[ CAS No. 1268454-23-4 ] {[proInfo.proName]}

Name: 1268454-23-4|(6-(2-Aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(morpholino)methanone|98+%
Brand: Ambeed
SKU: A446445
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Quality Control of [ 1268454-23-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1268454-23-4 ]

SDS Specification

Alternatived Products of [ 1268454-23-4 ]

Product Details of [ 1268454-23-4 ]

CAS No. :	1268454-23-4	MDL No. :	MFCD15146372
Formula :	C₁₉H₁₇N₅O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BLGWHBSBBJNKJO-UHFFFAOYSA-N
M.W :	363.37	Pubchem ID :	70798655
Synonyms :	MLN1117;INK1117;TAK-117

Calculated chemistry of [ 1268454-23-4 ]

Physicochemical Properties

Num. heavy atoms :	27
Num. arom. heavy atoms :	18
Fraction Csp3 :	0.21
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	103.0
TPSA :	98.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.88 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.52
Log Po/w (XLOGP3) :	2.3
Log Po/w (WLOGP) :	1.82
Log Po/w (MLOGP) :	0.86
Log Po/w (SILICOS-IT) :	1.33
Consensus Log Po/w :	1.77

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.84
Solubility :	0.0529 mg/ml ; 0.000145 mol/l
Class :	Soluble
Log S (Ali) :	-4.01
Solubility :	0.0351 mg/ml ; 0.0000967 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.85
Solubility :	0.00517 mg/ml ; 0.0000142 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.11

Safety of [ 1268454-23-4 ]

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 [ 1268454-23-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1268454-23-4 ]
Downstream synthetic route of [ 1268454-23-4 ]

