US2004082647A1PendingUtilityA1
Method for the preparation of tetrahydrobenzothiepines
Est. expiryMar 10, 2020(expired)· nominal 20-yr term from priority
Inventors:Kevin A. BabiakAndrew CarpenterShine K. ChouPierre-Jean ColsonPayman FaridRobert HettChristian HuberKevin J. KoellerJon P. LawsonJames LiEduardo MarLawrence MillerVladislav OrlovskiJames PetersonMark PozzoClaire A. PrzybylaSamuel J. TremontJay TrivediGrace WagnerGerald WeisenburgerBenxin Zhi
C07D 409/12A61K 31/235A61K 31/495A61P 3/06C07D 487/08A61P 43/00C07D 337/08A61K 31/38
49
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Claims
Abstract
Among its several embodiments, the present invention provides an improved process for the preparation of tetrahydrobenzothiepine-1,1-dioxide compounds; the provision of a process for preparing a diastereomeric mixture of tetrahydrobenzothiepine-1,1-dioxide compounds from a single diastereomer of such compounds; the provision of a process for the preparation of 3-bromo-2-substituted propionaldehyde compounds; and the provision of a process for the preparation of 3-thio-2-substituted propionaldehyde compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for the preparation of a benzylammonium compound having the structure of Formula 60
wherein the method comprises treating a benzyl alcohol ether compound having the structure of Formula (61)
under derivatization conditions to form a derivatized benzyl ether compound having the structure of Formula (62)
and contacting the derivatized benzyl ether compound with an amine having the structure of Formula (2)
under amination conditions thereby producing the benzylammonium compound or a derivative thereof, wherein:
R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl;
R 3 , R 4 , and R 5 independently are selected from the group consisting of H and C 1 to about C 20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R 3 , R 4 , and R 5 taken together with the atom to which they are attached form a cyclic structure;
R 9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR 3 , NR 3 R 4 , N + R 3 R 4 R 5 A − , SR 3 , S(O)R 3 , SO 2 R 3 , SO 3 R 3 , oxo, CO 2 R 3 , CN, halogen, NCO, CON 3 R 4 , SO 2 OM, SO 2 NR 3 R 4 , PO(OR 23 )OR 24 , P + R 3 R 4 R 5 A − , S + R 3 R 4 A − , and C(O)OM;
R 23 and R 24 are independently selected from the substituents constituting R 3 and M;
n is a number from 0 to 4;
A − is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; and
X is a nucleophilic substitution leaving group.
2 . A method for the preparation of a benzylammonium compound having the structure of Formula (1)
wherein the method comprises treating a benzyl alcohol ether compound having the structure of Formula (6)
under derivatization conditions to form a derivatized benzyl ether compound having the structure of Formula (2)
and contacting the derivatized benzyl ether compound with an amine having the structure of Formula (42):
under amination conditions thereby producing the benzylammonium compound or a derivative thereof, wherein:
R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl;
R 3 , R 4 , and R 5 independently are selected from the group consisting of H and C 1 to about C 20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R 3 , R 4 , and R 5 taken together with the atom to which they are attached form a cyclic structure; and
X is a nucleophilic substitution leaving group.
3 . The method of claim 2 wherein R 3 , R 4 , and R 5 independently are selected from the group consisting of H and C 1 to about C 20 hydrocarbyl.
4 . The method of claim 3 wherein R 3 , R 4 , and R 5 independently are selected from the group consisting of H and C 1 to about C 10 hydrocarbyl.
5 . The method of claim 4 wherein R 3 , R 4 , and R 5 independently are C 1 to about C 10 hydrocarbyl.
6 . The method of claim 5 wherein R 3 , R 4 , and R 5 independently are C 1 to about C 5 hydrocarbyl.
7 . The method of claim 6 wherein R 3 , R 4 , and R 5 independently are selected from the group consisting of methyl, ethyl, and propyl.
8 . The method of claim 7 wherein R 3 , R 4 , and R 5 each are methyl.
9 . The method of claim 2 wherein the amine comprises a heterocycle.
10 . The method of claim 9 wherein the amine comprises a bicyclic heterocycle.
11 . The method of claim 10 wherein the amine is 1,4-diazabicyclo[2.2.2]octane and the benzylammonium compound has the structure of Formula (3)
12 . The method of claim 2 wherein R 1 and R 2 independently are C 1 to about C 10 hydrocarbyl.
13 . The method of claim 2 wherein R 1 and R 2 independently are C 1 to about C 5 hydrocarbyl.
14 . The method of claim 13 wherein R 1 and R 2 are both butyl.
15 . The method of claim 14 wherein the benzylammonium compound is an essentially racemic mixture of enantiomers.
16 . The method of claim 14 wherein the benzylammonium compound produced by the method comprises a (4R,5R) enantiomer that preponderates over a (4S,5S) enantiomer.
17 . The method of claim 9 wherein one of R 1 and R 2 is ethyl and the other of R 1 and R 2 is butyl.
18 . The method of claim 17 wherein the benzylammonium compound produced comprises a (3R) enantiomer that preponderates over a (3S) enantiomer.
19 . The method of claim 17 wherein the benzylammonium compound produced comprises a (3S) enantiomer that preponderates over a (3R) enantiomer.
20 . The method of claim 9 wherein the amination conditions comprise a solvent.
21 . The method of claim 20 wherein the solvent comprises a hydrophilic solvent.
22 . The method of claim 21 wherein the hydrophilic solvent comprises a compound selected from the group consisting of water, a nitrile, an ether, an alcohol, a ketone, and an ester.
23 . The method of claim 22 wherein the hydrophilic solvent comprises a ketone.
24 . The method of claim 23 wherein the hydrophilic solvent comprises a compound selected from the group consisting of acetone and methyl ethyl ketone.
25 . The method of claim 24 wherein the hydrophilic solvent comprises methyl ethyl ketone.
26 . The method of claim 22 wherein the hydrophilic solvent comprises methyl ethyl ketone and water.
27 . The method of claim 21 wherein the solvent further comprises a hydrophobic solvent.
28 . The method of claim 27 wherein the hydrophobic solvent is selected from the group consisting of an aliphatic hydrocarbon, an aromatic solvent, and a chlorinated solvent.
