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In water; acetone; at 0 - 6℃; for 5.0h; |
A compound of Formula I (1.0 X) was added to Reactor A. Methanesulfonic acid (0.56 X, 2.40 eq), water (4 X, 4 V) and acetone (3.2 X, 4 V) were added to Reactor B. The contents of Reactor B were added to Reactor A while maintaining the temperature in Reactor A below 35 C. After the solids dissolved, the contents of Reactor A were transferred to Reactor B. Reactor A was rinsed with water (1 X, 1 V) and acetone (0.8 X, 1 V), and transferred to Reactor B. The temperature of Reactor B was adjusted to 19-25 C. Under high agitation, acetone (11.9 X, 15 V) was added to Reactor B. The temperature of Reactor B was adjusted to 0-6 C. and the contents of Reactor B were mixed for 5 h, then filtered, and rinsed with acetone (4.0 X, 5 V) to provide polymorph Form 7. Form 7 was dried under vacuum at 60 C. until constant weight was achieved. Representative patterns of an XRPD of polymorph Form 7 are shown in FIGS. 1C and 1D. [0599] The isolated polymorph Form 7 was added to polymorph Form 3 seeds of a compound of Formula IA (0.01 X, 1 mol %) in Reactor B. Acetone (15.4 X, 19.5 V), and water (0.5 X, 0.5 V) were added to Reactor B and mixed at 19-25 C. until polymorph Form 7 was converted to Form 3. The conversion was monitored by XRPD or DSC. The contents of Reactor B was filtered, rinsed with acetone (2.4 X, 3 V) and dried under vacuum at 60 C. until constant weight was achieved. Representative patterns of an XRPD of polymorph Form 3 are shown in FIGS. 1A and 1B. |
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In water; acetone; at 0 - 6℃; for 5.0h; |
Example 1 Synthesis of Polymorph Form 3 [0243] Methods for generally making various forms of the compound of Formula I may be found in U.S. Pat. Nos. 8,450,321 and 8,455,493. The following is a method for producing polymorph Form 3, which is a polymorph of a monohydrate, bis-mesylate salt of a compound of Formula I (and may also be described as a polymorph of a monohydrate of the compound of Formula IA shown in the reaction scheme below). [0244] A compound of Formula I (1.0×) was added to Reactor A. Methanesulfonic acid (0.56×, 2.40 eq), water (4×, 4 V) and acetone (3.2×, 4 V) were added to Reactor B. The contents of Reactor B were added to Reactor A while maintaining the temperature in Reactor A below 35 C. After the solids dissolved, the contents of Reactor A were transferred to Reactor B. Reactor A was rinsed with water (1×, 1V) and acetone (0.8×, 1V), and transferred to Reactor B. The temperature of Reactor B was adjusted to 19-25 C. Under high agitation, acetone (11.9×, 15 V) was added to Reactor B. The temperature of Reactor B was adjusted to 0-6 C. and the contents of Reactor B were mixed for 5 h, then filtered, and rinsed with acetone (4.0×, 5 V) to provide polymorph Form 7. Form 7 was dried under vacuum at 60 C. until constant weight was achieved. Representative patterns of XRPD and DSC of polymorph Form 7 are shown in FIGS. 2A and 4A, respectively. [0245] The isolated polymorph Form 7 was added to polymorph Form 3 seeds of a compound of Formula IA (0.01×, 1 mol %) in Reactor B. Acetone (15.4×, 19.5 V), and water (0.5×, 0.5 V) were added to Reactor B and mixed at 19-25 C. until polymorph Form 7 was converted to Form 3. The conversion was monitored by XRPD or DSC. The contents of Reactor B was filtered, rinsed with acetone (2.4×, 3 V) and dried under vacuum at 60 C. until constant weight was achieved. Representative patterns of XRPD and DSC of polymorph Form 3 of a compound of Formula IA are shown in FIGS. 1A and 3A, respectively. Other representative patterns of XRPD and DSC of polymorph Form 3 of a compound of Formula IA are shown in FIGS. 1B and 3C, respectively. |
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In water; acetone; at 0 - 25℃; for 5.0h; |
