Non-solvated crystalline 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene hydrochloride
OwnerWayne Douglas Lukeinventor
Life of this patent
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Abstract
The present invention is directed to chemical processes for preparing 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)benzoyl]benzo[b]-thiophenes. The present invention is also directed to crystalline solvates and a non-solvated crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene hydrochloride, as well as processes for their preparation.
Claims76
A process for preparing a crystalline solvate of a compound of the formula
- 14
- wherein:
- R1 is hydrogen or hydroxyl;
- R2 and R3 are independently C1-C4 alkyl, or R2 and R3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino;
- and
- HX is HCl or HBr;
- comprising the steps of:
- (a) acylating a benzothiophene of the formula
- 15
- wherein:
- R4 is hydrogen or C1-C4 alkoxy, and
- R5 is C1-C4 alkyl,
- with an acylating agent of the formula
- 16
- wherein:
- R6 is chloro, bromo, or hydroxyl, and
- HX, R2, and R3 are as defined above,
- in the presence of BX′3, wherein X′ is chloro or bromo;
- (b) dealkylating one or more phenolic groups of the acylation product of step (a) by reacting with additional BX3′, wherein X′ is as defined above;
- and
- (c) isolating the crystalline solvate.
A process for preparing a compound of the formula
- 17
- or the hydrochloride or hydrobromide salt thereof, wherein:
- R4 is hydrogen or C1-C4 alkoxy;
- R5 is C1-C4 alkyl;
- and
- R2 and R3 are independently C1-C4 alkyl, or R2 and R3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino;
- comprising acylating a benzothiophene of the formula
- 18
- wherein:
- R4 and R5 are as defined above,
- with an acylating agent of the formula
- 19
- wherein:
- R6 is chloro, bromo, or hydroxyl;
- R2 and R3 are independently C1-C4 alkyl, or R2 and R3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino;
- and
- HX is HCl or HBr;
- in the presence of BX′3, wherein X′ is chloro or bromo.
A process for preparing a crystalline solvate of a compound of the formula
- 20
- wherein
- R1 is hydrogen or hydroxyl;
- R2 and R3 are independently C1-C4 alkyl, or R2 and R3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino;
- and
- HX is HCl or HBr;
- comprising (a) dealkylation of one or more of the phenolic groups of a compound of the formula
- 21
- wherein:
- R4 is hydrogen or C1-C4 alkoxy;
- R5 is C1-C4 alkyl;
- and
- HX, R2, and R3 are as defined above;
- by reacting with BX′3, wherein X′ is chloro or bromo;
- and
- (b) isolating the crystalline solvate.
A crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride having the following X-ray diffraction pattern obtained with copper radiation:
- 9 d-line spacing I/Io (Angstroms) (×100) 10.4311 22.64 8.9173 10.73 8.4765 5.31 8.0095 50.39 7.3068 4.23 6.6094 79.23 5.6196 22.34 5.4223 89.86 5.1959 11.81 5.0746 74.90 4.8017 100.00 4.7262 57.97 4.6569 53.35 4.5378 96.75 4.4376 10.83 4.3397 56.89 4.2782 48.23 4.2129 40.94 4.1037 12.80 3.9880 14.76 3.8863 8.17 3.7999 42.13 3.7662 57.09 3.6738 38.58 3.5701 18.50 3.5393 19.00 3.4622 39.57 3.3867 5.02 3.3321 4.33 3.2686 6.79 3.1535 14.86 3.0450 13.58 2.9028 12.30 2.8302 19.59 2.7544 12.30 2.6366 6.89
A crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride having the following X-ray diffraction pattern obtained with copper radiation:
