[ CAS No. 620175-39-5 ] {[proInfo.proName]}

Name: 620175-39-5|(E)-N-Methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide|98%
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Quality Control of [ 620175-39-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 620175-39-5 ]

SDS Specification

Alternatived Products of [ 620175-39-5 ]

Product Details of [ 620175-39-5 ]

CAS No. :	620175-39-5	MDL No. :	MFCD18633190
Formula :	C₂₂H₂₁N₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QXTWSUQCXCWEHF-JXMROGBWSA-N
M.W :	375.42	Pubchem ID :	10407120
Synonyms :	API-1252;Debio 1452	Chemical Name :	(E)-N-Methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

Calculated chemistry of [ 620175-39-5 ]

Physicochemical Properties

Num. heavy atoms :	28
Num. arom. heavy atoms :	15
Fraction Csp3 :	0.23
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	111.17
TPSA :	75.44 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.81 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.03
Log Po/w (XLOGP3) :	2.51
Log Po/w (WLOGP) :	2.86
Log Po/w (MLOGP) :	1.91
Log Po/w (SILICOS-IT) :	4.0
Consensus Log Po/w :	2.86

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.82
Solubility :	0.0574 mg/ml ; 0.000153 mol/l
Class :	Soluble
Log S (Ali) :	-3.74
Solubility :	0.0683 mg/ml ; 0.000182 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-6.7
Solubility :	0.0000753 mg/ml ; 0.0000002 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.31

Safety of [ 620175-39-5 ]

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

Application In Synthesis of [ 620175-39-5 ]

* 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.

Upstream synthesis route of [ 620175-39-5 ]
Downstream synthetic route of [ 620175-39-5 ]

[ 620175-39-5 ] Synthesis Path-Upstream 1~4

1
[ 92367-50-5 ]
[ 620175-39-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20.3 - 41.9℃; for 17.5 h;	E. (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide[0232] A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N₂. The flask was charged with DMF (7.5 L, 5 v) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)acrylic acid (1.49 kg, 4.98 mol, 1.0 eq.). To the yellow suspension, HOBT (0.74 kg, 5.48 mol, 1.1 eq.), EDCI (1.15 kg, 5.98 mol, 1.2 eq) and N-methyl-l-(3-methylbenzofuran-2- yl)methanamine (0.96 kg, 5.48 mol, 1.1 eq) were added. During the addition an exotherm was observed and the temperature increased from 20.3 ⁰C to 36.4 ⁰C. To the resulting thick <n="55"/>suspension was added DIPEA (1.93 kg, 14.94 mol, 3 eq.) and an exotherm was observed to 41.9 ⁰C. During the addition the suspension changed to a clear brown solution. The resulting solution was stirred at 38 - 42 ⁰C. After about 45 min a new solid started to form. After stirring for 1.5 h, ~ 1 mL of suspension was taken, the progress of the reaction was monitored by HPLC and the results indicated >95percent reaction completion. After another 16 hours of stirring at the same temperature, ¹H NMR and HPLC analysis indicated the reaction was complete. Half of the reaction mixture was transferred to another 22-L three-necked round-bottomed flask containing a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet. The contents of both flasks were allowed to cool to 20 - 25 ⁰C and each reaction mixture was diluted with H₂O (8 L, 5.3 v) over 15 min. Both reaction mixtures showed an exotherm during the water addition to 30 - 35 ⁰C. The resulting suspensions were allowed to stir at 20 - 25 ⁰C for 3.5 h. Solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with water (4X 1.4 v), heptane (IX 1.4 v) and ethyl acetate (3X 1 v). The damp solid was dried under vacuum at 30 -35 ⁰C with a slow N₂ bleed for 120 h to a constant weight to give 1.67 kg of the title compound as yellow solid. The material was analyzed indicating 98.48areapercent HPLC purity with 146 ppm residual Pd.[0233] A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N₂. The flask was charged with DMF (7 L, 4v) and a potion of the crude product from above (1.65 kg, 4.98 mol, 1.0 eq.). To the resulting thick suspension was added DIPEA (1 L, 0.75 v.). The suspension was heated to 52-57 ⁰C and stirred at the same temperature. After 20 hours of stirring at 52-57 ⁰C the suspension was allowed to cool to 20-25 ⁰C. Solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with DMF (2X 0.7 v), H₂O (3X 2 v) and methanol (2X 2 v). The damp solid was dried under vacuum at 30 -35 ⁰C with a slow N₂ bleed for 110 h to a constant weight to give 1.56 kg of the desired product as a yellow solid. The material was analyzed and the results indicated 99areapercent HPLC purity with 20 ppm Pd. A 0.75 kg of this material was used for the salt formation and the remaining 0.813 kg was subjected to the procedure as described above beginning with suspension in DMF. A 0.78 kg portion of desired product was isolated as solid in 95percent yield with 99.0 areapercent HPLC purity with 14 ppm of residual Pd. This material was used for subsequent milling (Micron technologies). <n="56"/>[0234] ¹H NMR {DMSO (d₆)}: δ (ppm) 10.69 (br, H, NH), 8.38 ( two s, 1 H, CH), 8.09 (two s, 1 H, CH), 7.48 - 7.58 (m, 3.4 H), 7.19 - 7.31 (m, 2.5 H), 5.01 ( s, 0.8 H), 4.80 (s, 1.2 H), 3.37 (s, 0.4 H), 3.20 (s, 1.6 H) 2.89 - 2.94 (m, 2 H), 2.50 - 2.94 (m, 5 H, CH₂, CH₃), 2.27 (s, 3 H, CH₃)[0235] ¹³C NMR {DMSO (d₆)}:} : δ (ppm) 171.5(C), 165.9(C), 154.0, 152.9, 149.8, 147.7, 139.2, 138.8, 134.2, 126.1, 125.0, 124.8, 122.9, 120.0, 119.5, 118.0, 111.3, 42.4 (CH₂), 35.4 (CH₃), 30.5 (CH₂), 23.8 (CH₂) _{8.0 (CH&3})[0236] DSC: 245.4 ⁰C[0237] TGA: 0.2652 (at) 240 ⁰C[0238] HPLC: 99.7 areapercent (R₇ = 11.52 min)[0239] LC-MS: 376 amu (MW. 376.17)[0240] KF: 0.23percent[0241] Pd: 16 ppm[0242] Heavy Metals: <20 ppm[0243] Residue on Ignition: 0.16percent[0244] C_{2 I}H₂₂N₃O₃: Calcd. C 70.38percent; H 5.64percent; N 11.19percent[0245] Found C 70.08percent; H 5.57percent; N 11.17percent

Reference： [1] Patent: WO2008/98374, 2008, A1, . Location in patent: Page/Page column 53-55; 24

2
[ 24673-56-1 ]
[ 620175-39-5 ]

Reference： [1] Patent: WO2008/98374, 2008, A1,

3
[ 2256-86-2 ]
[ 620175-39-5 ]

Reference： [1] Patent: WO2008/98374, 2008, A1,

4
[ 527758-07-2 ]
[ 620175-39-5 ]

