[ CAS No. 2435-36-1 ]

Name: 2435-36-1|Dimethyl cyclopentane-1,3-dicarboxylate|95%
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Quality Control of [ 2435-36-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 2435-36-1 ]

CAS No. :	2435-36-1	MDL No. :	MFCD01735429
Formula :	C₉H₁₄O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SQFQEQDRLAZVJQ-UHFFFAOYSA-N
M.W :	186.21	Pubchem ID :	200652
Synonyms :

Calculated chemistry of [ 2435-36-1 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.78
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	45.83
TPSA :	52.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.87 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.36
Log Po/w (XLOGP3) :	0.79
Log Po/w (WLOGP) :	0.75
Log Po/w (MLOGP) :	0.86
Log Po/w (SILICOS-IT) :	1.02
Consensus Log Po/w :	1.16

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.23
Solubility :	11.0 mg/ml ; 0.0591 mol/l
Class :	Very soluble
Log S (Ali) :	-1.48
Solubility :	6.23 mg/ml ; 0.0335 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.96
Solubility :	20.4 mg/ml ; 0.109 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.61

Safety of [ 2435-36-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P305+P351+P338	UN#:	N/A
Hazard Statements:	H227-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 2435-36-1 ]

* 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.

Upstream synthesis route of [ 2435-36-1 ]
Downstream synthetic route of [ 2435-36-1 ]

[ 2435-36-1 ] Synthesis Path-Upstream 1~5

1
[ 67-56-1 ]
[ 4056-78-4 ]
[ 2435-36-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 7 - 12℃; for 16 h; Reflux	A 5-L, 3-neck, roundbottom flask was equipped with a mechanical stirrer, a J-KEM temperature controller, and a reflux condenser. The flask was charged with cyclopentane-l,3-dicarboxylic acid(357 g, 2.262 mol) and methanol (1.75 L). The solution was cooled to 7 °C using anice/water bath. Concentrated sulfuric acid (70 mL) was added dropwise over 30 minresulting in an exotherm up to 12 °C. The reaction mixture was heated to reflux andstirred for 16 h when TLC analysis (10 percent methanol/ethyl acetate) indicated that thereaction was complete. The reaction mixture was concentrated, redissolved in methyl- 179 -ATI-2514175vl tert-butyl ether, and washed with saturated aqueous sodium bicarbonate (2 x 150 mL) and brine (2 x 150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting clear oil was dissolved in hexane (2 L) and treated with a 2 N aqueous sodium hydroxide solution (950 mL) until the pH ~ 10. The layers were separated and the aqueous layer was extracted with hexane (4 x 1 L). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to provide 360 g (100percent) of dimethyl cyclopentane-l,3-dicarboxylate as a clear oil. 1H NMR (500 Hz, CDCls) δ ppm 3.67 (s, 6H), 2.75-2.83 (m, 2H), 2.20-2.26 (m, 1H), 2.05-2.12 (m, 1H), 1.90-2.0 (m, 4H).
88%	With sulfuric acid In water at 0 - 90℃;	Step A: Dimethyl cyclopentane-1,3-dicarboxylate. A solution of cyclopentane-1,3-dicarboxylic acid (70.0 g, 443 mmol) and anhydrous methanol (300 mL) was cooled to 0° C. in an ice water bath. Concentrated sulfuric acid (14 mL) was added dropwise, maintaining the temperature at <15° C. After the addition, the reaction was heated to 90° C. and stirred overnight. The reaction was cooled to room temperature and concentrated to dryness. The residue was treated with MTBE (500 mL) and H₂O (100 mL). The aqueous layer was separated and extracted with MTBE (2100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2100 mL), brine (100 mL), dried over anhydrous MgSO₄, filtered, and concentrated to dryness to provide the title compound (72.5 g, 88percent) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.65 (s, 6H), 2.84-2.72 (m, 2H), 2.26-2.17 (m, 1H), 2.11-2.02 (m, 1H), 1.96-1.88 (m, 4H).
88%	at 15 - 90℃;	. A solution of cyclopentane-1,3- dicarboxylic acid (70.0 g, 443 mmol) and anhydrous methanol (300 mL) was cooled to 0 °C in an ice water bath. Concentrated sulfuric acid (14 mL) was added dropwise, maintaining the temperature at < 15 °C. After the addition, the reaction was heated to 90 °C and stirred overnight. The reaction was cooled to room temperature and concentrated to dryness. Theresidue was treated with MTBE (500 mL) and H20 (100 mL). The aqueous layer was separated and extracted with MTBE (2 x 100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 100 mL), brine (100 mL), dried over anhydrous Mg504, filtered, and concentrated to dryness to provide the title compound (72.5 g, 88percent) as a pale yellow oil. ‘HNMR(400 IVIFIz, CDC13) 3.65 (s, 6H), 2.84-2.72 (m, 2H), 2.26-2.17 (m, 1H),2.11 -2.02(m, 1H), 1.96- 1.88(m,4H).

64%

at 20℃; for 15 h; Heating / reflux

To a solution of the title compound from Step A above (11.2 g) in MeOH (250 mL) was added concentrated H₂SO₄ (0.5 mL) at room temperature. The mixture was heated to reflux for 15 h, cooled to room temperature, filtrated and concentrated. The remaining residue was diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO₃ (3 x 50 mL) and saturated aqueous NaCl (50 mL), dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (8.43 g, 64percent). [MH]⁺ = 187.