29 . The method of claim 27 wherein the hydrophobic solvent comprises an aromatic solvent.
30 . The method of claim 29 wherein the hydrophobic solvent is selected from the group consisting of benzene, toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, mesitylene, and naphthalene.
31 . The method of claim 30 wherein the hydrophobic solvent is toluene.
32 . The method of claim 27 wherein the solvent comprises methyl ethyl ketone, toluene, and water.
33 . The method of claim 20 wherein the solvent comprises a hydrophobic solvent.
34 . The method of claim 9 wherein the amination conditions comprise performing the amination at a temperature in the range of about 0° C. to about 100° C.
35 . The method of claim 34 wherein the amination conditions comprise performing the amination at a temperature in the range of about 15° C. to about 75° C.
36 . The method of claim 35 wherein the amination conditions comprise performing the anination at a temperature in the range of about 20° C. to about 65° C.
37 . The method of claim 2 further comprising an enantiomeric enrichment step.
38 . The method of claim 37 wherein the enantiomeric enrichment step comprises chiral chromatography.
39 . The method of claim 37 wherein the enantiomeric enrichment step comprises an asymmetric synthesis step.
40 . The method of claim 37 wherein the enantiomeric enrichment step comprises crystallization of a diastereomeric salt.
41 . The method of claim 2 wherein X is selected from the group consisting of chloro, bromo, iodo, methanesulfonato, toluenesulfonato, benzenesulfonato, and trifluoromethanesulfonato.
42 . The method of claim 41 wherein X is selected from the group consisting of chloro, bromo, and iodo.
43 . The method of claim 42 wherein X is chloro.
44 . The method of claim 2 wherein the benzyl alcohol ether compound has an absolute configuration predominantly of (4R,5R).
45 . The method of claim 2 wherein the benzyl alcohol ether compound has an absolute configuration predominantly of (4S,5S).
46 . The method of claim 2 wherein the derivatization conditions comprise contacting the benzyl alcohol ether compound with a halogenating agent.
47 . The method of claim 46 wherein the halogenating agent is selected from the group consisting of a thionyl halide, a sulfuryl halide, a phosphorus trihalide, a phosphorus pentahalide, an oxalyl halide, and a hydrogen halide.
48 . The method of claim 47 wherein the halogenating agent is a chlorinating agent.
49 . The method of claim 47 wherein the halogenating agent is selected from the group consisting of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and hydrogen chloride.
50 . The method of claim 49 wherein the halogenating agent is selected from the group consisting of thionyl chloride, phosphorus trichloride, and phosphorus pentachloride.
51 . The method of claim 49 wherein the halogenating agent is thionyl chloride.
52 . The method of claim 47 wherein the halogenating agent comprises a mixture of triphenylphosphine and a carbon tetrahalide.
53 . The method of claim 47 wherein the halogenating agent comprises a mixture of triphenylphosphine and carbon tetrachloride.
54 . The method of claim 2 further comprising a step in which a benzyl alcohol ether compound having the structure of Formula (6)
is prepared wherein the step comprises contacting a phenol compound having the structure of Formula (4)
with a substituted xylene compound having the structure of Formula (5)
under substitution conditions to produce the benzyl alcohol ether compound (6) wherein X 2 is a leaving group.
55 . The method of claim 54 wherein the phenol compound has an absolute configuration of (4R,5R).
56 . The method of claim 54 wherein the phenol compound has an absolute configuration of (4S,5S).
57 . The method of claim 54 wherein X 2 is selected from the group consisting of halo, methanesulfonato, toluenesulfonato, benzenesulfonato, and trifluoromethanesulfonato.
58 . The method of claim 57 wherein X 2 is selected from the group consisting of chloro, bromo, and iodo.
59 . The method of claim 58 wherein X 2 is chloro.
60 . The method of claim 54 wherein R 1 and R 2 independently are C 1 to about C 10 hydrocarbyl.
61 . The method of claim 60 wherein R 1 and R 2 independently are C 1 to about C 5 hydrocarbyl.
62 . The method of claim 61 wherein R 1 and R 2 are both butyl.
63 . The method of claim 61 wherein one of R 1 and R 2 is ethyl and the other of R 1 and R 2 is butyl.
64 . The method of claim 54 wherein the contacting of the phenol compound with the substituted xylene compound is performed in the presence of a solvent.
65 . The method of claim 64 wherein the solvent comprises an amide.
66 . The method of claim 65 wherein the amide is selected from the group consisting of dimethylformamide and N,N-dimethylacetamide.
67 . The method of claim 54 wherein the contacting of the phenol compound with the substituted xylene compound is performed in the presence of a base.
68 . The method of claim 67 wherein the base comprises a compound selected from the group consisting of a metal hydroxide, a metal alcoholate, a metal hydride, an alkyl metal complex, and an amide base.
69 . The method of claim 68 wherein the base comprises a metal hydroxide.
70 . The method of claim 2 further comprising a deprotecting step wherein a protected phenol compound having the structure of Formula (7)
is deprotected to form a phenol compound having the structure of Formula (4)
wherein R 6 is a protecting group.
71 . The method of claim 70 wherein R 6 is a C 1 to about C 10 hydrocarbyl group.
72 . The method of claim 71 wherein R 6 is a C 1 to about C 10 alkyl group.
73 . The method of claim 72 wherein R 6 is a C 1 to about C 5 alkyl group.
74 . The method of claim 73 wherein R 6 is methyl.
75 . The method of claim 71 wherein the deprotecting step comprises treating the protected phenol compound with a deprotection reagent.
76 . The method of claim 75 wherein the deprotecting step comprises treating the protected phenol compound with a deprotecting reagent comprising a compound selected from the group consisting of a boron trihalide, a hydrogen halide, and a metal hydrocarbyl thiolate.
77 . The method of claim 76 wherein the deprotecting reagent is selected from the group consisting of boron tribromide, boron trichloride, hydrogen iodide, hydrogen bromide, and hydrogen chloride.
78 . The method of claim 77 wherein the deprotecting reagent is selected from the group consisting of boron tribromide and boron trichloride.
79 . The method of claim 77 wherein the deprotecting reagent is boron tribromide.
80 . The method of claim 77 wherein the deprotecting reagent is a metal hydrocarbyl thiolate.