Reference： [1] Patent: WO2008/98374, 2008, A1,

[ 620175-39-5 ] Synthesis Path-Downstream 1~17

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 52 - 57℃; for 20h;Purification / work up;	E. (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide[0232] A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with DMF (7.5 L, 5 v) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)acrylic acid (1.49 kg, 4.98 mol, 1.0 eq.). To the yellow suspension, HOBT (0.74 kg, 5.48 mol, 1.1 eq.), EDCI (1.15 kg, 5.98 mol, 1.2 eq) and N-methyl-l-(3-methylbenzofuran-2- yl)methanamine (0.96 kg, 5.48 mol, 1.1 eq) were added. During the addition an exotherm was observed and the temperature increased from 20.3 0C to 36.4 0C. To the resulting thick <n="55"/>suspension was added DIPEA (1.93 kg, 14.94 mol, 3 eq.) and an exotherm was observed to 41.9 0C. During the addition the suspension changed to a clear brown solution. The resulting solution was stirred at 38 - 42 0C. After about 45 min a new solid started to form. After stirring for 1.5 h, ~ 1 mL of suspension was taken, the progress of the reaction was monitored by HPLC and the results indicated >95% reaction completion. After another 16 hours of stirring at the same temperature, 1H NMR and HPLC analysis indicated the reaction was complete. Half of the reaction mixture was transferred to another 22-L three-necked round-bottomed flask containing a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet. The contents of both flasks were allowed to cool to 20 - 25 0C and each reaction mixture was diluted with H2O (8 L, 5.3 v) over 15 min. Both reaction mixtures showed an exotherm during the water addition to 30 - 35 0C. The resulting suspensions were allowed to stir at 20 - 25 0C for 3.5 h. Solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with water (4X 1.4 v), heptane (IX 1.4 v) and ethyl acetate (3X 1 v). The damp solid was dried under vacuum at 30 -35 0C with a slow N2 bleed for 120 h to a constant weight to give 1.67 kg of the title compound as yellow solid. The material was analyzed indicating 98.48area% HPLC purity with 146 ppm residual Pd.[0233] A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with DMF (7 L, 4v) and a potion of the crude product from above (1.65 kg, 4.98 mol, 1.0 eq.). To the resulting thick suspension was added DIPEA (1 L, 0.75 v.). The suspension was heated to 52-57 0C and stirred at the same temperature. After 20 hours of stirring at 52-57 0C the suspension was allowed to cool to 20-25 0C. Solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with DMF (2X 0.7 v), H2O (3X 2 v) and methanol (2X 2 v). The damp solid was dried under vacuum at 30 -35 0C with a slow N2 bleed for 110 h to a constant weight to give 1.56 kg of the desired product as a yellow solid. The material was analyzed and the results indicated 99area% HPLC purity with 20 ppm Pd. A 0.75 kg of this material was used for the salt formation and the remaining 0.813 kg was subjected to the procedure as described above beginning with suspension in DMF. A 0.78 kg portion of desired product was isolated as solid in 95% yield with 99.0 area% HPLC purity with 14 ppm of residual Pd. This material was used for subsequent milling (Micron technologies). <n="56"/>[0234] 1H NMR {DMSO (d6)}: delta (ppm) 10.69 (br, H, NH), 8.38 ( two s, 1 H, CH), 8.09 (two s, 1 H, CH), 7.48 - 7.58 (m, 3.4 H), 7.19 - 7.31 (m, 2.5 H), 5.01 ( s, 0.8 H), 4.80 (s, 1.2 H), 3.37 (s, 0.4 H), 3.20 (s, 1.6 H) 2.89 - 2.94 (m, 2 H), 2.50 - 2.94 (m, 5 H, CH2, CH3), 2.27 (s, 3 H, CH3)[0235] 13C NMR {DMSO (d6)}:} : delta (ppm) 171.5(C), 165.9(C), 154.0, 152.9, 149.8, 147.7, 139.2, 138.8, 134.2, 126.1, 125.0, 124.8, 122.9, 120.0, 119.5, 118.0, 111.3, 42.4 (CH2), 35.4 (CH3), 30.5 (CH2), 23.8 (CH2) & 8.0 (CH3)[0236] DSC: 245.4 0C[0237] TGA: 0.2652 (at) 240 0C[0238] HPLC: 99.7 area% (R7 = 11.52 min)[0239] LC-MS: 376 amu (MW. 376.17)[0240] KF: 0.23%[0241] Pd: 16 ppm[0242] Heavy Metals: <20 ppm[0243] Residue on Ignition: 0.16%[0244] C2 IH22N3O3: Calcd. C 70.38%; H 5.64%; N 11.19%[0245] Found C 70.08%; H 5.57%; N 11.17%

2
[ 620175-39-5 ]
[ 104-15-4 ]
[ 1047981-31-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	In tetrahydrofuran; n-heptane; at 20 - 60℃;Product distribution / selectivity;	Example 12: (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide Tosylate (Anhydrate): Large-scale process[0261] The reaction forming the title compound can be processed in multiple, e.g. eleven 150-g batches and one 25-g batch, and and combined during the final filtration. Described below is a representative 150-g run.[0262] A 72-L, four-neck, round-bottom flask was equipped with a reflux condenser, an overhead, mechanical stirrer, a temperature probe with a temperature controller, and a nitrogen inlet adapter. The reactor was charged with (E)-N-methyl-N-((3-methylbenzofuran-2- yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- 1 ,8-naphthyridin-3-yl)acryl-amide, prepared as described in Example 1OE, (150 g) and tetrahydrofuran (40 kg). The reaction mixture was heated to 60 0C to partially dissolve API. ^-Toluenesulfonic acid (80 g, 0.42 mol) was added to the reactor as a solution in tetrahydrofuran (400 mL). The reaction was aged for 1 h at 60 C. Heptane (10 kg) was then added and the internal temperature decreased to 51 0C. The reaction mixture was heated back to 60 0C and then allowed to cool to ambient temperature overnight. The white solid was collected via filtration through Sharkskin filter paper and combined with all other runs affording 3377 g of wet solid. The solid was dried at 50 0C in a vacuum oven for 48 hand combined with ten additional 150-g batches and one 25-g batch to afford 21 19.3 g of product. The solid was then milled in 12-g batches using a Fritsch Pulverisette 6-ball mill in a 240-mL bowl with 150 agate balls at 200 rpm for 1 min. The milled product was then blended in a large beaker affording 2134 g of product (87%). The 1H NMR and "C NMR spectra of the product were consistent with the assigned structure. ESI MS: m/z 376 [C22H21N3O3 + H]+. HPLC analysis (Method A): 98.8% (AUC), tkappa = 13.1 min. XRPD spectra depicted in Figure 13.
77.8%	In tetrahydrofuran; at 20℃;Heating / reflux;Product distribution / selectivity;	Method IIIGeneral Method of Salt formation III: Scale-up[0103] Scale-up reactions can be carried out on, for example, 1 gram of material. Table 2 summarizes typical amounts of solvents and reagents used for exemplary scale up reactions although variations in solvent and Compound A amount can be employed.Table 2 <n="23"/>[0104] Compound A is dissolved in the appropriate amount of solvent with heating and stirring. To this is added the acid solution at for example 1 M concentration, and the delivery solvent is matched with the reaction solvent. After stirring for 5 minutes the anti-solvent (typically a hydrocarbon e.g. heptane) is added. Enough anti-solvent is added to form a turbid solution that typically clears up after a few seconds. The reactions are heated back to the reaction temperature if any cooling occurred during the anti-solvent addition. The temperatures are then ramped down to room temperature at a rate of about 20 C/hour. The solids are then collected by filtration and dried in vacuo (55 0C and 30 inches of Hg).; Example 8[0212] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide p-toluene sulfonate[0213] Using general method III, described above, the title salt was prepared in a yield of 77.8 % with analytical data consistent with those previously described for example 5: Analysis calculated for C23H26N3O6^CH3PhSOH: C: 63.60, H: 5.34, N: 7.67; Found: C: 63.31, H: 5.44, N: 7.56.[0214] A portion of this material was subjected to ball milling as described above: XRPD shows crystalline material as depicted in Figure 1OA; DSC (Figure 10 B) shows one thermal event.
	In tetrahydrofuran; 1,4-dioxane; at 20 - 58℃;Product distribution / selectivity;	Variant B[0102] In a variant of general method II vials are charged with between 19 - 21 mg of the API were treated with one of the above solvents (i.e. DCM or THF). These vials are heated (DCM 32 0C, THF 58 0C) with stirring to ensure dissolution. Each vial is then charged with between 425 to 465 muL of a 0.126 M solution of the acid in dioxane corresponding to 1.05 equivalents of each acid. The temperature is held (DCM 32 C, THF 58 C) for 10 minutes before the introduction of an anti-solvent such as heptane. Heptane can be added until the solution became turbid, 3 mL for THF experiment and 1.5 mL for DCM experiment. After addition the vials are allowed to cool to room temperate at a rate of 20 C/hour. Precipitation typically occurs during the cooling phase and the solids can be collected by filtration and dried in vacuo at 50 0C and 30 inches of Hg. Example 5[0204] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide/»-toluene sulfonate[0205] Using method HB, compound A, p-toluene sulfonic acid and THF as solvent, a solid crystallized during the cooling phase which was isolated as the title compound. The product showed a unique diffraction (XRPD) as compared to the free base as shown in Figure 7A (high intensity peaks include those occurring at 6.5, 11.5, 12.25, 13.5, 14.5, 14.25, 15.5, 16, 18.5, 19, 26, and 27 2theta); mp 180.5 0C (DSC); 1H-NMR supports a ratio between compound aand counter-ion of 1 : 1 ; no weight loss in TGA. The DCS of this salt from THF is depicted in Figure 7B.[0206] In a similar manner from DCM upon concentration (about half volume reduction), crystallization occurred to yield the title compound: unique XRPD; three thermal events in DSC, 1H-NMR supports an assignment with the ratio between compound A and counter-ion of 1 :1.