[ 1268454-23-4 ] Synthesis Path-Upstream 1~6

1
[ 1404480-15-4 ]
[ 1434089-03-8 ]
[ 1268454-23-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: at 20℃; for 0.166667 h; Stage #2: With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,4-dioxane; water at 20 - 102℃; Inert atmosphere; Reflux	[00342] Example6[00343] Formula I[00344] Preparation of (6-(2-aminobenzo [d] oxazol-5 -yl)imidazo [ 1 ,2-a]pyridin-3 - yl)(morpholino)methanone (Formula I):[00345] 1. A 5 L three-neck round bottom flask was equipped with a mechanical stirrer, thermocouple probe, Nitrogen / vacuum inlet and reflux condenser and placed into a heating mantle.[00346] 2. 1,4-Dioxane (3.75 L) and water (1.25 L) were added at room temperature.[00347] 3. Compound 9 (250 g) and Compound 3 (210 g) were added to the flask at room temperature.[00348] 4. The reaction mixture was stirred for 10 min at room temperature.[00349] 5. Sodium carbonate (300 g) was added to the flask followed byPd(PPh₃)₄ (47 g) undemitrogen at room temperature.[00350] 6. With stirring, the reactor was sparged with nitrogen for -30 minutes at [00351] 7. The reaction mixture was deoxygenated by performing 5 to 6 vacuum / nitrogen cycles.[00352] 8. The reaction mixture was heated to reflux (88°C to 102°C) under slight nitrogen bubbling and stirredfor 5 to 8 hours.[00353] 9. The reaction was monitored by HPLC.[00354] 10. Upon completion, the reaction mixture was cooled to 75 - 80°C.[00355] 11. Water (3.75 L) and ethyl acetate (1.25 L) were added to the reaction mixture at 75 - 80°C.[00356] 12. The resulting mixture was cooled to room temperature and stirred for 2 hours at room temperature.[00357] 13. The mixture was filtered and the solid collected was washed with water (2x 1.25 L), methanol (1.25 L) andethyl acetate (2 x 1.25 L).[00358] 14. The solidwas suspended in ethyl acetate (1.5 L) at room temperature for 1 hour.[00359] 15. The suspension was filtered and the solidcollected was washed with ethyl acetate (250 mL).[00360] 16. This process was repeated two more times.[00361] 17. The solidobtained was dried under vacuum to give a crude product (250 g, 85percent yield; HPLC purity 98.1percent; Pd level 1831 ppm).[00362] Further purification of the crude product:[00363] 18. The crude product (250g) was suspended in methanol (2.5 L) and HCl (158 mL) at room temperature.[00364] 19. The mixture was heated to 40 to 45°C to give a slightly cloudy solution.[00365] 20. Charcoal (250 g) was added to the reaction mixture at 40 to 45°C. [00366] 21. The resulting mixture was stirred for 30 minutes at 40 to 45 °C.[00367] 22. The hot solution was filtered through a poly pad with 2 inch celite bed and the cake was washed withmethanol (3 x 500 mL).[00368] 23. The solution was recharged to the flask (Pd level: 330 ppm).[00369] 24. The solution was heated to 40 to 45°C.[00370] 25. Charcoal (50 g) and silica thiol (50 g) were added at 40 to 45°C.[00371] 26. The mixture was stirred for 30 minutes at 40 to 45°C.[00372] 27. The hot solution was filtered through a poly pad and the cake was washed with methanol (250 mL)[00373] 28. This process was repeated one more time.[00374] 29. The methanol was removed under vacuum at 30 - 35°C to ~2.5 L.[00375] 30. The solution was cooled to 10 to 15°C.[00376] 31. Concentrated aqueous ammonia solution (200 mL) was added until reaching pH 8-9.[00377] 32. The reaction mixture was cooled to 0 to 5°C and stirred for 1 to 2 hours at 0 to 5°C.[00378] 33. The mixture was filtered and the cake was washed with water (2 x 500 mL) and methanol (2 x 500mL).[00379] 34. The solid collected was transfered back into a round bottom flask and suspended in ethyl acetate (2.5 L) at roomtemperature for 2 to 3 hours.[00380] 35. The solid was collected by filtration and washed with ethyl acetate (750 mL).36. The solid was dried under vacuum at ~50°C to constant weight to give thecompound of Formila I as an off-white solid (180 g, 61percent yield; HPLC purity 98.5percent; 'HNMR (DMSO-d6, 300 MHz) ? 9.1 (s, 1H), 8.1 (s, 1H), 7.8-7.65 (2H), 7.60-7.40 (m, 4H), 7.3-7.2 (1H), 3.8-3.6 (m, 8H); Pd level lppm).