81 . The method of claim 80 wherein the deprotecting reagent is a lithium hydrocarbyl thiolate.
82 . The method of claim 81 wherein the deprotecting reagent is a lithium C 1 to about C 10 alkyl thiolate.
83 . The method of claim 82 wherein the deprotecting reagent is lithium ethanethiolate.
84 . The method of claim 75 wherein the deprotecting reagent comprises a sulfonic acid in combination with methionine.
85 . The method of claim 84 wherein the deprotecting reagent comprises methanesulfonic acid in combination with methionine.
86 . The method of claim 85 wherein the deprotecting step is performed substantially neat.
87 . The method of claim 85 wherein the deprotecting step is performed in the presence of a solvent.
88 . The method of claim 87 wherein the solvent comprises a compound selected from the group consisting of an alkane, an aromatic solvent, a chlorinated solvent, a sulfonic acid, and an inorganic solvent.
89 . The method of claim 70 wherein the protected phenol compound has an absolute configuration of (4R,5R).
90 . The method of claim 70 wherein the protected phenol compound has an absolute configuration of (4S,5S).
91 . The method of claim 2 further comprising a cyclization step wherein an amino sulfur oxide aldehyde compound having the structure of Formula
is treated under cyclization conditions to form a protected phenol compound having the structure of Formula (7a)
wherein R 6 is a protecting group, and y is 1 or 2.
92 . The method of claim 91 wherein R 6 is a C 1 to about C 10 hydrocarbyl group.
93 . The method of claim 92 wherein R 6 is a C 1 to about C 10 alkyl group.
94 . The method of claim 93 wherein R 6 is a C 1 to about C 5 alkyl group.
95 . The method of claim 94 wherein R 6 is methyl.
96 . The method of claim 91 wherein the cyclization conditions comprise treating the amino sulfur oxide aldehyde with a base.
97 . The method of claim 96 wherein the base comprises a compound selected from the group consisting of MOR 11 , a metal hydroxide, and an alkyl metal complex, wherein R 11 is a C 1 to about C 10 hydrocarbyl group and M is an alkali metal.
98 . The method of claim 97 wherein the base comprises MOR 11 .
99 . The method of claim 98 wherein M is selected from the group consisting of sodium, lithium, and potassium.
100 . The method of claim 98 wherein R 11 is a C 1 to about C 10 alkyl group.
101 . The method of claim 100 wherein R 11 is a C 1 to about C5 alkyl group.
102 . The method of claim 101 wherein R 11 is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl.
103 . The method of claim 102 wherein R 11 is tert-butyl.
104 . The method of claim 103 wherein the base is potassium t-butoxide.
105 . The method of claim 91 wherein the cyclization conditions comprise a solvent.
106 . The method of claim 105 wherein the solvent comprises a hydrophilic solvent.
107 . The method of claim 106 wherein the solvent is selected from the group consisting of an ether and an alcohol.
108 . The method of claim 106 wherein the solvent is an ether.
109 . The method of claim 108 wherein the solvent is selected from the group consisting of tetrahydrofuran, tetrahydrofuran, diethyl ether, methyl t-butyl ether, 1,4-dioxane, glyme, and diglyme.
110 . The method of claim 109 wherein the solvent is tetrahydrofuran.
111 . The method of claim 107 wherein the solvent is an alcohol.
112 . The method of claim 111 wherein the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropyl alcohol, butanol, sec-butyl alcohol, isobutyl alcohol, and t-butyl alcohol.
113 . The method of claim 91 wherein y is 1.
114 . The method of claim 113 further comprising an oxidation step in which the amino sulfur oxide aldehyde compound is treated under oxidation conditions to form an amino sulfone aldehyde compound having the structure of Formula (8)
115 . The method of claim 91 wherein y is 2.
116 . The method of claim 2 further comprising an reductive alkylation step in which a nitro sulfur oxide aldehyde compound having the structure of Formula (9a)
is reductively alkylated to form an amino sulfur oxide aldehyde compound having the structure of Formula (8a)
wherein R 6 is a protecting group, and z is 0, 1, or 2.
117 . The method of claim 116 wherein z is 0 or 1.
118 . The method of claim 117 further comprising an oxidation step in which the nitro sulfur oxide aldehyde compound is treated under oxidation conditions to form a nitro sulfone aldehyde compound having the structure of Formula (9)
119 . The method of claim 116 wherein z is 2.
120 . The method of claim 2 further comprising a step for the preparation of an aniline sulfur oxide compound having the structure of Formula (39)
wherein the step comprises reducing a nitro sulfur oxide aldehyde compound having the structure of Formula (9a)
to form the aniline sulfur oxide compound, wherein R 6 is a protecting group, and z is 0, 1, or 2.
121 . The method of claim 120 further comprising a methylation step in which the aniline sulfur oxide compound is treated under methylation conditions to form an amino sulfur oxide aldehyde compound having the structure of Formula (8a)
122 . The method of claim 2 further comprising an oxidation step in which a nitro sulfide aldehyde compound having the structure of Formula (10)
is oxidized to form a nitro sulfone aldehyde compound having the structure of Formula (9a)
wherein R 6 is a protecting group and z is 1 or 2.
123 . The method of claim 122 wherein z is 2.
124 . The method of claim 123 wherein z is 1.
125 . The method of claim 124 in which the oxidation conditions comprise enantioselective oxidation conditions.
126 . The method of claim 2 further comprising a sulfide-forming step in which a substituted diphenyl methane compound having the structure of Formula (11)
is coupled with a substituted propionaldehyde compound having the structure of Formula (12)
in the presence of a source of sulfur to form a nitro sulfide aldehyde having the structure of Formula (10)
wherein R 6 is a protecting group; X 3 is an aromatic substitution leaving group; and X 4 is a nucleophilic substitution leaving group.
127 . The method of claim 2 further comprising a reduction step in which a substituted benzophenone compound having the structure of Formula (13)
is reduced to form a substituted diphenyl methane compound having the structure of Formula (11)
wherein R 6 is a protecting group and X 3 is an aromatic substitution leaving group.
128 . The method of claim 2 further comprising an acylation step in which a protected phenol compound having the structure of Formula (14)
is treated with a substituted benzoyl compound having the structure of Formula (15)
under acylation conditions to produce a substituted benzophenone compound having the structure of Formula (13)
wherein R 6 is a protecting group, X 3 is an aromatic substitution leaving group, and X 5 is selected from the group consisting of hydroxy and halo.