- 10 d-line spacing I/Io (Angstroms) (×100) 16.1265 3.80 10.3744 8.63 8.3746 5.29 7.9883 36.71 7.2701 5.06 6.5567 70.77 6.2531 6.79 5.5616 24.05 5.3879 100.00 5.0471 89.64 4.7391 85.96 4.6777 39.36 4.6332 62.60 4.5191 77.56 4.2867 36.82 4.2365 41.66 4.1816 49.60 4.0900 11.28 3.9496 11.85 3.7869 36.25 3.7577 56.16 3.6509 40.62 3.5751 15.65 3.5181 21.52 3.4964 18.53 3.4361 33.60 3.3610 6.21 3.3115 4.95 3.2564 7.36 3.2002 3.80 3.1199 15.77 3.0347 14.84 2.8744 9.67 2.8174 10.82 2.7363 11.51
A process for preparing a crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride having the following X-ray diffraction pattern obtained with copper radiation:
- 11 d-line spacing I/Io (Angstroms) (x100) 14.3518 7.24 10.3335 6.17 8.8305 4.29 7.9475 38.16 6.5904 64.25 6.2848 6.52 5.6048 28.06 5.4107 100.00 5.1544 11.26 5.0493 53.26 5.0224 46.11 4.8330 76.94 4.7694 34.23 4.6461 50.22 4.5754 38.61 4.4953 72.65 4.3531 49.15 4.2940 41.64 4.2425 35.75 4.1856 21.63 4.1338 9.47 4.0793 12.69 3.9960 18.50 3.9037 9.03 3.7854 40.39 3.7521 54.16 3.6787 28.60 3.6509 17.96 3.5444 31.72 3.4679 41.55 3.3899 7.69 3.3101 5.72 3.2561 7.42 3.1784 15.19 3.0445 11.17 3.0146 8.94 2.9160 11.89 2.8217 18.23 2.7500 12.06 2.6436 9.65 2.6156 6.97
- comprising the steps of:
- (a) dealkylating the hydrochloride salt of a compound of the formula
- 24
- wherein R7 is C1-C4 alkyl,
- by reacting with BCl3 in chlorobenzene;
- (b) quenching the reaction of step (a) with methanol;
- and
- (c) isolating the crystalline solvate.
A process for preparing a crystalline solvate of a compound of the formula
- 25
- wherein:
- R1 is hydrogen or hydroxyl;
- R2 and R3 are independently C1-C4 alkyl, or R2 and R3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino;
- and
- HX is HCl or HBr;
- comprising the steps of:
- (a) chlorinating with phosgene a compound of the formula
- 26
- wherein:
- HX, R2, and R3 are as defined above, and
- R6 is hydroxyl
- to produce a formula III compound wherein R6 is chloro;
- (b) acylating a benzothiophene of the formula
- 27
- wherein:
- R4 is hydrogen or C1-C4 alkoxy, and
- R5 is C1-C4 alkyl,
- with a compound of formula III, wherein R6 is chloro, in the presence of BX′3, wherein X′ is chloro or bromo;
- (c) dealkylating one or more phenolic groups of the acylation product of step (b) by reacting with additional BX′3, wherein X′ is as defined above;
- and
- (d) isolating the crystalline solvate.
A process for preparing a crystalline solvate of a compound of the formula
- 28
- wherein:
- R1 is hydrogen or hydroxyl;
- R2 and R3 are independently C1-C4 alkyl, or R2 and R3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino;
- and
- HX is HCl or HBr;
- comprising the steps of:
- (a) chlorinating a compound of the formula
- 29
- wherein:
- HX, R2, and R3 are as defined above, and
- R6 is hydroxyl,
- with a chlorination reagent to produce a formula III compound wherein R6 is chloro;
- (b) removing the excess chlorination agent;
- (c) acylating a benzothiophene of the formula
- 30
- wherein:
- R4 is hydrogen or C1-C4 alkoxy, and
- R5 is C1-C4 alkyl,
- with a compound of formula III, wherein R6 is chloro, in the presence of BX′3, wherein X′ is chloro or bromo;
- (d) dealkylating one or more phenolic groups of the acylation product of step (c) by reacting with additional BX′3, wherein X′ is as defined above;
- and
- (e) isolating the crystalline solvate.