Reference： [1] Patent: WO2012/145569, 2012, A1, . Location in patent: Page/Page column 179; 180
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3480 - 3491
[3] Patent: US2018/170931, 2018, A1, . Location in patent: Paragraph 0188
[4] Patent: WO2018/112382, 2018, A1, . Location in patent: Page/Page column 174
[5] Tetrahedron Letters, 2005, vol. 46, # 18, p. 3201 - 3203
[6] Patent: WO2006/128184, 2006, A2, . Location in patent: Page/Page column 167
[7] Australian Journal of Chemistry, 1985, vol. 38, # 11, p. 1705 - 1718
[8] Patent: WO2016/106623, 2016, A1, . Location in patent: Page/Page column 113
[9] Patent: WO2016/106624, 2016, A1, . Location in patent: Page/Page column 64

2
[ 67-56-1 ]
[ 84545-00-6 ]
[ 2435-36-1 ]

Reference： [1] Patent: WO2016/106623, 2016, A1, . Location in patent: Page/Page column 69
[2] Patent: WO2016/106624, 2016, A1, . Location in patent: Page/Page column 46
[3] Patent: WO2016/109219, 2016, A1, . Location in patent: Page/Page column 47

3
[ 498-66-8 ]
[ 2435-36-1 ]

Reference： [1] Patent: WO2012/145569, 2012, A1,

4
[ 2435-36-1 ]
[ 107-04-0 ]
[ 15448-76-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 0.5 h; Stage #2: at 20℃; for 12 h;	Dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate. n-Butyllithium (2.5 M in hexane, 419.0 mL, 1048 mmol) was added slowly to a solution of diisopropylamine (152 mL, 1090 mmol) and anhydrous THF (1000 mL) at −78° C. (dry ice/acetone) under N₂. Next, the reaction was stirred for 0.5 hours at 0° C. before cooling to −78° C. DMPU (404 mL, 3350 mmol) was added via an addition funnel. Then a solution of dimethyl cyclopentane-1,3-dicarboxylate (78.0 g, 419 mmol) and anhydrous THF (300 mL) was added slowly via an addition funnel. The reaction was warmed to 0° C. and stirred for 30 minutes, then cooled to −78° C. and treated with a solution of 1-bromo-2-chloroethane (59.0 mL, 712 mmol) and anhydrous THF (200 mL). The reaction was allowed to warm slowly to room-temperature and was stirred for 12 hours at room-temperature. The reaction was quenched with saturated aqueous ammonium chloride (400 mL). The reaction was diluted with ethyl acetate (500 mL), the organic layer separated, and the aqueous layer was further extracted with ethyl acetate (2×500 mL). The combined organic extracts were washed with brine (2×300 mL), dried over anhydrous MgSO₄, filtered, and concentrated to dryness. The residue was filtered through a pad of silica gel and washed with ethyl acetate (2000 mL). The filtrate was concentrated to dryness and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 30:1 to 20:1, gradient elution) to provide the title compound (48.5 g, 54percent) as white solid. ¹H NMR (400 MHz, CDCl₃): δ 3.69 (s, 6H), 2.08-1.99 (m, 4H), 1.91 (s, 2H), 1.73-1.63 (m, 4H).
54%	Stage #1: With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - 20℃; for 12 h;	Step B: Dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate. n-Butyllithium (2.5 M in hexane, 419.0 mL, 1048 mmol) was added slowly to a solution of diisopropylamine (152 mL, 1090 mmol) and anhydrous THF (1000 mL) at -78 °C (dry ice/acetone) underN2. Next, the reaction was stirred for 0.5 hours at 0 °C before cooling to -78 °C. DIVIPU (404 mL, 3350mmol) was added via an addition funnel. Then a solution of dimethyl cyclopentane-1,3- dicarboxylate (78.0 g, 419 mmol) and anhydrous THF (300 mL) was added slowly via an addition funnel. The reaction was warmed to 0 °C and stirred for 30 minutes, then cooled to -78°C and treated with a solution of 1-bromo-2-chloroethane (59.0 mL, 712 mmol) and anhydrous THF (200 mL). The reaction was allowed to warm slowly to room-temperature and was stirred for 12 hours at room-temperature. The reaction was quenched with saturated aqueous ammonium chloride (400 mL). The reaction was diluted with ethyl acetate (500 mL), the organic layer separated, and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The combined organic extracts were washed with brine (2 x 300 mL), dried overanhydrous MgSO4, filtered, and concentrated to dryness. The residue was filtered through a pad of silica gel and washed with ethyl acetate (2000 mL). The filtrate was concentrated to dryness and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 30 :1 to 20 :1, gradient elution) to provide the title compound (48.5 g, 54percent) as white solid. ‘H NIVIR (400MHz, CDC13): 3.69 (s, 6H), 2.08 - 1.99 (m, 4H), 1.91 (s, 2H), 1.73 - 1.63 (m, 4H)