In 1,4-dioxane; dichloromethane; at 20 - 32℃;Product distribution / selectivity;

Variant B[0102] In a variant of general method II vials are charged with between 19 - 21 mg of the API were treated with one of the above solvents (i.e. DCM or THF). These vials are heated (DCM 32 0C, THF 58 0C) with stirring to ensure dissolution. Each vial is then charged with between 425 to 465 muL of a 0.126 M solution of the acid in dioxane corresponding to 1.05 equivalents of each acid. The temperature is held (DCM 32 C, THF 58 C) for 10 minutes before the introduction of an anti-solvent such as heptane. Heptane can be added until the solution became turbid, 3 mL for THF experiment and 1.5 mL for DCM experiment. After addition the vials are allowed to cool to room temperate at a rate of 20 C/hour. Precipitation typically occurs during the cooling phase and the solids can be collected by filtration and dried in vacuo at 50 0C and 30 inches of Hg. Example 5[0204] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide/»-toluene sulfonate[0205] Using method HB, compound A, p-toluene sulfonic acid and THF as solvent, a solid crystallized during the cooling phase which was isolated as the title compound. The product showed a unique diffraction (XRPD) as compared to the free base as shown in Figure 7A (high intensity peaks include those occurring at 6.5, 11.5, 12.25, 13.5, 14.5, 14.25, 15.5, 16, 18.5, 19, 26, and 27 2theta); mp 180.5 0C (DSC); 1H-NMR supports a ratio between compound aand counter-ion of 1 : 1 ; no weight loss in TGA. The DCS of this salt from THF is depicted in Figure 7B.[0206] In a similar manner from DCM upon concentration (about half volume reduction), crystallization occurred to yield the title compound: unique XRPD; three thermal events in DSC, 1H-NMR supports an assignment with the ratio between compound A and counter-ion of 1 :1.

Reference： [1]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 57
[2]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 21-22; 49
[3]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 48
[4]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 48

3
[ 620175-39-5 ]
[ 104-15-4 ]
[ 1047981-30-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	In tetrahydrofuran; 1,4-dioxane; for 1h;Inert atmosphere;	S7, Debio-1452 (1 eq, 1.5 mmol) was suspended in THF (120 mL) and heated to reflux. After 30 min, p-toluene sulfonic acid monohydrate (1.05 eq, 1.58 mmol) in dioxane (12 mL) was added to the reaction mixture and stirred for lh. The reaction mixture was allowed to cool to room temperature and diluted with a mixture of 1:1 etherm-pentane (80 mL), filtered, rinsed with 1:1 etherm-pentane, and dried to afford (£?)-A/-methyl-A/-((3-methylbenzofuran-2-yl)methyl)-3-(7- oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)acrylamide p-toluenesulfonic acid (S8, Debio-1452 Tosylate, 0.756 g, 1.38 mmol, 92%) as a white solid. The product was further processed for in vivo efficacy studies to improve solubility. For these studies, Debio-1452 Tosylate was ground in a mortar and pestle and then sieved through a 75 mM mesh. Note: Tabulated NMR data for acrylamide derivatives consist of two rotamers that exist at room temperature in a ratio of 40:60 and is reflected in the reported integral values. 1H NMR (500 MHz, DMSO-ifc): d 10.69 (s, 1H), (0553) 9.49 (brs, 1H), 8.42 - 8.32 (m, 1H), 8.17 - 8.05 (m, 1H), 7.59 - 7.54 (m, 1H), 7.54 - 7.43 (m, 4.4H), 7.31 - 7.22 (m, 2H), 7.21 (d, / = 12.6 Hz, 0.6H), 7.15 - 7.09 (m, 2H), 4.99 (s, 0.8H), 4.79 (s, 1.2H), 3.18 (s, 1.8H), 2.96 - 2.89 (m, 3.2H), 2.57 - 2.51 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H).
		F. (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide Tosylate Monohydrate[0247] A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with DCM (12 L, 16 v) and (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7- oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)acrylamide (0.75 kg, 1.999 mol, 1.0 eq.). To the suspension, MeOH (1 L, 1.33 eq) was added and resulting suspension was heated to IT = 35-40 0C. When IT = 35 0C, a solution of TsORH2O (0.38 kg, 1.999 mol. 1 eq.) in methanol (0.5 L, <n="57"/>0.67 v) was added over 10 min while maintaining IT = 35-40 0C. After the addition was complete a clear solution was formed which was then filtered through 0.45 mum filter paper. The filtrate was divided in to two halves and transferred into two 22-L three-necked round- bottomed flasks with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet. Each solution was stirred at IT = 35-40 0C and water (32 g, 2 mol, 1 eq.) was added. The clear solutions were then diluted with heptane (6 L, 8 v) over 15 min while maintaining IT = 35-40 0C. The resulting suspensions were allowed cooled to IT = 20-25 0C over 3 h and allowed to stir at the same temperature for 18 h. The solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with heptane (3X 2.7 v). The damp solid was dried under vacuum at 30 -35 0C with a slow N2 bleed for 72 h to a constant weight to give 1.06 kg of the desired product as a white solid. The material was analyzed and the results indicated 98.3%area HPLC purity with 7.7 ppm Pd. This material was used for ball milling.[0248] 1H NMR {DMSO (d6)}: delta (ppm) 10.80 (br, H, NH), 8.38 ( two s, 1 H, CH), 8.16 (two s, 1 H, CH), 7.48 - 7.58 (m, 5.4 H), 7.21 - 7.28 (m, 2.5 H), 7.13 (d, J= 7.8 Hz, 2 H, CH), 6.80 ( br, 3 H, TsOH, H2O), 5.0 ( s, 0.8 H), 4.80 (s, 1.2 H), 3.20 (s, 1.6 H) 2.91 - 2.96 (m, 2.4 H), 2.50 - 2.94 (m, 5 H), 2.29 (s, 3 H, CH3), 2.27 (s, 3 H, CH3)[0249] 13C NMR {DMSO (d6)}:} : delta (ppm) 171.5(C), 165.9(C), 154.0, 152.9, 149.8, 147.7, 139.2, 138.8, 134.2, 128.8, 126.3, 126.1, 125.0, 124.8, 122.9, 120.0, 119.5, 118.0, 111.3, 42.4 (CH2), 39.2(CH3), 30.5 (CH2), 23.8 (CH2), 21.3 (CH3) & 8.0 (CH3)[0250] DSC: 176.1 0C[0251] TGA: 0.2652 (at) 240 0C[0252] HPLC: 98.3 %area (R7 = 11.52 min)[0253] LC-MS: 376 amu (MW. 376.17)[0254] KF: 3.72%[0255] Pd: 6.5 ppm[0256] Heavy Metals: <20 ppm <n="58"/>[0257] Residue on Ignition: 0.1%[0258] C28H32N3O7: Calcd. C 61.58%; H 5.52%; N 7.43%[0259] Found C 61.49%; H 5.53%; N 7.46%[0260] The resulting solid was filtered to collect the title compound; XPRD of title compound depicted in Figure 12. High intensity peaks include those occurring at 5, 10.5, 1 1.25, 14.5, 16.5, 18, 19, 19.5 and 22.5 2theta.