61%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,4-dioxane; water at 20 - 102℃; Inert atmosphere	Example 6 Preparation of (6-(2-aminobenzo [d] oxazol-5 -yl)imidazo [1,2-a]pyridin-3 -yl)(morpholino)methanone (Formula V): 1. A 5 L three-neck round bottom flask was equipped with a mechanical stirrer, thermocouple probe, Nitrogen / vacuum inlet and reflux condenser and placed into a heating mantle. 2. 1,4-Dioxane (3.75 L) and water (1.25 L) were added at room temperature. 3. Compound 9 (250 g) and Compound 3 (210 g) were added to the flask at room temperature. 4. The reaction mixture was stirred for 10 min at room temperature. 5. Sodium carbonate (300 g) was added to the flask followed byPd(PPh3)4 (47 g) undemitrogen at room temperature. 6. With stirring, the reactor was sparged with nitrogen for -30 minutes at < 20°C. 7. The reaction mixture was deoxygenated by performing 5 to 6 vacuum / nitrogen cycles. 8. The reaction mixture was heated to reflux (88°C to 102°C) under slight nitrogen bubbling and stirredfor 5 to 8 hours. 9. The reaction was monitored by HPLC. 10. Upon completion, the reaction mixture was cooled to 75 - 80°C. 11. Water (3.75 L) and ethyl acetate (1.25 L) were added to the reaction mixture at 75 - 80°C. 12. The resulting mixture was cooled to room temperature and stirred for 2 hours at room temperature. 13. The mixture was filtered and the solid collected was washed with water (2x 1.25 L), methanol (1.25 L) andethyl acetate (2 x 1.25 L). 14. The solidwas suspended in ethyl acetate (1.5 L) at room temperature for 1 hour. 15. The suspension was filtered and the solidcollected was washed with ethyl acetate (250 mL). 16. This process was repeated two more times. 17. The solidobtained was dried under vacuum to give a crude product (250 g, 85percent yield; HPLC purity 98.1percent; Pd level 1831 ppm). Further purification of the crude product: 18. The crude product (250g) was suspended in methanol (2.5 L) and HCl (158 mL) at room temperature. 19. The mixture was heated to 40 to 45°C to give a slightly cloudy solution. 20. Charcoal (250 g) was added to the reaction mixture at 40 to 45°C. 21. The resulting mixture was stirred for 30 minutes at 40 to 45 °C. 22. The hot solution was filtered through a poly pad with 2 inch celite bed and the cake was washed with methanol (3 x 500 mL). 23. The solution was recharged to the flask (Pd level: 330 ppm). 24. The solution was heated to 40 to 45°C. 25. Charcoal (50 g) and silica thiol (50 g) were added at 40 to 45°C. 26. The mixture was stirred for 30 minutes at 40 to 45°C. 27. The hot solution was filtered through a poly pad and the cake was washed with methanol (250 mL). 28. This process was repeated one more time. 29. The methanol was removed under vacuum at 30 - 35°C to ∼2.5 L. 30. The solution was cooled to 10 to 15°C. 31. Concentrated aqueous ammonia solution (200 mL) was added until reaching pH 8-9. 32. The reaction mixture was cooled to 0 to 5°C and stirred for 1 to 2 hours at 0 to 5°C. 33. The mixture was filtered and the cake was washed with water (2 x 500 mL) and methanol (2 x 500mL). 34. The solid collected was transfered back into a round bottom flask and suspended in ethyl acetate (2.5 L) at roomtemperature for 2 to 3 hours. 35. The solid was collected by filtration and washed with ethyl acetate (750 mL). 36. The solid was dried under vacuum at ∼50°C to constant weight to give thecompound of Formila I as an off-white solid (180 g, 61percent yield; HPLC purity 98.5percent; 'HNMR (DMSO-d6, 300 MHz) δ 9.1 (s, 1H), 8.1 (s, 1H), 7.8-7.65 (2H), 7.60-7.40 (m, 4H), 7.3-7.2 (1H), 3.8-3.6 (m, 8H); Pd level lppm).