129 . The method of claim 2 further comprising one or more steps in which an amino sulfone aldehyde compound having the structure of Formula (17)
is prepared wherein an alkenyl sulfone aldehyde compound having the structure of Formula (16)
is reduced and reductively alkylated to form the amino sulfone aldehyde compound (17), wherein R 1 is a C 1 to about C 20 hydrocarbyl group, R 6 is a protecting group, and R 12 is a C 1 to about C 10 hydrocarbyl group.
130 . The method of claim 2 further comprising a thermolysis step wherein an acetal compound having the structure of Formula (18)
is thermolyzed to form an alkenyl sulfone aldehyde compound having the structure of Formula (16)
wherein
R 1 is a C 1 to about C 20 hydrocarbyl group;
R 6 is a protecting group;
R 7 is selected from the group consisting of H and C 1 to about C 17 hydrocarbyl; and
R 13 is selected from the group consisting of H and C 1 to about C 20 hydrocarbyl.
131 . The method of claim 130 in which R 13 is a group having the structure of Formula (43)
132 . The method of claim 2 further comprising an acetal-forming step in which a monoalkyl sulfone aldehyde compound having the structure of Formula (19)
is reacted with an allyl alcohol compound having the structure of Formula (20)
optionally in the presence of a hydroxylated solvent having the structure HOR 13 to form an acetal compound having the structure of Formula (18)
wherein:
R 1 is a C 1 to about C 20 hydrocarbyl;
R 6 is a protecting group;
R 7 is selected from the group consisting of H and a C 1 to about C 17 hydrocarbyl; and
R 13 is selected from the group consisting of H and C 1 to about C 20 hydrocarbyl.
133 . The method of claim 132 in which R 13 is a group having the structure of Formula (43)
134 . The method of claim 133 wherein R 7 is a C 1 to about C 10 hydrocarbyl.
135 . The method of claim 134 wherein R 7 is a C 1 to about C 5 hydrocarbyl.
136 . The method of claim 135 wherein R 7 is methyl.
137 . The method of claim 2 further comprising a sulfone-forming step in which a substituted diphenyl methane compound having the structure of Formula (11)
is reacted under sulfination conditions and coupled with a 2-substituted acrolein compound having the structure of Formula (21)
to form a monoalkyl sulfone aldehyde compound having the structure of Formula (19)
wherein:
R 1 is a C 1 to about C 20 hydrocarbyl;
R 6 is a protecting group; and
X 3 is an aromatic substitution leaving group.
138 . A method for the preparation of a benzylammonium compound having the structure of Formula (1)
wherein the method comprises the steps of:
(a) treating a protected phenol compound having the structure of Formula (14)
with a substituted benzoyl compound having the structure of Formula (15)
under acylation conditions to produce a substituted benzophenone compound having the structure of Formula (13)
(b) reducing the substituted benzophenone compound to produce a substituted diphenyl methane compound having the structure of Formula (11)
(c) coupling the substituted diphenyl methane compound with a substituted propionaldehyde compound having the structure of Formula (10)
in the presence of a source of sulfur to form a nitro sulfide aldehyde compound having the structure of Formula (10)
(d) oxidizing the nitro sulfide aldehyde compound to form a nitro sulfone aldehyde compound having the structure of Formula (9)
(e) reductively alkylating the nitro sulfone aldehyde compound to form an amino sulfone aldehyde compound having the structure of Formula (8)
(f) treating the amino sulfone aldehyde compound under cyclization conditions to form protected phenol compound having the
(g) deprotecting the protected phenol compound to form a phenol compound having the structure of Formula (4)
(h) coupling the phenol compound with a substituted xylene having the structure of Formula (5)
under substitution conditions to produce a benzyl alcohol ether compound having the structure of Formula (6)
(i) treating the benzyl alcohol ether compound with a leaving group-forming reagent to produce a derivatized benzyl ether compound having the structure of Formula (2)
(j) treating the derivatized benzyl ether compound with an amine having the structure of Formula (42):
under amination conditions to produce the benzylammonium compound;
wherein:
R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl;
R 3 , R 4 , and R 5 independently are selected from the group consisting of H and C 1 to about C 20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R 3 , R 4 , and R 5 taken together with the atom to which they are attached form a cyclic structure;
R 6 is a protecting group;
X and X 4 independently are nucleophilic leaving groups;
X 2 is selected from the group consisting of chloro, bromo, iodo, methanesulfonato, trifluoromethanesulfonato, benzenesulfonato, and toluenesulfonato;
X 3 is an aromatic substitution leaving group; and
X 5 is selected from the group consisting of hydroxy and halo.
139 . The method of claim 138 further comprising an enantiomeric enrichment step.
140 . The method of claim 139 wherein the benzylammonium compound produced by the method comprises a (4R,5R) enantiomer that preponderates over a (4S,5S) enantiomer.
141 . A method for the preparation of a derivatized benzyl ether compound having the structure of Formula (2).
wherein the method comprises treating a benzyl alcohol ether compound having the structure of Formula (6)
with a halogenating agent to form the derivatized benzyl ether compound, wherein R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl, and X is halo.
142 . The method of claim 141 wherein the derivatized benzyl ether compound produced by the method comprises a (4R,5R) enantiomer that preponderates over a (4S,5S) enantiomer.
143 . A method for the preparation of a benzyl alcohol ether compound having the structure of Formula (6)
wherein the method comprises contacting a phenol compound having the structure of Formula (4)
with a substituted xylene compound having the structure of Formula (5)
under substitution conditions to produce the benzyl alcohol ether compound, wherein R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl, and X 2 is selected from the group consisting of chloro, bromo, iodo, methanesulfonato, trifluoromethylsuflonato, and toluenesulfonato.
144 . The method of claim 143 wherein R 1 and R 2 independently are C 1 to about C 10 hydrocarbyl.
145 . The method of claim 144 wherein R 1 and R 2 independently are C 1 to about C 5 hydrocarbyl.
146 . The method of claim 145 wherein R 1 and R 2 are both butyl.
147 . The method of claim 145 wherein one of R 1 and R 2 is ethyl and the other of R 1 and R 2 is butyl.