Reference： [1]Patent: WO2019/177975,2019,A1 .Location in patent: Page/Page column 53; 64; 66
[2]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 55-57

4
[ 620175-39-5 ]
[ 75-75-2 ]
(E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide methanesulfonate monohydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.4%	In dichloromethane; at 20℃;Heating / reflux;Product distribution / selectivity;	Method IIIGeneral Method of Salt formation III: Scale-up[0103] Scale-up reactions can be carried out on, for example, 1 gram of material. Table 2 summarizes typical amounts of solvents and reagents used for exemplary scale up reactions although variations in solvent and Compound A amount can be employed.Table 2 <n="23"/>[0104] Compound A is dissolved in the appropriate amount of solvent with heating and stirring. To this is added the acid solution at for example 1 M concentration, and the delivery solvent is matched with the reaction solvent. After stirring for 5 minutes the anti-solvent (typically a hydrocarbon e.g. heptane) is added. Enough anti-solvent is added to form a turbid solution that typically clears up after a few seconds. The reactions are heated back to the reaction temperature if any cooling occurred during the anti-solvent addition. The temperatures are then ramped down to room temperature at a rate of about 20 C/hour. The solids are then collected by filtration and dried in vacuo (55 0C and 30 inches of Hg).; Example 7[0209] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide methane sulfonate[0210] Using general method III, described above, the title salt was prepared in a yield of 84.4 % with analytical data consistent with those previously described for example 3: elemental analysis calculated for C23H26N3O6 CH3SO3H as a monohydrate: C: 56.43, H: 5.56, N: 8.58; Found: C: 56.10, H: 5.38, N: 8.46.[0211] A portion of this material was subjected to ball milling as described above; the XRPD shows crystalline material as depicted in Figure 9A; DSC (Figure 9B) shows one major thermal event and a decomposition exotherm.

Reference： [1]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 21-22; 49

5
[ 620175-39-5 ]
[ 75-75-2 ]
[ 1047981-45-2 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; 1,4-dioxane; at 20 - 58℃;Product distribution / selectivity;	Variant B[0102] In a variant of general method II vials are charged with between 19 - 21 mg of the API were treated with one of the above solvents (i.e. DCM or THF). These vials are heated (DCM 32 0C, THF 58 0C) with stirring to ensure dissolution. Each vial is then charged with between 425 to 465 muL of a 0.126 M solution of the acid in dioxane corresponding to 1.05 equivalents of each acid. The temperature is held (DCM 32 C, THF 58 C) for 10 minutes before the introduction of an anti-solvent such as heptane. Heptane can be added until the solution became turbid, 3 mL for THF experiment and 1.5 mL for DCM experiment. After addition the vials are allowed to cool to room temperate at a rate of 20 C/hour. Precipitation typically occurs during the cooling phase and the solids can be collected by filtration and dried in vacuo at 50 0C and 30 inches of Hg.; Example 3[0198] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide methane sulfonate[0199] Compound A, methane sulfonic acid and THF were processed as described in method IIB(Table 1) above. A solid crystallized during the cooling phase which was isolated as the title compound. The product showed a unique diffraction (XRPD) as compared to the free base as shown in Figure 4. High intensity peaks include those occurring at 7, 14, 15.5, 20, 21, 23, 28, 35.5 and 42.5 2theta. Two thermal events were seen (DSC)[0200] In a similar manner from DCM upon concentration (about half volume reduction), crystallization occurred to yield the title compound: unique XRPD; mp 187 C; (DSC); 1H- NMR supports an assignment with the ratio between compound A and counter-ion being 1 :1 ; the material also showed no retained solvent by weight loss in the TGA.
	In 1,4-dioxane; dichloromethane; at 20 - 32℃;Product distribution / selectivity;	Variant B[0102] In a variant of general method II vials are charged with between 19 - 21 mg of the API were treated with one of the above solvents (i.e. DCM or THF). These vials are heated (DCM 32 0C, THF 58 0C) with stirring to ensure dissolution. Each vial is then charged with between 425 to 465 muL of a 0.126 M solution of the acid in dioxane corresponding to 1.05 equivalents of each acid. The temperature is held (DCM 32 C, THF 58 C) for 10 minutes before the introduction of an anti-solvent such as heptane. Heptane can be added until the solution became turbid, 3 mL for THF experiment and 1.5 mL for DCM experiment. After addition the vials are allowed to cool to room temperate at a rate of 20 C/hour. Precipitation typically occurs during the cooling phase and the solids can be collected by filtration and dried in vacuo at 50 0C and 30 inches of Hg.; Example 3[0198] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide methane sulfonate[0199] Compound A, methane sulfonic acid and THF were processed as described in method IIB(Table 1) above. A solid crystallized during the cooling phase which was isolated as the title compound. The product showed a unique diffraction (XRPD) as compared to the free base as shown in Figure 4. High intensity peaks include those occurring at 7, 14, 15.5, 20, 21, 23, 28, 35.5 and 42.5 2theta. Two thermal events were seen (DSC)[0200] In a similar manner from DCM upon concentration (about half volume reduction), crystallization occurred to yield the title compound: unique XRPD; mp 187 C; (DSC); 1H- NMR supports an assignment with the ratio between compound A and counter-ion being 1 :1 ; the material also showed no retained solvent by weight loss in the TGA.