Reference： [1] Patent: WO2013/71272, 2013, A1, . Location in patent: Paragraph 00342-00380
[2] Patent: EP2792360, 2014, A1, . Location in patent: Paragraph 0226-0227

2
[ 944896-42-8 ]
[ 1268454-23-4 ]

Reference： [1] Patent: WO2013/71272, 2013, A1,
[2] Patent: EP2792360, 2014, A1,

3
[ 40925-68-6 ]
[ 1268454-23-4 ]

Reference： [1] Patent: WO2013/71272, 2013, A1,
[2] Patent: EP2792360, 2014, A1,

4
[ 64037-07-6 ]
[ 1268454-23-4 ]

Reference： [1] Patent: WO2013/71272, 2013, A1,
[2] Patent: EP2792360, 2014, A1,

5
[ 372198-69-1 ]
[ 1268454-23-4 ]

Reference： [1] Patent: WO2013/71272, 2013, A1,

6
[ 1224844-66-9 ]
[ 1268454-23-4 ]

Reference： [1] Patent: WO2013/71272, 2013, A1,

[ 1268454-23-4 ] Synthesis Path-Downstream 1~17

1
[ 372198-69-1 ]
[ 1268454-23-4 ]

Reference： [1]Patent: WO2013/71272,2013,A1

2
[ 944896-42-8 ]
[ 1268454-23-4 ]

Reference： [1]Patent: WO2013/71272,2013,A1
[2]Patent: EP2792360,2014,A1

3
[ 1404480-15-4 ]
[ 1434089-03-8 ]
[ 1268454-23-4 ]