148 . The method of claim 143 wherein the contacting of the phenol compound with the substituted xylene compound is performed in the presence of a solvent.
149 . The method of claim 148 wherein the solvent comprises a compound selected from the group consisting of an aromatic solvent, an amide, an ester, a ketone, an ether, and a sulfoxide.
150 . The method of claim 149 wherein the solvent comprises an amide.
151 . The method of claim 150 wherein the amide is selected from the group consisting of dimethylformamide and N,N-dimethylacetamide.
152 . The method of claim 149 wherein the solvent comprises an aprotic solvent.
153 . The method of claim 143 wherein the contacting of the phenol compound with the substituted xylene compound is performed in the presence of a base.
154 . The method of claim 153 wherein the base comprises a compound selected from the group consisting of a metal hydroxide, a metal alcoholate, a metal hydride, an alkyl metal complex, and an amide base.
155 . The method of claim 154 wherein the base comprises a metal hydroxide.
156 . The method of claim 155 wherein the metal hydroxide is selected from the group consisting of sodium hydroxide, lithium hydroxide, and calcium hydroxide.
157 . The method of claim 156 wherein the metal hydroxide is sodium hydroxide.
158 . The method of claim 143 wherein the benzyl alcohol ether compound produced by the method comprises a (4R,5R) enantiomer that preponderates over a (4S,5S) enantiomer.
159 . A method for the preparation of a phenol compound having the structure of Formula (4)
wherein the method comprises deprotecting a protected phenol compound having the structure of Formula (7)
to form the phenol compound, wherein R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl, and R 6 is a protecting group.
160 . The method of claim 159 wherein the phenol compound produced by the method comprises a (4R,5R) enantiomer that preponderates over a (4S,5S) enantiomer.
161 . A method for the preparation of a protected phenol compound having the structure of Formula (7)
wherein the method comprises cyclizing an amino sulfone aldehyde compound having the structure of Formula (8)
under cyclization conditions to form the protected phenol compound, wherein R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl, and R 6 is a protecting group.
162 . The method of claim 161 wherein the protected phenol compound produced by the method comprises a (4R,5R) enantiomer that preponderates over a (4S,5S) enantiomer.
163 . A method for the preparation of an amino sulfone aldehyde compound having the structure of Formula (8)
wherein the method comprises reductively alkylating a nitro sulfone aldehyde compound having the structure of Formula (9)
to form the amino sulfone aldehyde compound, wherein R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl, and R 6 is a protecting group.
164 . A method for the preparation of a nitro sulfone aldehyde compound having the structure of Formula (9)
wherein the method comprises oxidizing a nitro sulfide aldehyde compound having the structure of Formula (10)
to form the nitro sulfone aldehyde compound, wherein R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl, and R 6 is a protecting group.
165 . A method for the preparation of a nitro sulfide aldehyde having the structure of Formula (10)
wherein the method comprises coupling a substituted diphenyl methane compound having the structure of Formula (11)
with a substituted propionaldehyde compound having the structure of Formula (12)
in the presence of a source of sulfur to form the nitro sulfide aldehyde, wherein:
R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl;
R 6 is a protecting group;
X 3 is an aromatic substitution leaving group; and
X 4 is a nucleophilic substitution leaving group.
166 . A method for the preparation of a substituted diphenyl methane compound having the structure of Formula (11)
wherein the method comprises reducing a substituted benzophenone compound having the structure of Formula (13)
to form the substituted diphenyl methane compound, wherein:
R 6 is a protecting group; and
X 3 is an aromatic substitution leaving group.
167 . A method for the preparation of a substituted benzophenone compound having the structure of Formula (13)
wherein the method comprises reacting a protected phenol compound having the structure of Formula (14)
with a substituted benzoyl compound having the structure of Formula (15)
under acylation conditions to produce the substituted benzophenone compound, wherein:
R 6 is a protecting group;
X 3 is an aromatic substitution leaving group;
X 5 is selected from the group consisting of hydroxy, bromo, iodo, and —OR 14 ; and
R 14 is an acyl group.
168 . The method of claim 167 wherein X5 is hydroxy.
169 . The method of claim 168 wherein the acylation conditions comprise a strong protic acid.
170 . The method of claim 169 wherein the strong protic acid is selected from the group consisting of sulfuric acid, a sulfonic acid, or a phosphorus oxy acid.
171 . The method of claim 170 wherein the strong protic acid is a phosphorus oxy acid.
172 . The method of claim 171 wherein the phosphorus oxy acid is selected from the group consisting of orthophosphoric acid, pyrophosphoric acid, and polyphosphoric acid.
173 . The method of claim 171 wherein the phosphorus oxy acid comprises polyphosphoric acid.
174 . The method of claim 167 wherein R 6 is a C 1 to about C 10 hydrocarbyl group.
175 . The method of claim 174 wherein R 6 is a C 1 to about C 10 alkyl group.
176 . The method of claim 175 wherein R 6 is a C 1 to about C 5 alkyl group.
177 . The method of claim 176 wherein R 6 is methyl.
178 . A method for the preparation of a substituted benzophenone compound having the structure of Formula (13)
wherein the method comprises reacting an aryl metal complex having the structure of Formula (56)
with a substituted benzoyl compound having the structure of Formula (15)
under acylation conditions to produce the substituted benzophenone compound, wherein:
R 6 is a protecting group;
L is a metal-containing moiety;
X 3 is an aromatic substitution leaving group;
X 5 is selected from the group consisting of halo and —OR 14 ; and
R 14 is an acyl group.
179 . The method of claim 178 wherein L is selected from the group consisting of MgX 6 , Na, and Li, wherein X 6 is a halogen.
180 . A method for the preparation of an amino sulfone aldehyde compound having the structure of Formula (17)
wherein the method comprises reducing and reductively alkylating an alkenyl sulfone aldehyde compound having the structure of Formula (16)
to form the amino sulfone aldehyde compound
wherein R 1 is a C 1 to about C 20 hydrocarbyl group; R 6 is a protecting group; and R 7 is selected from the group consisting of H and C1 to about C17 hydrocarbyl.