Reference： [1]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 47
[2]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 47

6
[ 92367-50-5 ]
(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrobromide [ No CAS ]
[ 620175-39-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20.3 - 41.9℃; for 17.5h;Product distribution / selectivity;	E. (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide[0232] A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with DMF (7.5 L, 5 v) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3- yl)acrylic acid (1.49 kg, 4.98 mol, 1.0 eq.). To the yellow suspension, HOBT (0.74 kg, 5.48 mol, 1.1 eq.), EDCI (1.15 kg, 5.98 mol, 1.2 eq) and N-methyl-l-(3-methylbenzofuran-2- yl)methanamine (0.96 kg, 5.48 mol, 1.1 eq) were added. During the addition an exotherm was observed and the temperature increased from 20.3 0C to 36.4 0C. To the resulting thick <n="55"/>suspension was added DIPEA (1.93 kg, 14.94 mol, 3 eq.) and an exotherm was observed to 41.9 0C. During the addition the suspension changed to a clear brown solution. The resulting solution was stirred at 38 - 42 0C. After about 45 min a new solid started to form. After stirring for 1.5 h, ~ 1 mL of suspension was taken, the progress of the reaction was monitored by HPLC and the results indicated >95% reaction completion. After another 16 hours of stirring at the same temperature, 1H NMR and HPLC analysis indicated the reaction was complete. Half of the reaction mixture was transferred to another 22-L three-necked round-bottomed flask containing a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet. The contents of both flasks were allowed to cool to 20 - 25 0C and each reaction mixture was diluted with H2O (8 L, 5.3 v) over 15 min. Both reaction mixtures showed an exotherm during the water addition to 30 - 35 0C. The resulting suspensions were allowed to stir at 20 - 25 0C for 3.5 h. Solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with water (4X 1.4 v), heptane (IX 1.4 v) and ethyl acetate (3X 1 v). The damp solid was dried under vacuum at 30 -35 0C with a slow N2 bleed for 120 h to a constant weight to give 1.67 kg of the title compound as yellow solid. The material was analyzed indicating 98.48area% HPLC purity with 146 ppm residual Pd.[0233] A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with DMF (7 L, 4v) and a potion of the crude product from above (1.65 kg, 4.98 mol, 1.0 eq.). To the resulting thick suspension was added DIPEA (1 L, 0.75 v.). The suspension was heated to 52-57 0C and stirred at the same temperature. After 20 hours of stirring at 52-57 0C the suspension was allowed to cool to 20-25 0C. Solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with DMF (2X 0.7 v), H2O (3X 2 v) and methanol (2X 2 v). The damp solid was dried under vacuum at 30 -35 0C with a slow N2 bleed for 110 h to a constant weight to give 1.56 kg of the desired product as a yellow solid. The material was analyzed and the results indicated 99area% HPLC purity with 20 ppm Pd. A 0.75 kg of this material was used for the salt formation and the remaining 0.813 kg was subjected to the procedure as described above beginning with suspension in DMF. A 0.78 kg portion of desired product was isolated as solid in 95% yield with 99.0 area% HPLC purity with 14 ppm of residual Pd. This material was used for subsequent milling (Micron technologies). <n="56"/>[0234] 1H NMR {DMSO (d6)}: delta (ppm) 10.69 (br, H, NH), 8.38 ( two s, 1 H, CH), 8.09 (two s, 1 H, CH), 7.48 - 7.58 (m, 3.4 H), 7.19 - 7.31 (m, 2.5 H), 5.01 ( s, 0.8 H), 4.80 (s, 1.2 H), 3.37 (s, 0.4 H), 3.20 (s, 1.6 H) 2.89 - 2.94 (m, 2 H), 2.50 - 2.94 (m, 5 H, CH2, CH3), 2.27 (s, 3 H, CH3)[0235] 13C NMR {DMSO (d6)}:} : delta (ppm) 171.5(C), 165.9(C), 154.0, 152.9, 149.8, 147.7, 139.2, 138.8, 134.2, 126.1, 125.0, 124.8, 122.9, 120.0, 119.5, 118.0, 111.3, 42.4 (CH2), 35.4 (CH3), 30.5 (CH2), 23.8 (CH2) & 8.0 (CH3)[0236] DSC: 245.4 0C[0237] TGA: 0.2652 (at) 240 0C[0238] HPLC: 99.7 area% (R7 = 11.52 min)[0239] LC-MS: 376 amu (MW. 376.17)[0240] KF: 0.23%[0241] Pd: 16 ppm[0242] Heavy Metals: <20 ppm[0243] Residue on Ignition: 0.16%[0244] C2 IH22N3O3: Calcd. C 70.38%; H 5.64%; N 11.19%[0245] Found C 70.08%; H 5.57%; N 11.17%