Reference： [1] Patent: US2018/170931, 2018, A1, . Location in patent: Paragraph 0189
[2] Patent: WO2018/112382, 2018, A1, . Location in patent: Page/Page column 1714; 175
[3] Patent: US2010/267738, 2010, A1, . Location in patent: Page/Page column 32
[4] Patent: WO2012/145569, 2012, A1, . Location in patent: Page/Page column 180; 181
[5] Patent: WO2016/106623, 2016, A1, . Location in patent: Page/Page column 80
[6] Patent: WO2016/106624, 2016, A1, . Location in patent: Page/Page column 52

5
[ 2435-36-1 ]
[ 107-04-0 ]
[ 15448-76-7 ]
[ 106004-07-3 ]

Reference： [1] Australian Journal of Chemistry, 1985, vol. 38, # 11, p. 1705 - 1718

[ 2435-36-1 ] Synthesis Path-Downstream 1~68

1
[ 2435-36-1 ]
<i>cis</i>-cyclopentane-1,3-dicarboxylic acid dihydrazide [ No CAS ]

Reference： [1]Justus Liebigs Annalen der Chemie,1925,vol. 443,p. 247

2
[ 67-56-1 ]
[ 4056-78-4 ]
[ 2435-36-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfuric acid; at 7 - 12℃; for 16.0h;Reflux;	A 5-L, 3-neck, roundbottom flask was equipped with a mechanical stirrer, a J-KEM temperature controller, and a reflux condenser. The flask was charged with cyclopentane-l,3-dicarboxylic acid(357 g, 2.262 mol) and methanol (1.75 L). The solution was cooled to 7 C using anice/water bath. Concentrated sulfuric acid (70 mL) was added dropwise over 30 minresulting in an exotherm up to 12 C. The reaction mixture was heated to reflux andstirred for 16 h when TLC analysis (10 % methanol/ethyl acetate) indicated that thereaction was complete. The reaction mixture was concentrated, redissolved in methyl- 179 -ATI-2514175vl tert-butyl ether, and washed with saturated aqueous sodium bicarbonate (2 x 150 mL) and brine (2 x 150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting clear oil was dissolved in hexane (2 L) and treated with a 2 N aqueous sodium hydroxide solution (950 mL) until the pH ~ 10. The layers were separated and the aqueous layer was extracted with hexane (4 x 1 L). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to provide 360 g (100%) of dimethyl cyclopentane-l,3-dicarboxylate as a clear oil. 1H NMR (500 Hz, CDCls) delta ppm 3.67 (s, 6H), 2.75-2.83 (m, 2H), 2.20-2.26 (m, 1H), 2.05-2.12 (m, 1H), 1.90-2.0 (m, 4H).
88%	With sulfuric acid; In water; at 0 - 90℃;	Step A: Dimethyl cyclopentane-1,3-dicarboxylate. A solution of <strong>[4056-78-4]cyclopentane-1,3-dicarboxylic acid</strong> (70.0 g, 443 mmol) and anhydrous methanol (300 mL) was cooled to 0 C. in an ice water bath. Concentrated sulfuric acid (14 mL) was added dropwise, maintaining the temperature at <15 C. After the addition, the reaction was heated to 90 C. and stirred overnight. The reaction was cooled to room temperature and concentrated to dryness. The residue was treated with MTBE (500 mL) and H2O (100 mL). The aqueous layer was separated and extracted with MTBE (2100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2100 mL), brine (100 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness to provide the title compound (72.5 g, 88%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) delta 3.65 (s, 6H), 2.84-2.72 (m, 2H), 2.26-2.17 (m, 1H), 2.11-2.02 (m, 1H), 1.96-1.88 (m, 4H).
88%	With sulfuric acid; at 15 - 90℃;	. A solution of cyclopentane-1,3- dicarboxylic acid (70.0 g, 443 mmol) and anhydrous methanol (300 mL) was cooled to 0 C in an ice water bath. Concentrated sulfuric acid (14 mL) was added dropwise, maintaining the temperature at < 15 C. After the addition, the reaction was heated to 90 C and stirred overnight. The reaction was cooled to room temperature and concentrated to dryness. Theresidue was treated with MTBE (500 mL) and H20 (100 mL). The aqueous layer was separated and extracted with MTBE (2 x 100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 100 mL), brine (100 mL), dried over anhydrous Mg504, filtered, and concentrated to dryness to provide the title compound (72.5 g, 88%) as a pale yellow oil. ?HNMR(400 IVIFIz, CDC13) 3.65 (s, 6H), 2.84-2.72 (m, 2H), 2.26-2.17 (m, 1H),2.11 -2.02(m, 1H), 1.96- 1.88(m,4H).