Yield	Reaction Conditions	Operation in experiment
85%		[00342] Example6[00343] Formula I[00344] Preparation of (6-(2-aminobenzo [d] oxazol-5 -yl)imidazo [ 1 ,2-a]pyridin-3 - yl)(morpholino)methanone (Formula I):[00345] 1. A 5 L three-neck round bottom flask was equipped with a mechanical stirrer, thermocouple probe, Nitrogen / vacuum inlet and reflux condenser and placed into a heating mantle.[00346] 2. 1,4-Dioxane (3.75 L) and water (1.25 L) were added at room temperature.[00347] 3. Compound 9 (250 g) and Compound 3 (210 g) were added to the flask at room temperature.[00348] 4. The reaction mixture was stirred for 10 min at room temperature.[00349] 5. Sodium carbonate (300 g) was added to the flask followed byPd(PPh3)4 (47 g) undemitrogen at room temperature.[00350] 6. With stirring, the reactor was sparged with nitrogen for -30 minutes at [00351] 7. The reaction mixture was deoxygenated by performing 5 to 6 vacuum / nitrogen cycles.[00352] 8. The reaction mixture was heated to reflux (88C to 102C) under slight nitrogen bubbling and stirredfor 5 to 8 hours.[00353] 9. The reaction was monitored by HPLC.[00354] 10. Upon completion, the reaction mixture was cooled to 75 - 80C.[00355] 11. Water (3.75 L) and ethyl acetate (1.25 L) were added to the reaction mixture at 75 - 80C.[00356] 12. The resulting mixture was cooled to room temperature and stirred for 2 hours at room temperature.[00357] 13. The mixture was filtered and the solid collected was washed with water (2x 1.25 L), methanol (1.25 L) andethyl acetate (2 x 1.25 L).[00358] 14. The solidwas suspended in ethyl acetate (1.5 L) at room temperature for 1 hour.[00359] 15. The suspension was filtered and the solidcollected was washed with ethyl acetate (250 mL).[00360] 16. This process was repeated two more times.[00361] 17. The solidobtained was dried under vacuum to give a crude product (250 g, 85% yield; HPLC purity 98.1%; Pd level 1831 ppm).[00362] Further purification of the crude product:[00363] 18. The crude product (250g) was suspended in methanol (2.5 L) and HCl (158 mL) at room temperature.[00364] 19. The mixture was heated to 40 to 45C to give a slightly cloudy solution.[00365] 20. Charcoal (250 g) was added to the reaction mixture at 40 to 45C. [00366] 21. The resulting mixture was stirred for 30 minutes at 40 to 45 C.[00367] 22. The hot solution was filtered through a poly pad with 2 inch celite bed and the cake was washed withmethanol (3 x 500 mL).[00368] 23. The solution was recharged to the flask (Pd level: 330 ppm).[00369] 24. The solution was heated to 40 to 45C.[00370] 25. Charcoal (50 g) and silica thiol (50 g) were added at 40 to 45C.[00371] 26. The mixture was stirred for 30 minutes at 40 to 45C.[00372] 27. The hot solution was filtered through a poly pad and the cake was washed with methanol (250 mL)[00373] 28. This process was repeated one more time.[00374] 29. The methanol was removed under vacuum at 30 - 35C to ~2.5 L.[00375] 30. The solution was cooled to 10 to 15C.[00376] 31. Concentrated aqueous ammonia solution (200 mL) was added until reaching pH 8-9.[00377] 32. The reaction mixture was cooled to 0 to 5C and stirred for 1 to 2 hours at 0 to 5C.[00378] 33. The mixture was filtered and the cake was washed with water (2 x 500 mL) and methanol (2 x 500mL).[00379] 34. The solid collected was transfered back into a round bottom flask and suspended in ethyl acetate (2.5 L) at roomtemperature for 2 to 3 hours.[00380] 35. The solid was collected by filtration and washed with ethyl acetate (750 mL).36. The solid was dried under vacuum at ~50C to constant weight to give thecompound of Formila I as an off-white solid (180 g, 61% yield; HPLC purity 98.5%; 'HNMR (DMSO-d6, 300 MHz) ? 9.1 (s, 1H), 8.1 (s, 1H), 7.8-7.65 (2H), 7.60-7.40 (m, 4H), 7.3-7.2 (1H), 3.8-3.6 (m, 8H); Pd level lppm).
61%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 20 - 102℃;Inert atmosphere;	Example 6 Preparation of (6-(2-aminobenzo [d] oxazol-5 -yl)imidazo [1,2-a]pyridin-3 -yl)(morpholino)methanone (Formula V): 1. A 5 L three-neck round bottom flask was equipped with a mechanical stirrer, thermocouple probe, Nitrogen / vacuum inlet and reflux condenser and placed into a heating mantle. 2. 1,4-Dioxane (3.75 L) and water (1.25 L) were added at room temperature. 3. Compound 9 (250 g) and Compound 3 (210 g) were added to the flask at room temperature. 4. The reaction mixture was stirred for 10 min at room temperature. 5. Sodium carbonate (300 g) was added to the flask followed byPd(PPh3)4 (47 g) undemitrogen at room temperature. 6. With stirring, the reactor was sparged with nitrogen for -30 minutes at < 20C. 7. The reaction mixture was deoxygenated by performing 5 to 6 vacuum / nitrogen cycles. 8. The reaction mixture was heated to reflux (88C to 102C) under slight nitrogen bubbling and stirredfor 5 to 8 hours. 9. The reaction was monitored by HPLC. 10. Upon completion, the reaction mixture was cooled to 75 - 80C. 11. Water (3.75 L) and ethyl acetate (1.25 L) were added to the reaction mixture at 75 - 80C. 12. The resulting mixture was cooled to room temperature and stirred for 2 hours at room temperature. 13. The mixture was filtered and the solid collected was washed with water (2x 1.25 L), methanol (1.25 L) andethyl acetate (2 x 1.25 L). 14. The solidwas suspended in ethyl acetate (1.5 L) at room temperature for 1 hour. 15. The suspension was filtered and the solidcollected was washed with ethyl acetate (250 mL). 16. This process was repeated two more times. 17. The solidobtained was dried under vacuum to give a crude product (250 g, 85% yield; HPLC purity 98.1%; Pd level 1831 ppm). Further purification of the crude product: 18. The crude product (250g) was suspended in methanol (2.5 L) and HCl (158 mL) at room temperature. 19. The mixture was heated to 40 to 45C to give a slightly cloudy solution. 20. Charcoal (250 g) was added to the reaction mixture at 40 to 45C. 21. The resulting mixture was stirred for 30 minutes at 40 to 45 C. 22. The hot solution was filtered through a poly pad with 2 inch celite bed and the cake was washed with methanol (3 x 500 mL). 23. The solution was recharged to the flask (Pd level: 330 ppm). 24. The solution was heated to 40 to 45C. 25. Charcoal (50 g) and silica thiol (50 g) were added at 40 to 45C. 26. The mixture was stirred for 30 minutes at 40 to 45C. 27. The hot solution was filtered through a poly pad and the cake was washed with methanol (250 mL). 28. This process was repeated one more time. 29. The methanol was removed under vacuum at 30 - 35C to ?2.5 L. 30. The solution was cooled to 10 to 15C. 31. Concentrated aqueous ammonia solution (200 mL) was added until reaching pH 8-9. 32. The reaction mixture was cooled to 0 to 5C and stirred for 1 to 2 hours at 0 to 5C. 33. The mixture was filtered and the cake was washed with water (2 x 500 mL) and methanol (2 x 500mL). 34. The solid collected was transfered back into a round bottom flask and suspended in ethyl acetate (2.5 L) at roomtemperature for 2 to 3 hours. 35. The solid was collected by filtration and washed with ethyl acetate (750 mL). 36. The solid was dried under vacuum at ?50C to constant weight to give thecompound of Formila I as an off-white solid (180 g, 61% yield; HPLC purity 98.5%; 'HNMR (DMSO-d6, 300 MHz) delta 9.1 (s, 1H), 8.1 (s, 1H), 7.8-7.65 (2H), 7.60-7.40 (m, 4H), 7.3-7.2 (1H), 3.8-3.6 (m, 8H); Pd level lppm).