Reference： [1]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 53-55; 24

7
[ 620175-39-5 ]
[ 98-11-3 ]
[ 1047981-43-0 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; 1,4-dioxane; at 20 - 58℃;Product distribution / selectivity;	Variant B[0102] In a variant of general method II vials are charged with between 19 - 21 mg of the API were treated with one of the above solvents (i.e. DCM or THF). These vials are heated (DCM 32 0C, THF 58 0C) with stirring to ensure dissolution. Each vial is then charged with between 425 to 465 muL of a 0.126 M solution of the acid in dioxane corresponding to 1.05 equivalents of each acid. The temperature is held (DCM 32 C, THF 58 C) for 10 minutes before the introduction of an anti-solvent such as heptane. Heptane can be added until the solution became turbid, 3 mL for THF experiment and 1.5 mL for DCM experiment. After addition the vials are allowed to cool to room temperate at a rate of 20 C/hour. Precipitation typically occurs during the cooling phase and the solids can be collected by filtration and dried in vacuo at 50 0C and 30 inches of Hg. Example 4[0201] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide benzene sulfonate[0202] Compound A, benzene sulfonic acid and THF were processed as described in method IIB (Table 1). A solid crystallized during the cooling phase which was isolated as the title compound. The product showed a unique diffraction (XRPD) as compared to the free base <n="49"/>as shown in Figure 5; (high intensity peaks include those occurring at 6,12, 23.5 and 312theta); mp 172 C (DSC); the 1H-NMR supported a ratio between the free base and counter-ion of1 :1.[0203] In a similar manner from DCM upon concentration (about half volume reduction), crystallization occurred to yield the title compound: unique XRPD as shown in Figure 6 (high intensity peaks include those occurring at 5.5, 6, 13, 15.5, 18 and 19 2theta); mp 168 0C; (DSC), 1H-NMR supports an assignment with the ratio between free base and counter-ion being 1 :1.
	In 1,4-dioxane; dichloromethane; at 20 - 32℃;Product distribution / selectivity;	Variant B[0102] In a variant of general method II vials are charged with between 19 - 21 mg of the API were treated with one of the above solvents (i.e. DCM or THF). These vials are heated (DCM 32 0C, THF 58 0C) with stirring to ensure dissolution. Each vial is then charged with between 425 to 465 muL of a 0.126 M solution of the acid in dioxane corresponding to 1.05 equivalents of each acid. The temperature is held (DCM 32 C, THF 58 C) for 10 minutes before the introduction of an anti-solvent such as heptane. Heptane can be added until the solution became turbid, 3 mL for THF experiment and 1.5 mL for DCM experiment. After addition the vials are allowed to cool to room temperate at a rate of 20 C/hour. Precipitation typically occurs during the cooling phase and the solids can be collected by filtration and dried in vacuo at 50 0C and 30 inches of Hg. Example 4[0201] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridin-3-yl)acrylamide benzene sulfonate[0202] Compound A, benzene sulfonic acid and THF were processed as described in method IIB (Table 1). A solid crystallized during the cooling phase which was isolated as the title compound. The product showed a unique diffraction (XRPD) as compared to the free base <n="49"/>as shown in Figure 5; (high intensity peaks include those occurring at 6,12, 23.5 and 312theta); mp 172 C (DSC); the 1H-NMR supported a ratio between the free base and counter-ion of1 :1.[0203] In a similar manner from DCM upon concentration (about half volume reduction), crystallization occurred to yield the title compound: unique XRPD as shown in Figure 6 (high intensity peaks include those occurring at 5.5, 6, 13, 15.5, 18 and 19 2theta); mp 168 0C; (DSC), 1H-NMR supports an assignment with the ratio between free base and counter-ion being 1 :1.

Reference： [1]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 47-48
[2]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 47-48

8
[ 620175-39-5 ]
[ 1047981-46-3 ]

Yield	Reaction Conditions	Operation in experiment
83.7 - 84.4%	With sulfuric acid; In tetrahydrofuran; water; at 20℃;Heating / reflux;Product distribution / selectivity;	Method IIIGeneral Method of Salt formation III: Scale-up[0103] Scale-up reactions can be carried out on, for example, 1 gram of material. Table 2 summarizes typical amounts of solvents and reagents used for exemplary scale up reactions although variations in solvent and Compound A amount can be employed.Table 2 <n="23"/>[0104] Compound A is dissolved in the appropriate amount of solvent with heating and stirring. To this is added the acid solution at for example 1 M concentration, and the delivery solvent is matched with the reaction solvent. After stirring for 5 minutes the anti-solvent (typically a hydrocarbon e.g. heptane) is added. Enough anti-solvent is added to form a turbid solution that typically clears up after a few seconds. The reactions are heated back to the reaction temperature if any cooling occurred during the anti-solvent addition. The temperatures are then ramped down to room temperature at a rate of about 20 C/hour. The solids are then collected by filtration and dried in vacuo (55 0C and 30 inches of Hg).; Example 9[0215] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- 1 ,8-naphthyridin-3-yl)acrylamide sulfate: <n="51"/>[0216] Using method III, described above, the title salt was prepared in a yield of 84.4 % with analytical data consistent with those previously described for example 6: Analysis calculated for C23H26N3O6 H2SO4: C: 55.80, H: 4.90, N: 8.87; Found: C: 56.00, H: 5.46, N: 7.87. The DSC is depicted in Figure 11.[0217] A portion of this material was subjected to ball milling as described above: XRPD shows amorphous material is obtained.
	With sulfuric acid; In tetrahydrofuran; 1,4-dioxane; water; at 20 - 58℃;Product distribution / selectivity;	Variant B[0102] In a variant of general method II vials are charged with between 19 - 21 mg of the API were treated with one of the above solvents (i.e. DCM or THF). These vials are heated (DCM 32 0C, THF 58 0C) with stirring to ensure dissolution. Each vial is then charged with between 425 to 465 muL of a 0.126 M solution of the acid in dioxane corresponding to 1.05 equivalents of each acid. The temperature is held (DCM 32 C, THF 58 C) for 10 minutes before the introduction of an anti-solvent such as heptane. Heptane can be added until the solution became turbid, 3 mL for THF experiment and 1.5 mL for DCM experiment. After addition the vials are allowed to cool to room temperate at a rate of 20 C/hour. Precipitation typically occurs during the cooling phase and the solids can be collected by filtration and dried in vacuo at 50 0C and 30 inches of Hg. Example 6[0207] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- 1 ,8-naphthyridin-3-yl)acrylamide sulfate[0208] Compound A, sulfuric acid and THF were processed as described in method HB (Table 1) to yield the title compound as a crystalline solid. The product produced a unique XRPD pattern (Figure 8) compared to the free-base as well as a different (lower) thermal event <n="50"/>in the DSC. High intensity peaks include those occurring at 4.5, 10, 14.75, 14, 22, 24.5, and 26 2theta.

Reference： [1]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 21-22; 49-50
[2]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 48-49

9
[ 620175-39-5 ]
[ 1047981-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20 - 32℃;	Method II General Method of Salt formation II: Intermediate ScaleVariant A[0100] This method employs combinations of counter-ion and solvent. Vials were charged with between 19 - 21 mg of (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo- 5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)acrylamide and are followed by one of the following solvents: DCM 2 mL, THF 10 mL, AcOH 4.5 mL, and DMA 3-4 mL. These vials are heated (DCM 32 0C, THF 58 C, AcOH and DMA 90 0C) with stirring to ensure dissolution. Each vial is then charged with between 425 - 465 muL of a 0.126 M solution of the acid in dioxane corresponding to 1.05 equivalents of each of the acids. <n="22"/>[0101] The temperature is held at the dissolution temperature for 10 minutes and is then ramped down to room temperature at a rate of 20 C/hour. Typically, upon reaching room temperature the vials do not show any precipitation at this stage. The vials are allowed to evaporate to induce precipitation. Upon losing about one quarter of the volume the THF examples typically start to precipitate. The solids are then generally collected by filtration. In some cases the (eg. some DCM examples) most of the volume of solvent can evaporate before precipitation occurs and can not not be filtered. In other situations, the vial contents may have to be concentrated before crystallization occurs. All solid products can be analyzed directly by XRPD and DSC.; Example 1[0194] (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro- 1 ,8-naphthyridin-3-yl)acrylamide hydrochloride[0195] Using method HA, the vial containing the starting compound A, HCl and DCM solvent, upon cooling, yielded the title compound as a white solid. XRPD analysis indicated a crystalline solid distinct from the free base (compound A). The XRPD spectra is as shown in Figure 3. High intensity peaks include those occurring at 6.75, 8.25,12.5, 16,17, 17.75,18, 20.25, 20.5, 23, 24.5, 27.5, 29, 31, and 32 2theta. The DSC of the solid HCL salt showed two thermal events, as depicted in Figure 3.

