chemistry, 2019]

60
[ 501-53-1 ]
[ 127199-45-5 ]
benzyl (S)-7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]heptane-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In tetrahydrofuran at 20℃; for 0.5h;	5.1.5 Tert-butyl N-[(7S)-5-azaspiro[2.4]heptan-7-yl]-N-methyl-carbamate (9b) To the mixture of tert-butyl N-[(7S)-5-azaspiro[2.4]heptan-7-yl]carbamate (8, 4.18g, 19.7mmol) in THF (80mL), benzyl chloroformate (3.22mL, 22.6mmol) and triethylamine (3.28mL, 23.6mmol) were added. The mixture was stirred at room temperature for 30min. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with 1N HCl and brine, dried over sodium sulfate, and concentrated in vacuo to obtain benzyl (7S)-7-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane-5-carboxylate as a solid, which was used for the next reaction without further purification. To the mixture of benzyl (7S)-7-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane-5-carboxylate in THF (100mL), potassium tert-butoxide (2.40g, 21.0mmol) was added. After the mixture was stirred for 1h, iodomethane (3.60mL, 58.0mmol) was added and stirred overnight. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was passed through a short pad of a silica gel column to obtain crude benzyl (7S)-7-[tert-butoxycarbonyl(methyl)amino]-5-azaspiro[2.4]heptane-5-carboxylate. To the mixture of crude benzyl (7S)-7-[tert-butoxycarbonyl(methyl)amino]-5-azaspiro[2.4]heptane-5-carboxylate in ethanol (60mL), 10% palladium carbon (1.0g) was added and stirred under hydrogen atmosphere for 3h. The insoluble matter was removed, and then, the filtrate was concentrated in vacuo. The residue was purified by column chromatography using silica gel and eluted with 0%-18% methanol in dichloromethane to obtain the title compound 9b (3.77g, 85%) as an oil. 1H NMR (400MHz, CDCl3) δ: 4.52-4.31 (1H, m), 3.38-3.35 (1H, m), 3.01-2.99 (1H, m), 3.00 (1H, d, J=10.9Hz), 2.84 (3H, s), 2.72 (1H, d, J=10.9Hz), 1.43 (9H, s), 0.62-0.56 (4H, m) ; 13C NMR (500MHz, DMSO-d6) δ: 155.21, 78.35, 61.45, 55.67, 50.70, 30.05, 27.97, 25.43, 14.26, 8.49; HRMS (Positive ESI) m/z 227.1772 (227.1759 calcd for C12H22N2O2+H); EA Anal. calcd for C12H22N2O2. C, 63.68; H, 9.80; N, 12.38. Found: C, 63.72; H, 9.74; N, 12.00; []D20 : 51.919 (c=1.017, MeOH).
	With triethylamine In dichloromethane at 20℃; for 3h;	14.1 Step 1 To a solution of tert-butyl (S)-(5-azaspiro[2.4]heptan-7-yl)carbamate (0.20g) and trimethylamine (0.42 mL) in dichloromethane (6.0 mL), benzyl chloroformate (0.22 mL) was added, followed by stirring at room temperature for 3 hours. Chloroform and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the organic layer was separated. The separated organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, thereby obtaining the crude benzyl (S)-7-((tert-butoxycarbonyl)amino)-5- azaspiro[2.4]heptane-5-carboxylate, and it was used in the next step without further purification.

Reference： [1]Arita, Tsuyoshi; Asano, Masayoshi; Domon, Yuki; Kubota, Kazufumi; Machinaga, Nobuo; Shimada, Kousei [Bioorganic and Medicinal Chemistry, 2020, vol. 28, # 21]
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2021/215544, 2021, A1 Location in patent: Paragraph 00141

61
[ 127199-45-5 ]
methyl 2-[[(7S)-7-[tert-butoxycarbonyl(methyl)amino]-5-azaspiro[2.4]heptan-5-yl]methyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran / 0.5 h / 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h 3: palladium 10% on activated carbon; hydrogen / ethanol / 3 h 4: potassium carbonate / dichloromethane / 14 h