Preparation of Form 7: The compound of Formula I (1.0 X) was added to reaction vessel A. Methanesulfonic acid (0.56 X, 2.40 eq), water (4 X, 4 V) and acetone (3.2 X, 4 V) were added to reaction vessel B. The contents of reaction vessel B were added to reaction vessel A while maintaining the temperature in reaction vessel A below 35C. After the solids dissolved, the resulting solution of reaction vessel B was adjusted to 19-25 C. Under high agitation, acetone (11.9 X, 15 V) was added to reaction vessel B and the content temperature resulting slurry of Reaction Vessel B was adjusted to 0-6 C, and the contents of reaction vessel B were mixed for 5 h. The slurry was filtered, and rinsed with acetone (4.0 X, 5 V) to provide polymorph Form 7. Form 7 was dried under vacuum at 60 C. [0194] The isolated polymorph Form 7, acetone (15.4 X, 19.5 V), and water (0.5 X, 0.5 V) were combined and added to Polymorph Form 3 seeds (0.01 X, 1 mol%). Acetone (15.4 X, 19.5 V), and water (0.5 X, 0.5 V) were added to reaction vessel B and the resulting slurry was agitated at 20-40 C until polymorph Form 7 was converted to Form 3. The conversion was monitored by XRPD or DSC. The slurry was adjusted to 19-25 C, was filtered, and rinsed with acetone (2.4 X, 3 V). The wet cake was dried under vacuum at 60 C until constant weight was achieved. [0195] Form 3: The following is a method for producing polymorph Form 3, a hydrate, bis- mesylate salt of a compound of Formula I (which may also be described as a polymorph of a hydrate of [0196] Polymorph Form 7 was obtained as described in Example above. [0197] The isolated polymorph Form 7 was added to polymorph Form 3 seeds of a compound of Formula IA (0.01 X, 1 mol%) in reaction vessel B. Acetone (15.0 X, 19.0 V), and water (1.0 X, 1.0 V) were added to reaction vessel B. The mixture was heated to reflux (about 55 C) until polymorph Form 7 was converted to Form 3. The conversion was monitored by XRPD or DSC. The contents of reaction vessel B was a slurry and was cooled to 19-25 C, then filtered, rinsed with acetone (2.4 X, 3 V) and dried under vacuum at 60 C until constant weight is achieved to provide the polymorph Form 3. [0199] Synthesis of Polymorph Form I: Form I was isolated by heating Form VI at about 150 C for about two hours in an open reaction vessel followed by cooling to room temperature or by Form III at aboutl75 C for about two hours in an open reaction vessel followed by cooling to room temperature. XRPD analysis of the sample after the DVS experiment shows that the material had converted to Form VII. [0200] Synthesis of Polymorph Form II: Form II was isolated by heating Form VI under vacuum at about 120 C overnight, as well as slurring Form VI in isopropyl alcohol at room temperature for about 1 week. [0201] Synthesis of Polymorph Form XIII: Form XIII was isolated by exposing Form VII to about 0% RH in a P2O5 chamber heated to about 40 C under vacuum for approximately 4 days. [0202] Synthesis of Polymorph Form XIV: Form XIV was isolated by heating Form I, Form II, Form III, or Form XVI to about 250 C on a DSC. [0203] Synthesis of Polymorph Form XV: Form XV was prepared by slurring a mixture of Form III and Form XV in 2.5% water in acetone at room temperature for about 5 days. It can also be made by slurring Form VII in 4% water in acetone at room temperature for about 3 days. [0204] Synthesis of Polymorph Form XVI: Form XVI was prepared by slurring Form VII in acetone at room temperature for about 1 day or slurring Form XIX in 1% water in acetone or 2% water in acetone for about 1-5 days at room temperature. [0205] Synthesis of Polymorph Form XVIII: Form XVIII was isolated from solvent-wet starting material of compound of Formula I, from 20% water in acetone and drying it in an oven at about 80 C under vacuum. |
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