Reference： [1]Patent: WO2008/98374,2008,A1 .Location in patent: Page/Page column 46-47

10
[ 24673-56-1 ]
[ 620175-39-5 ]

Reference： [1]Patent: WO2008/98374,2008,A1
[2]Patent: WO2019/177975,2019,A1

11
[ 2256-86-2 ]
[ 620175-39-5 ]

Reference： [1]Patent: WO2008/98374,2008,A1

12
6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrobromide [ No CAS ]
[ 620175-39-5 ]

Reference： [1]Patent: WO2008/98374,2008,A1

13
[ 527758-07-2 ]
[ 620175-39-5 ]

Reference： [1]Patent: WO2008/98374,2008,A1

14
[ 52819-45-1 ]
[ 620175-39-5 ]

Reference： [1]Patent: WO2019/177975,2019,A1

15
[ 92367-50-5 ]
(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride [ No CAS ]
[ 620175-39-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 6h;Inert atmosphere;	To a solution of /V- methyl- 1 -(3- methylbenzofuran-2-yl)methanamine (1.1 eq, 6.93 mmol), (£?)-3-(7-oxo-5,6,7,8-tetrahydro-l,8- naphthyridin-3-yl)acrylic acid hydrochloride (1 eq, 6.3 mmol), l-hydroxy-7- azabenzotriazole (1.1 eq, 6.93 mmol), in /V,/V-Dimethylformamide (32 mL) was added N,N- diisopropylethylamine (2.2 eq, 13.86 mmol) followed by l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (1.1 eq, 6.93 mmol). The reaction mixture was heated to 60 C for 6 h. The crude reaction mixture was diluted with water, filtered, rinsed with water, rinsed with ether, and dried to afford (£?)-A/-methyl-A/-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo- 5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)acrylamide (S7, Debio-1452, 1.970 g, 5.25 mmol, 83%) as a light beige solid. Note: Tabulated NMR data for acrylamide derivatives consist of two rotamers that exist at room temperature in a ratio of 40:60 and is reflected in the reported integral value. *H NMR (500 MHz, DMSO -d6) d 10.65 (s, 1H), 8.41 - 8.34 (m, 1H), 8.18 - 8.00 (m, 1H), 7.59 - 7.54 (m, 1H), 7.54 - 7.45 (m, 2.4H), 7.31 - 7.26 (m, 1H), 7.26 - 7.22 (m, 1H), 7.22 - 7.16 (m, 0.6H), 4.99 (s, 0.8H), 4.79 (s, 1.2H), 3.18 (s, 1.8H), 2.92 (s, 1.2H), 2.92 - 2.87 (m, 2H), 2.57 - 2.51 (m, 2H), 2.26 (s, 3H).

Reference： [1]Patent: WO2019/177975,2019,A1 .Location in patent: Page/Page column 53; 64; 65

16
[ 92367-50-5 ]
[ 620175-63-5 ]
[ 620175-39-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 6h; Inert atmosphere;	1 (E)-N-Methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide- To a solution of N-methyl-1-(3-methylbenzofuran-2-yl)methanamine (1.1 eq, 6.93 mmol), (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (1 eq, 6.3 mmol), 1-hydroxy-7-azabenzotriazole (1.1 eq, 6.93 mmol), in N,N-Dimethylformamide (32 mL) was added N,N-diisopropylethylamine (2.2 eq, 13.86 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.1 eq, 6.93 mmol). The reaction mixture was heated to 60 oC for 6 h. The crude reaction mixture was diluted with water, filtered, rinsed with water, rinsed with ether, and dried to afford (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (1.970 g, 5.25 mmol, 83%) as a light beige solid. Note: Tabulated NMR data for acrylamide derivatives consist of two rotamers that exist at room temperature in a ratio of 40:60 and is reflected in the reported integral value. 1H NMR (500 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.41 - 8.34 (m, 1H), 8.18 - 8.00 (m, 1H), 7.59 - 7.54 (m, 1H), 7.54 - 7.45 (m, 2.4H), 7.31 - 7.26 (m, 1H), 7.26 - 7.22 (m, 1H), 7.22 - 7.16 (m, 0.6H), 4.99 (s, 0.8H), 4.79 (s, 1.2H), 3.18 (s, 1.8H), 2.92 (s, 1.2H), 2.92 - 2.87 (m, 2H), 2.57 - 2.51 (m, 2H), 2.26 (s, 3H).
83%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 6h; Inert atmosphere;	1 (E)-N-Methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide- To a solution of N-methyl-1-(3-methylbenzofuran-2-yl)methanamine (1.1 eq, 6.93 mmol), (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (1 eq, 6.3 mmol), 1-hydroxy-7-azabenzotriazole (1.1 eq, 6.93 mmol), in N,N-Dimethylformamide (32 mL) was added N,N-diisopropylethylamine (2.2 eq, 13.86 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.1 eq, 6.93 mmol). The reaction mixture was heated to 60 oC for 6 h. The crude reaction mixture was diluted with water, filtered, rinsed with water, rinsed with ether, and dried to afford (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (1.970 g, 5.25 mmol, 83%) as a light beige solid. Note: Tabulated NMR data for acrylamide derivatives consist of two rotamers that exist at room temperature in a ratio of 40:60 and is reflected in the reported integral value. 1H NMR (500 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.41 - 8.34 (m, 1H), 8.18 - 8.00 (m, 1H), 7.59 - 7.54 (m, 1H), 7.54 - 7.45 (m, 2.4H), 7.31 - 7.26 (m, 1H), 7.26 - 7.22 (m, 1H), 7.22 - 7.16 (m, 0.6H), 4.99 (s, 0.8H), 4.79 (s, 1.2H), 3.18 (s, 1.8H), 2.92 (s, 1.2H), 2.92 - 2.87 (m, 2H), 2.57 - 2.51 (m, 2H), 2.26 (s, 3H).
83 %	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; Inert atmosphere;	1 (E)-N-Methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide- To a solution of N-methyl-1-(3-methylbenzofuran-2-yl)methanamine (1.1 eq, 6.93 mmol), (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (1 eq, 6.3 mmol), 1-hydroxy-7-azabenzotriazole (1.1 eq, 6.93 mmol), in N,N-Dimethylformamide (32 mL) was added N,N-diisopropylethylamine (2.2 eq, 13.86 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.1 eq, 6.93 mmol). The reaction mixture was heated to 60 oC for 6 h. The crude reaction mixture was diluted with water, filtered, rinsed with water, rinsed with ether, and dried to afford (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (1.970 g, 5.25 mmol, 83%) as a light beige solid. Note: Tabulated NMR data for acrylamide derivatives consist of two rotamers that exist at room temperature in a ratio of 40:60 and is reflected in the reported integral value. 1H NMR (500 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.41 - 8.34 (m, 1H), 8.18 - 8.00 (m, 1H), 7.59 - 7.54 (m, 1H), 7.54 - 7.45 (m, 2.4H), 7.31 - 7.26 (m, 1H), 7.26 - 7.22 (m, 1H), 7.22 - 7.16 (m, 0.6H), 4.99 (s, 0.8H), 4.79 (s, 1.2H), 3.18 (s, 1.8H), 2.92 (s, 1.2H), 2.92 - 2.87 (m, 2H), 2.57 - 2.51 (m, 2H), 2.26 (s, 3H).