88%	With sulfuric acid; at 15 - 90℃;	A solution of cyclopentane-l,3- dicarboxylic acid (70.0 g, 443 mmol) and anhydrous methanol (300 mL) was cooled to 0 C in an ice water bath. Concentrated sulfuric acid (14 mL) was added drop wise, maintaining the temperature at < 15 C. After the addition, the reaction was heated to 90 C and stirred overnight. The reaction was cooled to room temperature and concentrated to dryness. The residue was treated with MTBE (500 mL) and H2O (100 mL). The aqueous layer was separated and extracted with MTBE (2 x 100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 100 mL), brine (100 mL), dried over anhydrous MgS04, filtered, and concentrated to dryness to provide the title compound (72.5 g, 88%) as a pale yellow oil. NMR (400 MHz, CDCb) d 3.65 (s, 6H), 2.84 - 2.72 (m, 2H), 2.26 - 2.17 (m, 1H), 2.11 - 2.02 (m, 1H), 1.96 - 1.88 (m, 4H).
64%	With sulfuric acid; at 20℃; for 15.0h;Heating / reflux;	To a solution of the title compound from Step A above (11.2 g) in MeOH (250 mL) was added concentrated H2SO4 (0.5 mL) at room temperature. The mixture was heated to reflux for 15 h, cooled to room temperature, filtrated and concentrated. The remaining residue was diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 (3 x 50 mL) and saturated aqueous NaCl (50 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (8.43 g, 64%). [MH]+ = 187.
	With oxalyl dichloride; at 20℃;Inert atmosphere; Cooling with ice;	Oxalyl dichloride (10.03 g, 79 mmol) was added to a solution of cyclopentane-1, 3-dicarboxylic acid (5g, 31.6 mmol) in dry MeOH (50 mL) under argon in an ice-water bath. The solution was allowed to warm to room temperature and stirred overnight. Volatiles were then removed under vacuum. The residue was taken up in EtOAc (2×50 mL) and the solution was washed with NaHCO3(2×50 mL) and brine (50 mL) , dried over MgSO4, filtered, and concentrated to give the title compound.1H NMR (400 MHz, CDCl3) : 3.70 (s, 6H) , 2.75-2.90 (m, 2H) , 2.20-2.30 (m, 1H) , 2.10-2.20 (m, 1H) , 1.90-2.20 (m, 4H) ppm.
	With oxalyl dichloride; at 20℃;Inert atmosphere; Cooling with ice;	Oxalyl dichloride (10.03 g, 79 mmol) was added to a solution of cyclopentane-1, 3-dicarboxylic acid (5g, 31.6 mmol) in dry MeOH (50 mL) under argon in an ice-water bath. The solution was allowed to warm to room temperature and stirred overnight. Volatiles were then removed under vacuum. The residue was taken up in EtOAc (2 × 50 mL) and the solution was washed with NaHCO3 (2 × 50 mL) and brine (50 mL) , dried over MgSO4, filtered, and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3) : delta3.70 (s, 6H) , 2.75-2.90 (m, 2H) , 2.20-2.30 (m, 1H), 2.10-2.20 (m, 1H) , 1.90-2.20 (m, 4H) .

Reference： [1]Patent: WO2012/145569,2012,A1 .Location in patent: Page/Page column 179; 180
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 3480 - 3491
[3]Patent: US2018/170931,2018,A1 .Location in patent: Paragraph 0188
[4]Patent: WO2018/112382,2018,A1 .Location in patent: Page/Page column 174
[5]Patent: WO2019/239387,2019,A1 .Location in patent: Page/Page column 56; 57
[6]Tetrahedron Letters,2005,vol. 46,p. 3201 - 3203
[7]Patent: WO2006/128184,2006,A2 .Location in patent: Page/Page column 167
[8]Australian Journal of Chemistry,1985,vol. 38,p. 1705 - 1718
[9]Patent: WO2016/106623,2016,A1 .Location in patent: Page/Page column 113
[10]Patent: WO2016/106624,2016,A1 .Location in patent: Page/Page column 64

3
[ 2435-36-1 ]
[ 107-04-0 ]
[ 15448-76-7 ]
[ 106004-07-3 ]

Reference： [1]Australian Journal of Chemistry,1985,vol. 38,p. 1705 - 1718

4
[ 2435-36-1 ]
[ 106-95-6 ]
dimethyl 1-allylcyclopentane-1,3-dicarboxylate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 925 - 938

5
[ 2435-36-1 ]
dimethyl 1-(formylmethyl)cyclopentane-1,3-dicarboxylate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 925 - 938

6
[ 2435-36-1 ]
dimethyl 1-<2-(N-methylamino)ethyl>cyclopentane-1,3-dicarboxylate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 925 - 938

7
[ 2435-36-1 ]
1-{2-[(E)-Methylimino]-ethyl}-cyclopentane-1,3-dicarboxylic acid dimethyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 925 - 938

8
[ 2435-36-1 ]
trans-N-methyl-3-(methylcarbamoyl)spiro<cyclopentane-1,3'-pyrrolidin>-2'-one [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 925 - 938

9
[ 2435-36-1 ]
cis-N-methyl-3-(methylcarbamoyl)spiro<cyclopentane-1,3'-pyrrolidin>-2'-one [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 925 - 938

10
[ 2435-36-1 ]
trans-N-methyl-3-(methoxycarbonyl)spiro<cyclopentane-1,3'-pyrrolidin>-2'-one [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 925 - 938

11
[ 2435-36-1 ]
cis-N-methyl-3-(methoxycarbonyl)spiro<cyclopentane-1,3'-pyrrolidin>-2'-one [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 925 - 938

12
[ 2435-36-1 ]
[ 107-04-0 ]
[ 15448-76-7 ]