Reference： [1]Patent: WO2013/71272,2013,A1 .Location in patent: Paragraph 00342-00380
[2]Patent: EP2792360,2014,A1 .Location in patent: Paragraph 0226-0227

4
[ 1268454-23-4 ]
(6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(morpholino)methanone hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen bromide; In tetrahydrofuran; for 72.0h;	General procedure: [00421] Formula I HBr salts were obtained by maturation for 3 days in acetonitrile and THF, and by maturation with additional solvent in nitromethane.Table 9. HBr salts obtained in the salt screen

Reference： [1]Patent: WO2013/71272,2013,A1 .Location in patent: Paragraph 00421

5
[ 1268454-23-4 ]
(6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(morpholino)methanone hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In acetonitrile; at 20 - 50℃;	General procedure: [00413] Example 8: Salt Selection[00414] Preparation of the hydrochloride salt was performed in the 20 solvents used for the solubility screen in order to select the optimal solvents for the salt screen. Formula I free base (ca. 10 mg) was suspended in the selected solvents (50 volumes; 500 ??) with stirring at 40C. HC1 (1.1 equivalents; 29 of 1M solution in THF) was added, and the temperature was maintained for 30 minutes. The vials were subjected to heating/cooling cycles between room temperature and 50C, four hours at each condition. After 1 day, an aliquot of each experiment was taken, isolated by vacuum filtration, dried by suction and analyzed by XRPD. The experiments were left cycling for further three days. An aliquot of each experiment was taken, isolated by vacuum filtration, dried by suction and analyzed by XRPD. Results are summarized in Table 2.[00415] Table 2. Results of HC1 salt screen from 20 different solventsyielded oil)

Reference： [1]Patent: WO2013/71272,2013,A1 .Location in patent: Paragraph 00413-00415

6
[ 1268454-23-4 ]
C₁₉H₁₇N₅O₃*(x)H₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In tetrahydrofuran; at 50℃;	General procedure: [00416] Formula I free base (ca. 30 mg) was suspended in selected solvents (THF, nitromethane, acetonitrile and MEK; 50 volumes, 1.5 mL) at 50C with stirring. The corresponding acid (1 equivalent) was added and the samples were stirred for 30 minutes, prior to ramping at l C -min_1 to 25C. The samples were placed in a shaker and subjected to heating/cooling cycles, between room temperature and 50C, with four hours at each condition. Details about the acids used for these experiments, including input materials and amounts, are summarized in Table 3 below.Table 3. Input materials used for the salt screensolution in THF)[00417] After 16 hours, an aliquot was taken, isolated by vacuum filtration, dried by suction and analyzed by XRPD. Further solvent (25 volumes) was added, and the suspensions were allowed to cycle for four more days. An aliquot was taken, isolated by vacuum filtration, dried by suction and analyzed by XRPD. Further acid (0.2 equivalents, 17 ??) and solvent (25 volumes) were added to those samples showing the presence of free base in the XRPD pattern, suggesting incomplete salt formation. The samples were stored in a shaker and subjected to heating/cooling cycles, between room temperature and 50C, with four hours at each condition for one week. An aliquot was taken, isolated by vacuum filtration, dried by suction and analyzed by XRPD. Water (10% for MeCN, and 5% for THF, MEK and nitromethane, based on ca. 1.5 mL solvent) was added and the samples were cycled for a further 5 days. An aliquot was taken, isolated by vacuum filtration, dried by suction and analyzed by XRPD.[00418] For samples exhibiting new XRPD patterns, the remaining solid was isolated by vacuum filtration, dried by suction and further characterization was undertaken as follows.