181 . A method for the preparation of an alkenyl sulfone aldehyde compound having the structure of Formula (16)
wherein the method comprises thermolyzing an acetal compound having the structure of Formula (18)
to form the alkenyl sulfone aldehyde compound, wherein
R 1 is a C 1 to about C 20 hydrocarbyl group;
R 6 is a protecting group;
R 7 is selected from the group consisting of H and C 1 to about C 17 hydrocarbyl; and
R 13 is selected from the group consisting of H and C 1 to about C 20 hydrocarbyl.
182 . A method for the preparation of an acetal compound having the structure of Formula (18)
wherein the method comprises reacting a monoalkyl sulfone aldehyde compound having the structure of Formula (19)
with an allyl alcohol having the structure of Formula (20)
optionally in the presence of a hydroxylated solvent having the structure HOR 13 to form the acetal compound, wherein:
R 1 is a C 1 to about C 20 hydrocarbyl;
R 6 is a protecting group;
R 7 is selected from the group consisting of H and a C 1 to about C 17 hydrocarbyl; and
R 13 is selected from the group consisting of H and C 1 to about C 20 hydrocarbyl.
183 . The method of claim 182 in which R 13 is a group having the structure of Formula (43)
184 . The method of claim 183 wherein R 7 is a C 1 to about C 10 hydrocarbyl.
185 . The method of claim 184 wherein R 7 is a C 1 to about C 5 hydrocarbyl.
186 . The method of claim 185 wherein R 7 is methyl.
187 . A method for the preparation of a monoalkyl sulfone aldehyde compound having the structure of Formula (19)
wherein the method comprises reacting a substituted diphenyl methane compound having the structure of Formula (11)
under sulfination conditions to produce a sulfination mixture and contacting the sulfination mixture with a 2-hydrocarbyl acrolein compound having the structure of Formula (21)
thereby forming the monoalkyl sulfone aldehyde compound, wherein:
R 1 is a C to about C 20 hydrocarbyl;
R 6 is a protecting group; and
X 3 is an aromatic substitution leaving group.
188 . A method for the preparation of a 3-sulfur-propionaldehyde olefin compound having the structure of Formula 49
wherein the method comprises contacting a 3-sulfur-propionaldehyde compound having the structure of Formula 48
with an allyl alcohol compound having the structure of Formula 50
in the presence of a source of acid, thereby forming the 3-sulfur-propionaldehyde olefin compound, wherein:
R 15 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkylaryl, and acyl, wherein alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkylaryl, and acyl optionally are substituted with at least one R 22 group;
R 16 , R 17 , R 21a , and R 21b are independently selected from the group consisting of H and hydrocarbyl;
R 22 is selected from the group consisting of H, —NO 2 , amino, C 1 to about C 10 alkylamino, di(C 1 to about C 10 )alkylamino, C 1 to about C 10 alkylthio, hydroxy, C 1 to about C 10 alkoxy, cyanato, isocyanato, halogen, OR 6 , SR 6 , SR 6 R 6a , and NR 6 R 6a ;
R 6 and R 6a independently are selected from the group consisting of H and a protecting group; and
q is 0, 1, or 2.
189 . The method of claim 188 wherein R 15 is selected from the group consisting of aryl, alkylaryl, and arylalkylaryl.
190 . The method of claim 188 wherein R 15 is substituted with at least one R 22 group.
191 . The method of claim 190 wherein R 15 is arylalkylaryl optionally substituted with at least one R 22 group.
192 . The method of claim 189 wherein R 15 is 2-(phenylmethyl)phenyl.
193 . The method of claim 192 wherein R 15 is substituted with at least one R 22 group.
194 . The method of claim 188 wherein R 16 is hydrocarbyl.
195 . The method of claim 194 wherein R 16 is a C 1 to about C 10 hydrocarbyl.
196 . The method of claim 195 wherein R 16 is a C 1 to about C 5 hydrocarbyl.
197 . The method of claim 196 wherein R 16 is selected from the group consisting of ethyl and butyl.
198 . The method of claim 188 wherein R 17 is hydrocarbyl.
199 . The method of claim 188 wherein q is 2.
200 . The method of claim 188 wherein the contacting is performed at a temperature of about 0° C. to about 200° C.
201 . The method of claim 200 wherein the contacting is performed at a temperature of about 20° C. to about 150° C.
202 . The method of claim 201 wherein the contacting is performed at a temperature of about 30° C. to about 135° C.
203 . The method of claim 202 wherein the contacting is performed at a temperature of about 30° C. to about 100° C.
204 . The method of claim 188 wherein the contacting is performed in the presence of a solvent.
205 . The method of claim 203 further comprising a step in which the solvent is azeotropically removed.
206 . A method of treating a diastereomer of a tetrahydrobenzothiepine compound having the structure of Formula (22)
wherein Formula (22) comprises a (4,5)-diastereomer selected from the group consisting of a (4S,5S) diastereomer, a (4R,5R) diastereomer, a (4R,5S) diastereomer, and a (4S,5R) diastereomer,
to produce a mixture comprising the (4S,5S) diastereomer and the (4R,5R) diastereomer,
wherein the method comprises contacting a base with a feedstock composition comprising the diastereomer of the tetrahydrobenzothiepine compound, thereby producing a mixture of diastereomers of the tetrahydrobenzothiepine compound; and wherein
R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl;
R 8 is selected from the group consisting of H, hydrocarbyl, heterocyclyl, ((hydroxyalkyl)aryl)-alkyl, ((cycloalkyl)alkylaryl)alkyl, ((heterocycloalkyl)alkylaryl)alkyl, ((quaternary heterocycloalkyl)alkylaryl)alkyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl,
wherein hydrocarbyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl optionally have one or more carbons replaced by a moiety selected from the group consisting of O, NR 3 , N + R 3 R 4 A − , S, SO, SO 2 , S + R 3 A − , PR 3 , P + R 3 R 4 A − , P(O)R 3 , phenylene, carbohydrate, amino acid, peptide, and polypeptide, and
R 8 is optionally substituted with one or more moieties selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 3 , NR 3 R 4 , N + R 3 R 4 R 5 A − , SR 3 , S(O)R 3 , SO 2 R 3 , SO 3 R 3 , oxo, CO 2 R 3 , CN, halogen, CONR 3 R 4 , SO 2 OM, SO 2 NR 3 R 4 , PO(OR 23 )OR 24 , P + R 3 R 4 R 5 A − , S + R 3 R 4 A − , and C(O)OM;
R 23 and R 24 are independently selected from the substituents constituting R 3 and M;
A − is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; and
R 9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR 3 , NR 3 R 4 , N + R 3 R 4 R 5 A − , SR 3 , S(O)R 3 , SO 2 R 3 , SO 3 R 3 , oxo, CO 2 R 3 , CN, halogen, NCO, CONR 3 R 4 , SO 2 OM, SO 2 NR 3 R 4 , PO(OR 23 )OR 24 , P + R 3 R 4 R 5 A − , S + R 3 R 4 A − , and C(O)OM;
R 3 , R 4 , and R 5 independently are selected from the group consisting of H and C 1 to about C 20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R 3 , R 4 , and R 5 taken together with the atom to which they are attached form a cyclic structure;
n is a number from 0 to 4; and
x is 1 or 2.