A process for preparing a crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene hydrochloride having the following X-ray diffraction pattern obtained with copper radiation:
- 12 d-line spacing I/Io (Angstroms) (x100) 14.3518 7.24 10.3335 6.17 8.8305 4.29 7.9475 38.16 6.5904 64.25 6.2848 6.52 5.6048 28.06 5.4107 100.00 5.1544 11.26 5.0493 53.26 5.0224 46.11 4.8330 76.94 4.7694 34.23 4.6461 50.22 4.5754 38.61 4.4953 72.65 4.3531 49.15 4.2940 41.64 4.2425 35.75 4.1856 21.63 4.1338 9.47 4.0793 12.69 3.9960 18.50 3.9037 9.03 3.7854 40.39 3.7521 54.16 3.6787 28.60 3.6509 17.96 3.5444 31.72 3.4679 41.55 3.3899 7.69 3.3101 5.72 3.2561 7.42 3.1784 15.19 3.0445 11.17 3.0146 8.94 2.9160 11.89 2.8217 18.23 2.7500 12.06 2.6436 9.65 2.6156 6.97
- comprising the steps of:
- (a) acylating a benzothiophene of the formula
- 37
- wherein:
- R4 is C1-C4 alkoxy and R5 is C1-C4 alkyl, with an acylating agent of the formula
- 38
- wherein:
- R6 is chloro, and R2 and R3 together with the adjacent nitrogen atom form a piperidino group, and HX is HCl, in the presence of BCl3 in chlorobenzene;
- (b) dealkylating the hydrochloride salt of the compound of the formula
- 39
- wherein R7 is C1-C4 alkyl;
- by reacting with additional BCl3;
- (c) quenching the reaction of step (b) with methanol;
- and
- (d) isolating the crystalline solvate.
A process for preparing non-soLvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene hydrochloride comprising (a) reacting a solvated form of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride in methanol or in a mixture of methanol and water with about one equivalent of base,
- (b) extracting the solution from step (a) with an aliphatic hydrocarbon solvent,
- (c) adding about one equivalent of hydrochloric acid to the methanolic solution from step (b), and
- (d) isolating the crystalline compound.
A process for preparing non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene hydrochloride comprising
- (a) reacting a solvated form of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride in methanol or in a mixture of methanol and water with about one equivalent of base, and
- (b) adding about one equivalent of hydrochloric acid to the methanolic solution from step (a), and
- (c) isolating the crystalline compound.
Non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride, having substantially the following X-ray diffraction pattern obtained with copper radiation:
- 13 d-line spacing I/Io (Angstroms) (x100) 13.3864 71.31 9.3598 33.16 8.4625 2.08 7.3888 7.57 6.9907 5.80 6.6346 51.04 6.1717 29.57 5.9975 5.67 5.9135 9.87 5.6467 38.47 5.4773 10.54 5.2994 4.74 4.8680 4.03 4.7910 5.98 4.6614 57.50 4.5052 5.75 4.3701 9.03 4.2516 69.99 4.2059 57.64 4.1740 65.07 4.0819 12.44 3.9673 22.53 3.9318 100.00 3.8775 9.07 3.7096 33.38 3.6561 21.65 3.5576 3.36 3.5037 7.97 3.4522 18.02 3.4138 4.65 3.2738 10.23 3.1857 8.90 3.1333 6.24 3.0831 9.43 3.0025 12.13 2.9437 4.96 2.8642 7.70 2.7904 11.95 2.7246 3.05 2.6652 3.32 2.5882 7.30
A process for preparing a crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride having the following X-ray diffraction pattern obtained with copper radiation:
- 14 d-line spacing I/Io (Angstroms) (x100) 10.3696 14.40 8.9032 10.19 8.3125 7.61 7.9818 41.03 7.2036 7.34 6.5411 74.18 6.2367 6.39 5.5539 20.11 5.3689 100.00 5.0272 95.92 4.7085 89.13 4.6406 73.37 4.6199 77.58 4.5347 69.70 4.4818 49.86 4.2589 47.69 4.2067 44.43 4.1659 44.16 4.0957 11.96 3.9347 11.28 3.7818 40.90 3.7614 53.53 3.6375 36.68 3.5773 20.11 3.5037 25.14 3.4409 32.34 3.4270 39.54 3.3088 12.64 3.2611 9.65 3.1046 12.77 3.0263 17.53 2.8536 8.29 2.8131 12.09 2.7309 8.97
- comprising the steps of:
- (a) dealkylating the hydrochloride salt of a compound of the formula
- 40
- wherein R7 is C1-C4 alkyl,
- by reacting with BCl3 in chloroform or methylene chloride;
- (b) quenching the reaction of step (a) with methanol, ethanol, or i-propanol;
- and
- (c) isolating the crystalline solvate.
Dependencies are inferred from the claim text.