Yield	Reaction Conditions	Operation in experiment
54%		Dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate. n-Butyllithium (2.5 M in hexane, 419.0 mL, 1048 mmol) was added slowly to a solution of diisopropylamine (152 mL, 1090 mmol) and anhydrous THF (1000 mL) at -78 C. (dry ice/acetone) under N2. Next, the reaction was stirred for 0.5 hours at 0 C. before cooling to -78 C. DMPU (404 mL, 3350 mmol) was added via an addition funnel. Then a solution of dimethyl cyclopentane-1,3-dicarboxylate (78.0 g, 419 mmol) and anhydrous THF (300 mL) was added slowly via an addition funnel. The reaction was warmed to 0 C. and stirred for 30 minutes, then cooled to -78 C. and treated with a solution of 1-bromo-2-chloroethane (59.0 mL, 712 mmol) and anhydrous THF (200 mL). The reaction was allowed to warm slowly to room-temperature and was stirred for 12 hours at room-temperature. The reaction was quenched with saturated aqueous ammonium chloride (400 mL). The reaction was diluted with ethyl acetate (500 mL), the organic layer separated, and the aqueous layer was further extracted with ethyl acetate (2×500 mL). The combined organic extracts were washed with brine (2×300 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was filtered through a pad of silica gel and washed with ethyl acetate (2000 mL). The filtrate was concentrated to dryness and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 30:1 to 20:1, gradient elution) to provide the title compound (48.5 g, 54%) as white solid. 1H NMR (400 MHz, CDCl3): delta 3.69 (s, 6H), 2.08-1.99 (m, 4H), 1.91 (s, 2H), 1.73-1.63 (m, 4H).
54%		Step B: Dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate. n-Butyllithium (2.5 M in hexane, 419.0 mL, 1048 mmol) was added slowly to a solution of diisopropylamine (152 mL, 1090 mmol) and anhydrous THF (1000 mL) at -78 C (dry ice/acetone) underN2. Next, the reaction was stirred for 0.5 hours at 0 C before cooling to -78 C. DIVIPU (404 mL, 3350mmol) was added via an addition funnel. Then a solution of dimethyl cyclopentane-1,3- dicarboxylate (78.0 g, 419 mmol) and anhydrous THF (300 mL) was added slowly via an addition funnel. The reaction was warmed to 0 C and stirred for 30 minutes, then cooled to -78C and treated with a solution of 1-bromo-2-chloroethane (59.0 mL, 712 mmol) and anhydrous THF (200 mL). The reaction was allowed to warm slowly to room-temperature and was stirred for 12 hours at room-temperature. The reaction was quenched with saturated aqueous ammonium chloride (400 mL). The reaction was diluted with ethyl acetate (500 mL), the organic layer separated, and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The combined organic extracts were washed with brine (2 x 300 mL), dried overanhydrous MgSO4, filtered, and concentrated to dryness. The residue was filtered through a pad of silica gel and washed with ethyl acetate (2000 mL). The filtrate was concentrated to dryness and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 30 :1 to 20 :1, gradient elution) to provide the title compound (48.5 g, 54%) as white solid. ?H NIVIR (400MHz, CDC13): 3.69 (s, 6H), 2.08 - 1.99 (m, 4H), 1.91 (s, 2H), 1.73 - 1.63 (m, 4H)
54%		-Butyllithium (2.5 M in hexane, 419.0 mL, 1048 mmol) was added slowly to a solution of diisopropylamine (152 mL, 1090 mmol) and anhydrous THF (1000 mL) at -78 C (dry ice/acetone) under N2. Next, the reaction was stirred for 0.5 hours at 0 C before cooling to -78 C. DMPU (404 mL, 3350 mmol) was added via an addition funnel. Then a solution of dimethyl cyclopentane-l,3- dicarboxylate (78.0 g, 419 mmol) and anhydrous THF (300 mL) was added slowly via an addition funnel. The reaction was warmed to 0 C and stirred for 30 minutes, then cooled to -78 C and treated with a solution of l-bromo-2-chloroethane (59.0 mL, 712 mmol) and anhydrous THF (200 mL). The reaction was allowed to warm slowly to room-temperature and was stirred for 12 hours at room-temperature. The reaction was quenched with saturated aqueous ammonium chloride (400 mL). The reaction was diluted with ethyl acetate (500 mL), the organic layer separated, and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The combined organic extracts were washed with brine (2 x 300 mL), dried over anhydrous MgS04, filtered, and concentrated to dryness. The residue was filtered through a pad of silica gel and washed with ethyl acetate (2000 mL). The filtrate was concentrated to dryness and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 30 : 1 to 20 : 1, gradient elution) to provide the title compound (48.5 g, 54%) as white solid. 'H NMR (400MHz, CDCb): d 3.69 (s, 6H), 2.08 - 1.99 (m, 4H), 1.91 (s, 2H), 1.73 - 1.63 (m, 4H).