207 . The method of claim 206 wherein the base is selected from the group consisting of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal alkoxide, a metal hydride, an alkali metal amide, and an alkali metal hydrocarbyl base.
208 . The method of claim 207 wherein the base is selected from the group consisting of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal alkoxide, and an alkali metal amide.
209 . The method of claim 208 wherein the base is an alkali metal alkoxide.
210 . The method of claim 209 wherein the base is selected from the group consisting of a sodium alkoxide and a potassium alkoxide.
211 . The method of claim 210 wherein the base is potassium t-butoxide.
212 . The method of claim 206 wherein R 8 is selected from the group consisting of H, C 1 to about C 20 alkyl, hydroxyalkylarylalkyl, and heterocycloalkylalkylarylalkyl.
213 . The method of claim 212 wherein R 8 is selected from the group consisting of H, and C 1 to about C 20 alkyl.
214 . The method of claim 213 wherein R 8 is C 1 to about C 20 alkyl.
215 . The method of claim 214 wherein R 8 is C 1 to about C 10 alkyl.
216 . The method of claim 217 wherein R 8 is C 1 to about C5 alkyl.
217 . The method of claim 214 wherein R 8 is methyl.
218 . The method of claim 206 wherein R 9 is selected from the group consisting of H, amino, alkylamino, alkoxy, and nitro.
219 . The method of claim 218 wherein R 9 is selected from the group consisting of H and alkylamino.
220 . The method of claim 219 wherein R 9 is alkylamino.
221 . The method of claim 219 wherein R 9 is dimethylamino and n is 1.
222 . The method of claim 221 wherein R 9 is in the 7-position of the tetrahydrobenzothiepine compound.
223 . The method of claim 206 wherein one of R 1 and R 2 is ethyl and the other of R 1 and R 2 is butyl.
224 . The method of claim 206 wherein are both R 1 and R 2 are butyl.
225 . The method of claim 206 wherein the (4,5)-diastereomer is selected from the group consisting of a (4S,5S) diastereomer, a (4R,5S) diastereomer, and a (4S,5R) diastereomer.
226 . The method of claim 225 wherein the (4,5)-diastereomer is a (4S,5S) diastereomer.
227 . The method of claim 206 wherein the tetrahydrobenzothiepine compound has the structure of Formula (24)
228 . The method of claim 206 wherein the feedstock composition further comprises an amino sulfone aldehyde compound having the structure of Formula (8)
wherein R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl, and R 6 is a protecting group.
229 . The method of claim 228 wherein R 1 and R 2 independently are C 1 to about C 10 hydrocarbyl.
230 . The method of claim 229 R 1 and R 2 independently are C 1 to about C 5 hydrocarbyl.
231 . The method of claim 230 wherein one of R 1 and R 2 is ethyl and the other of R 1 and R 2 is butyl.
232 . The method of claim 231 wherein both R 1 and R 2 are butyl.
233 . The method of claim 228 wherein R 6 is C 1 to about C 10 hydrocarbyl.
234 . The method of claim 233 wherein R 6 is methyl.
235 . A method of treating a diastereomer of a tetrahydrobenzothiepine compound having the structure of Formula (22)
wherein Formula (22) comprises a (4,5)-diastereomer selected from the group consisting of a (4S,5S) diastereomer, a (4R,5R) diastereomer, a (4R,5S) diastereomer, and a (4S,5R) diastereomer,
to produce a mixture comprising the (4S,5S) diastereomer and the (4R,5R) diastereomer,
wherein the method comprises treating the diastereomer of the tetrahydrobenzothiepine compound under elimination conditions to produce a dihydrobenzothiepine compound having the structure of Formula (23)
and oxidizing the dihydrobenzothiepine compound thereby producing the mixture comprising the (4S,5S) diastereomer and the (4R,5R) diastereomer, wherein
R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl;
R 8 is selected from the group consisting of H, hydrocarbyl, heterocyclyl, ((hydroxyalkyl)aryl)alkyl, ((cycloalkyl)alkylaryl)alkyl, ((heterocycloalkyl)alkylaryl)alkyl, ((quaternary heterocycloalkyl)alkylaryl)alkyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl,
wherein hydrocarbyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl optionally have one or more carbons replaced by a moiety selected from the group consisting of O, NR 3 , N + R 3 R 4 A − , S, SO, SO 2 , S + R 3 A − , PR 3 , P + R 3 R 4 A − , P(O)R 3 , phenylene, carbohydrate, amino acid, peptide, and polypeptide, and
R 8 is optionally substituted with one or more moieties selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 3 , NR 3 R 4 , N + R 3 R 4 R 5 A − , SR 3 , S(O)R 3 , SO 2 R 3 , SO 3 R 3 , oxo, CO 2 R 3 , CN, halogen, CONR 3 R 4 , SO 2 OM, SO 2 NR R 4 , PO(OR 23 )OR 24 , P + R 3 R 4 R 5 A − , S + R 3 R 4 A − , and C(O)OM;
R 3 , R 4 , and R 5 independently are selected from the group consisting of H and C 1 to about C 20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R 3 , R 4 , and R 5 taken together with the atom to which they are attached form a cyclic structure;
R 23 and R 24 are independently selected from the substituents constituting R 3 and M;
A − is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; and
R 9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR 3 , NR 3 R 4 , N + R 3 R 4 R 5 A − , SR 3 , S(O)R 3 , SO 2 R 3 , SO 3 R 3 , oxo, CO 2 R 3 , CN, halogen, NCO, CONR 3 R 4 , S 2 OM, SO 2 NR 3 R 4 , PO(OR 23 )OR 24 , P + R 3 R 4 R 5 A − , S + R 3 , R 4 A − , and C(O)OM;
n is a number from 0 to 4;
X 7 is selected from the group consisting of S, NH, and O; and
x is 0, 1, or 2.