Reference： [1]Current Patent Assignee: MASS GENERAL BRIGHAM INC; BROAD INSTITUTE; UNIVERSITY OF ILLINOIS (SYSTEM) - WO2022/187329, 2022, A1 Location in patent: Page/Page column 41; 52-53
[2]Current Patent Assignee: MASS GENERAL BRIGHAM INC; BROAD INSTITUTE; UNIVERSITY OF ILLINOIS (SYSTEM) - WO2022/187329, 2022, A1 Location in patent: Page/Page column 41; 52-53
[3]Current Patent Assignee: MASS GENERAL BRIGHAM INC; BROAD INSTITUTE; UNIVERSITY OF ILLINOIS (SYSTEM) - WO2022/187329, 2022, A1 Location in patent: Page/Page column 41; 52-53

17
[ 620175-39-5 ]
[ 104-15-4 ]
[ 1047981-31-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	In tetrahydrofuran; 1,4-dioxane for 1h; Heating; Inert atmosphere;	1 (E)-N-Methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide p-toluenesulfonic acid monohydride - Debio-1452 (1 eq, 1.5 mmol) was suspended in THF (120 mL) and heated to reflux. After 30 min, p-toluene sulfonic acid monohydrate (1.05 eq, 1.58 mmol) in dioxane (12 mL) was added to the reaction mixture and stirred for 1h. The reaction mixture was allowed to cool to room temperature and diluted with a mixture of 1:1 ether:n-pentane (80 mL), filtered, rinsed with 1:1 ether:n-pentane, and dried to afford (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide p-toluenesulfonic acid (Debio-1452 Tosylate, 0.756 g, 1.38 mmol, 92%) as a white solid. The product was further processed for in vivo efficacy studies to improve solubility. For these studies, Debio-1452 Tosylate was ground in a mortar and pestle and then sieved through a 75 μM mesh. Note: Tabulated NMR data for acrylamide derivatives consist of two rotamers that exist at room temperature in a ratio of 40:60 and is reflected in the reported integral values. 1H NMR (500 MHz, DMSO-d6): δ 10.69 (s, 1H), 9.49 (brs, 1H), 8.42 - 8.32 (m, 1H), 8.17 - 8.05 (m, 1H), 7.59 - 7.54 (m, 1H), 7.54 - 7.43 (m, 4.4H), 7.31 - 7.22 (m, 2H), 7.21 (d, J = 12.6 Hz, 0.6H), 7.15 - 7.09 (m, 2H), 4.99 (s, 0.8H), 4.79 (s, 1.2H), 3.18 (s, 1.8H), 2.96 - 2.89 (m, 3.2H), 2.57 - 2.51 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H).
92%	In tetrahydrofuran; 1,4-dioxane for 1h; Heating; Inert atmosphere;	1 (E)-N-Methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide p-toluenesulfonic acid monohydride - Debio-1452 (1 eq, 1.5 mmol) was suspended in THF (120 mL) and heated to reflux. After 30 min, p-toluene sulfonic acid monohydrate (1.05 eq, 1.58 mmol) in dioxane (12 mL) was added to the reaction mixture and stirred for 1h. The reaction mixture was allowed to cool to room temperature and diluted with a mixture of 1:1 ether:n-pentane (80 mL), filtered, rinsed with 1:1 ether:n-pentane, and dried to afford (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide p-toluenesulfonic acid (Debio-1452 Tosylate, 0.756 g, 1.38 mmol, 92%) as a white solid. The product was further processed for in vivo efficacy studies to improve solubility. For these studies, Debio-1452 Tosylate was ground in a mortar and pestle and then sieved through a 75 μM mesh. Note: Tabulated NMR data for acrylamide derivatives consist of two rotamers that exist at room temperature in a ratio of 40:60 and is reflected in the reported integral values. 1H NMR (500 MHz, DMSO-d6): δ 10.69 (s, 1H), 9.49 (brs, 1H), 8.42 - 8.32 (m, 1H), 8.17 - 8.05 (m, 1H), 7.59 - 7.54 (m, 1H), 7.54 - 7.43 (m, 4.4H), 7.31 - 7.22 (m, 2H), 7.21 (d, J = 12.6 Hz, 0.6H), 7.15 - 7.09 (m, 2H), 4.99 (s, 0.8H), 4.79 (s, 1.2H), 3.18 (s, 1.8H), 2.96 - 2.89 (m, 3.2H), 2.57 - 2.51 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H).
92 %	In tetrahydrofuran; 1,4-dioxane Heating; Inert atmosphere;	1 (E)-N-Methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide p-toluenesulfonic acid monohydride - Debio-1452 (1 eq, 1.5 mmol) was suspended in THF (120 mL) and heated to reflux. After 30 min, p-toluene sulfonic acid monohydrate (1.05 eq, 1.58 mmol) in dioxane (12 mL) was added to the reaction mixture and stirred for 1h. The reaction mixture was allowed to cool to room temperature and diluted with a mixture of 1:1 ether:n-pentane (80 mL), filtered, rinsed with 1:1 ether:n-pentane, and dried to afford (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide p-toluenesulfonic acid (Debio-1452 Tosylate, 0.756 g, 1.38 mmol, 92%) as a white solid. The product was further processed for in vivo efficacy studies to improve solubility. For these studies, Debio-1452 Tosylate was ground in a mortar and pestle and then sieved through a 75 μM mesh. Note: Tabulated NMR data for acrylamide derivatives consist of two rotamers that exist at room temperature in a ratio of 40:60 and is reflected in the reported integral values. 1H NMR (500 MHz, DMSO-d6): δ 10.69 (s, 1H), 9.49 (brs, 1H), 8.42 - 8.32 (m, 1H), 8.17 - 8.05 (m, 1H), 7.59 - 7.54 (m, 1H), 7.54 - 7.43 (m, 4.4H), 7.31 - 7.22 (m, 2H), 7.21 (d, J = 12.6 Hz, 0.6H), 7.15 - 7.09 (m, 2H), 4.99 (s, 0.8H), 4.79 (s, 1.2H), 3.18 (s, 1.8H), 2.96 - 2.89 (m, 3.2H), 2.57 - 2.51 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H).

Reference： [1]Current Patent Assignee: MASS GENERAL BRIGHAM INC; BROAD INSTITUTE; UNIVERSITY OF ILLINOIS (SYSTEM) - WO2022/187329, 2022, A1 Location in patent: Page/Page column 41; 53
[2]Current Patent Assignee: MASS GENERAL BRIGHAM INC; BROAD INSTITUTE; UNIVERSITY OF ILLINOIS (SYSTEM) - WO2022/187329, 2022, A1 Location in patent: Page/Page column 41; 53
[3]Current Patent Assignee: MASS GENERAL BRIGHAM INC; BROAD INSTITUTE; UNIVERSITY OF ILLINOIS (SYSTEM) - WO2022/187329, 2022, A1 Location in patent: Page/Page column 41; 53

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
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P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
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P405	Store locked up.
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P411
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P413
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P422
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P411 + P235	Keep cool.
Disposal
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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 620175-39-5 ] {[proInfo.proName]}

Quality Control of [ 620175-39-5 ]

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[ 620175-39-5 ] Synthesis Path-Upstream 1~4

[ 620175-39-5 ] Synthesis Path-Downstream 1~17

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