		Preparation of Bicyclic Amine Intermediate 3 (BAI-3) dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylateFreshly prepared lithium diisopropylamide (15 mL of n-butyllithium (2.5 M solution in hexane) and 5 mL of diisopropylamine were mixed at -30 C. in 50 mL of tetrahydrofuran) was cooled to -78 C. under nitrogen and stirred for 30 minutes. To a solution of dimethyl cyclopentane-1,3-dicarboxylate (2.67 g, 14.37 mmol) in tetrahydrofuran (12 mL) was drop added above freshly lithium diisopropylamide solution over 10 minutes (-75 C.-70 C.). The cold bath was then removed and the mixture was allowed to warm to 0 C. and maintained at that temperature for 20 minutes before being cooled to -80 C. A solution of 1-bromo-2-chloroethane (2 mL, 24 mmol) in tetrahydrofuran (25 mL) was added slowly to the reaction mixture over 35 minutes (-75 C.-70 C.). The reaction solution was then allowed to stir overnight with gradual warming to room temperature. The reaction was quenched by addition of saturated NH4Cl solution (20 mL). After removal of the solvent, 200 mL of ethyl acetate was added. The organic phase was washed with 2 N HCl (120 mL×2), washed with brine and then dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/petroleum ether=1/10) to afford the titled compound. 1H NMR (400 MHz, CDCl3), delta (ppm): 3.68 (s, 6H), 2.022.03 (m, 4H), 1.91 (s, 2H), 1.68 (s, 4H); LCMS (ESI+) m/z 213.1 (M+H)+.
		A 22-L, 3-neck, round bottom flask was equipped with a J-KEM temperature controller, a mechanical stirrer, a nitrogen inlet, and an addition funnel. The flask was flushed with nitrogen then charged with anhydrous THF (5 L) and diisopropylamine (731 mL, 5.219 mol). The solution was cooled to -20 C using a dry ice/acetone bath. The stirring mixture was slowly treated with 1.6 M n-butyllithium in hexanes (3.02 L, 4.833 mol) via cannula over 1 h maintaining the temperature between -20 C and -27 C. The reaction mixture was cooled to - 40 C and hexamethylphosphoramide (2.7 L, 16.317 mol) was slowly added via addition funnel over 40 min. The reaction mixture was cooled to -73 C and dimethyl cyclopentane-l,3-dicarboxylate (360 g, 1.933 mol) dissolved in anhydrous THF (2 L) was slowly added via addition funnel over 2 h. The reaction mixture was warmed to -10 C and stirred at that temperature for 30 min, then cooled to -70 C and treated with l-bromo-2-chloroethane (267 mL, 3.209 mol) via addition funnel over 4 h. The reaction mixture was allowed to slowly warm to room temperature over 12 h and then was quenched with saturated aqueous ammonium chloride (2 L) over 90 min. The reaction mixture was diluted with hexane (2 L), the layers were separated, and the aqueous layer was further extracted with hexane (3 x 2 L). The combined organic layers were washed with brine (2 x 1 L), dried over sodium sulfate, filtered, and concentrated to a brown oil. The crude product was purified by silica gel purification (0-10 % ethyl acetate/hexane). The product containing fractions were concentrated to near dryness and diluted with hexanes. The resulting crystalline solids were filtered and washed with hexane (200 mL) providing pure product as a clear crystalline solid. Additional batches of product were- 180 -ATI-2514175vl obtained from the filtrate in a similar manner. All product batches were combined to provide 208 g (51%) of dimethyl bicyclo[2.2.1]heptane-l,4-dicarboxylate as a clear crystalline solid. 1H NMR (500 Hz, CDC13) delta ppm 3.68 (s, 6H), 2.03 (d, J= 6.4 Hz, 4H), 1.90 (s, 2H), 1.67 (d, J= 7.0, 4H).
		To a solution of HMPA (13.08 mL, 75 mmol) and LDA (13.43 mL, 26.9 mmol) in THF (30 mL) was added a solution of dimethyl cyclopentane-1, 3-dicarboxylate (2 g, 10.74 mmol) in 10 mL THF dropwise over 30 minutes at -78 under N2protection and stirred at one point for another 30 minutes. The solution was warmed to 0 and stirred at one point for 1 hour. The solution was cooled to -78 and added a solution of 1-bromo-2-chloroethane (1.848 g, 12.89 mmol) in 10 mL THF dropwise. The solution was stirred at -78 for 1 hour and warmed to RT. Afrer stirred for 16 hours, the solution was added 1N HCl and extracted with EtOAc. The combined organic layer was dried over Na2SO4, concentrated in vacuo to give the title compound.1H NMR (CDCl3400 MHz) : 3.67 (s, 6H) , 2.01 (d, J6.7 Hz, 4H) , 1.89 (s, 2H) , 1.66 (d, J6.7 Hz, 3H)
		To a solution of HMPA (13.08 mL, 75 mmol) and LDA (13.43 mL, 26.9 mmol) in THF (30 mL) was added a solution of dimethyl cyclopentane-1, 3-dicarboxylate (2 g, 10.74 mmol) in 10 mL THF dropwise over 30 minutes at -78 under N2 protection and stirred at one point for another 30 minutes. The solution was warmed to 0 and stirred at one point for 1 hour. The solution was cooled to -78 and added a solution of 1-bromo-2-chloroethane (1.848 g, 12.89 mmol) in 10 mL THF dropwise. The solution was stirred at -78 for 1 hour and warmed to RT. Afrer stirred for 16 hours, the solution was added 1N HCl and extracted with EtOAc. The combined organic layer was dried over Na2SO4, concentrated in vacuo to give the title compound. 1H NMR (CDCl3 400 MHz) : delta 3.67 (s, 6H) , 2.01 (d, J6.7 Hz, 4H) , 1.89 (s, 2H) , 1.66 (d, J6.7 Hz, 3H) ppm.

Reference： [1]Patent: US2018/170931,2018,A1 .Location in patent: Paragraph 0189
[2]Patent: WO2018/112382,2018,A1 .Location in patent: Page/Page column 1714; 175
[3]Patent: WO2019/239387,2019,A1 .Location in patent: Page/Page column 57
[4]Patent: US2010/267738,2010,A1 .Location in patent: Page/Page column 32
[5]Patent: WO2012/145569,2012,A1 .Location in patent: Page/Page column 180; 181
[6]Patent: WO2016/106623,2016,A1 .Location in patent: Page/Page column 80
[7]Patent: WO2016/106624,2016,A1 .Location in patent: Page/Page column 52

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[ 2435-36-1 ]
[ 1315362-24-3 ]

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[ 2435-36-1 ]
[ 1315361-03-5 ]

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[ 2435-36-1 ]
[ 905457-34-3 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3480 - 3491

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[ 2435-36-1 ]
[ 1299426-10-0 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3480 - 3491

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[ 2435-36-1 ]
C₈H₁₀ClIO [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3480 - 3491

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[ 2435-36-1 ]
[ 123463-13-8 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3480 - 3491

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[ 2435-36-1 ]
[ 107-04-0 ]
dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3480 - 3491

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[ 498-66-8 ]
[ 2435-36-1 ]

Reference： [1]Patent: WO2012/145569,2012,A1

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[ 2435-36-1 ]
[ 15448-77-8 ]

Reference： [1]Patent: US2018/170931,2018,A1
[2]Patent: WO2012/145569,2012,A1
[3]Patent: WO2018/112382,2018,A1
[4]Patent: WO2019/239387,2019,A1

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[ 2435-36-1 ]
[ 1252672-36-8 ]

Reference： [1]Patent: WO2012/145569,2012,A1

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[ 2435-36-1 ]
[ 737693-57-1 ]

Reference： [1]Patent: WO2012/145569,2012,A1

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[ 2435-36-1 ]
[ 88888-30-6 ]

Reference： [1]Patent: WO2012/145569,2012,A1

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[ 2435-36-1 ]
[ 1403865-38-2 ]

Reference： [1]Patent: WO2012/145569,2012,A1

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[ 2435-36-1 ]
[ 1403865-39-3 ]

Reference： [1]Patent: WO2012/145569,2012,A1

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[ 67-56-1 ]
[ 84545-00-6 ]
[ 2435-36-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 70℃; for 2h;	To a solution of 3- (methoxycarbonyl) cyclopentanecarboxylic acid (18 g, 104.6 mmol) in MeOH (200 mL) was added H2SO4(30.8 g, 313.9 mmol) . The mixture was stirred at 70 for 2 h.The solvent was concentrated and the residue was purified by column chromatography on silica gel eluted with PE/EA4/1 to give dimethyl cyclopentane-1, 3-dicarboxylate.1H NMR (CDCl3, 400 MHz) delta 1.85-2.01 (m, 4 H) , 2.04-2.12 (m, 1 H) , 2.18-2.26 (m, 1 H) , 2.69-2.87 (m, 2 H) , 3.66 (s, 6 H) .
	With sulfuric acid; at 70℃; for 2h;	To a solution of 3- (methoxycarbonyl) cyclopentanecarboxylic acid (18 g, 104.6 mmol) in MeOH (200 mL) was added H2SO4 (30.8 g, 313.9 mmol) . The mixture was stirred at 70 for 2 h. The solvent was concentrated and the residue was purified by column chromatography on silica gel eluted with PE/EA 4/1 to give dimethyl cyclopentane-1, 3-dicarboxylate. 1H NMR (CDCl3, 400 MHz) delta 1.85 -2.01 (m, 4 H) , 2.04 -2.12 (m, 1 H) , 2.18 -2.26 (m, 1 H) , 2.69 -2.87 (m, 2 H) , 3.66 (s, 6 H) ppm.
	With sulfuric acid; at 70℃; for 2h;	To a solution of 3-(methoxycarbonyl)cyclopentanecarboxylic acid (18 g, 104.6 mmol) in MeOH (200 mL) was added H2S04 (30.8 g, 313.9 mmol). The mixture was stirred at 70 C for 2 h. The reaction was complete detected by TLC. The solvent was concentrated and the residue was purified by column chromatography on silica gel eluted with PE/EA = 4/1 to give dimethyl cyclopentane-1, 3-dicarboxylate. NMR (CDC13, 400 MHz) delta 1.85 - 2.01 (m, 4 H), 2.04 - 2.12 (m, 1 H), 2.18 - 2.26 (m, 1 H), 2.69 - 2.87 (m, 2 H), 3.66 (s, 6 H).

Reference： [1]Patent: WO2016/106623,2016,A1 .Location in patent: Page/Page column 69
[2]Patent: WO2016/106624,2016,A1 .Location in patent: Page/Page column 46
[3]Patent: WO2016/109219,2016,A1 .Location in patent: Page/Page column 47

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[ 2435-36-1 ]
[ 74-88-4 ]
trans-dimethyl 1,3-dimethylcyclopentane-1,3-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of dimethyl cyclopentane-1, 3-dicarboxylate (10 g, 53.7 mmol) in THF (20 mL) was added a solution of MeI (41.0 mL, 655 mmol) in 10 mL toluene under N2protection dropwise at-78 and stirred at-78 for 25 mimutes. To the solution was added a solution of LDA(161 mL, 322 mmol) in 10 mL toluene dropwise and stirred at RT for another 16 houtrs. The solution was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated in vacuo and purified by chromatography over silica gel (120 g) to give the title compound.1H NMR (trans) (400MHz, CDCl3) : 3.69 (s, 6H) , 2.29-2.20 (m, 2H) , 2.15 (s, 2H) , 1.65-1.57 (m, 2H) , 1.34-1.21 (m, 6H) ppm.1H NMR (cis) (400MHz, CDCl3) : 3.70-3.60 (m, 6H) , 2.85 (d, J14.1 Hz, 1H) , 2.32 -2.20 (m, 2H) , 1.61-1.52 (m, 2H) , 1.32-1.24 (m, 6H) ppm.

Reference： [1]Patent: WO2016/106623,2016,A1 .Location in patent: Page/Page column 98

29
[ 2435-36-1 ]
[ 74-88-4 ]
dimethyl 1,3-dimethylcyclopentane-1,3-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution a solution of LDA (33.6 mL, 67.1 mmol) in 10 mL THF was added a solution of dimethyl cyclopentane-1, 3-dicarboxylate (5 g, 26.9 mmol) in 10 mL THF under N2protection dropwise at -78 and stirred at -78 for 25 mimutes. To the solution was added iodomethane (9.53 g, 67.1 mmol) dropwise and stirred at RT for another 16 houtrs. The solution was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated in vacuo to give the title compound.1H NMR (400MHz, CDCl3) : 3.66 (major) , 3.63 (minor) (s, 6H) , 2.29-2.20 (m, 2H) , 2.12 (s, 2H) , 1.65-1.55 (m, 2H) , 1.30 -1.20 (m, 6H) ppm.
		To a solution a solution of LDA (33.6 mL, 67.1 mmol) in 10 mL THF was added a solution of dimethyl cyclopentane-1, 3-dicarboxylate (5 g, 26.9 mmol) in 10 mL THF under N2 protection dropwise at -78 and stirred at -78 for 25 mimutes. To the solution was added iodomethane (9.53 g, 67.1 mmol) dropwise and stirred at ROOM TEMPERATURE for another 16 houtrs. The solution was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated in vacuo to give the title compound. 1H NMR (400MHz, CDCl3) : delta3.66 (major) , 3.63 (minor) (s, 6H) , 2.29-2.20 (m, 2H) , 2.12 (s, 2H) , 1.65-1.55 (m, 2H) , 1.30 -1.20 (m, 6H) ppm.

Reference： [1]Patent: WO2016/106623,2016,A1 .Location in patent: Page/Page column 113
[2]Patent: WO2016/106624,2016,A1 .Location in patent: Page/Page column 64-65

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[ 2435-36-1 ]
methyl 3-(1-bromo-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-3-yl)-1-isopropylcyclopentanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2016/106623,2016,A1
[2]Patent: WO2016/106624,2016,A1
[3]Patent: WO2016/109219,2016,A1

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[ 2435-36-1 ]
3-(1-bromo-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-3-yl)-1-isopropylcyclopentanecarboxylic acid [ No CAS ]

Reference： [1]Patent: WO2016/106623,2016,A1
[2]Patent: WO2016/106624,2016,A1
[3]Patent: WO2016/109219,2016,A1

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[ 2435-36-1 ]
(1S,3R)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-isopropylcyclopentanecarboxylic acid [ No CAS ]
(1R,3S)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-isopropylcyclopentanecarboxylic acid [ No CAS ]
(1R,3R)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-isopropylcyclopentanecarboxylic acid [ No CAS ]
(1SR,3S)-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-isopropylcyclopentanecarboxylic acid [ No CAS ]

Reference： [1]Patent: WO2016/106623,2016,A1
[2]Patent: WO2016/109219,2016,A1

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[ 2435-36-1 ]
[ 15544-51-1 ]

Reference： [1]Patent: WO2016/106623,2016,A1
[2]Patent: WO2016/106624,2016,A1

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methyl 4-(((3-chloropyrazin-2-yl)methyl)carbamoyl)bicyclo[2.2.1]heptane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/106623,2016,A1
[2]Patent: WO2016/106623,2016,A1
[3]Patent: WO2016/106624,2016,A1

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methyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)bicyclo[2.2.1]heptane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/106623,2016,A1
[2]Patent: WO2016/106623,2016,A1
[3]Patent: WO2016/106624,2016,A1

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[ 2435-36-1 ]
methyl 4-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)bicyclo[2.2.1]heptane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/106623,2016,A1
[2]Patent: WO2016/106623,2016,A1
[3]Patent: WO2016/106624,2016,A1

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[ 2435-36-1 ]
methyl 4-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)bicyclo[2.2.1]heptane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/106623,2016,A1
[2]Patent: WO2016/106623,2016,A1
[3]Patent: WO2016/106624,2016,A1

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[ 2435-36-1 ]
trans-dimethyl 1-isopropyl-3-methylcyclopentane-1,3-dicarboxylate [ No CAS ]