236 . The method of claim 235 wherein the elimination conditions comprise an acid.
237 . The method of claim 235 wherein the elimination conditions comprise a base.
238 . The method of claim 235 wherein the elimination conditions comprise derivatizing the diastereomer of a tetrahydrobenzothiepine compound to form a tetrahydrobenzothiepine derivative having an elimination-labile group at the 4-position, and eliminating the elimination-labile group to form the dihydrobenzothiepine compound.
239 . The method of claim 235 wherein the oxidation step comprises an alcohol-forming step in which the dihydrobenzothiepine compound is reacted under alcohol-forming conditions to produce a mixture of diastereomers of the tetrahydrobenzothiepine compound.
240 . The method of claim 235 wherein the (4,5)-diastereomer is selected from the group consisting of a (4S,5S) diastereomer, a (4R,5S) diastereomer, and a (4S,5R) diastereomer.
241 . The method of claim 240 wherein the (4,5)-diastereomer is a (4S,5S) diastereomer.
242 . The method of claim 235 wherein the tetrahydrobenzothiepine compound has the structure of Formula (24)
and the dihydrobenzothiepine compound has the structure of Formula (25)
243 . A compound having the structure of Formula (2)
wherein R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl and X is selected from the group consisting of Br, I, and a nucleophilic substitution leaving group covalently bonded to the compound via an oxygen atom.
244 . The compound of claim 243 wherein R 1 and R 2 independently are C 1 to about C 10 hydrocarbyl.
245 . The compound of claim 244 wherein R 1 and R 2 independently are C 1 to about C 5 hydrocarbyl.
246 . The compound of claim 245 wherein one of R 1 and R 2 is ethyl and the other of R 1 and R 2 is butyl.
247 . The compound of claim 245 wherein R 1 and R 2 are both butyl.
248 . The compound of claim 243 wherein X is selected from the group consisting of Br, I, and hydroxy.
249 . The compound of claim 248 wherein X is selected from the group consisting of Br and I.
250 . The compound of claim 249 wherein X is chloro.
251 . The compound of claim 248 wherein X is hydroxy.
252 . The compound of claim 243 having the structure of Formula (26)
253 . The compound of claim 252 having a (4R,5R) absolute configuration.
254 . The compound of claim 243 having the structure of Formula (27)
255 . The compound of claim 254 having a (4R,5R) absolute configuration.
256 . A compound having the structure of Formula (28)
257 . The compound of claim 256 having a (4R,5R) absolute configuration.
258 . A compound having the structure of Formula (24)
wherein Formula (22) represents a (4,5)-diastereomer selected from the group consisting of a (4S,5S) diastereomer, a (4R,5R) diastereomer, a (4R,5S) diastereomer, and a (4S,5R) diastereomer.
259 . The compound of claim 258 wherein the (4,5)-diastereomer is a (4R,5R) diastereomer.
260 . A compound having the structure of Formula (29)
261 . A compound having the structure of Formula (30)
262 . 2-Bromomethyl-2-butylhexanal.
263 . 2-Bromomethyl-2-butylhexanol.
264 . 1-Acetato-2-butyl-2-(hydroxymethyl)hexane.
265 . A compound having the structure of Formula (31)
wherein Formula (31) represents a compound having either an E or a Z configuration about the butenyl double bond.
266 . The compound of claim 265 having an E configuration about the butenyl double bond.
267 . The compound of claim 265 having a Z configuration about the butenyl double bond.
268 . A compound having the structure of Formula (32)
269 . A compound having the structure of Formula (32)
wherein R 6 is a protecting group and X 3 is an aromatic substitution leaving group.
270 . The compound of claim 269 wherein X 3 is a halo group.
271 . The compound of claim 270 wherein X 3 is chloro.
272 . The compound of claim 269 wherein R 6 is C 1 to about C 20 alkyl.
273 . The compound of claim 272 wherein R 6 is C 1 to about C 10 alkyl.
274 . The compound of claim 273 wherein R 6 is C 1 to about Cs alkyl.
275 . The compound of claim 274 wherein R 6 is methyl.
276 . A compound having the structure of Formula (13)
wherein R 6 is a protecting group and X 3 is an aromatic substitution leaving group.
277 . The compound of claim 276 wherein X 3 is a halo group.
278 . The compound of claim 277 wherein X 3 is chloro.
279 . The compound of claim 276 wherein R 6 is C 1 to about C 20 alkyl.
280 . The compound of claim 279 wherein R 6 is C 1 to about C 10 alkyl.
281 . The compound of claim 280 wherein R 6 is C 1 to about C 5 alkyl.
282 . The compound of claim 281 wherein R 6 is methyl.
283 . A method for the preparation of a substituted propionaldehyde compound having the structure of Formula 12
wherein the method comprises oxidizing a substituted propanol compound having the structure of Formula 35
wherein R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl and X 4 is a nucleophilic substitution leaving group.
284 . The method of claim 283 wherein one of R 1 and R 2 is ethyl and the other of R 1 and R 2 is butyl.
285 . The method of claim 284 wherein the substituted propionaldehyde compound has an R absolute configuration.
286 . The method of claim 284 wherein the substituted propionaldehyde compound has an S absolute configuration.
287 . The method of claim 283 wherein R 1 and R 2 are both butyl.
288 . The method of claim 283 further comprising a step in which an acid ester having the structure of Formula 36
is solvolyzed to form the substituted propanol compound, wherein R 10 is a C 1 to about C 20 alkyl group.
289 . The method of claim 283 wherein X 4 is halo.
290 . The method of claim 289 wherein X 4 is bromo.
291 . The method of claim 289 further comprising a step in which a diol compound having the structure of Formula 37
is reacted in the presence of carbonyl compound having the structure of Formula 38
and a source of halide to form the acid ester, wherein X 6 is selected from the group consisting of hydroxy, halogen, and —OC(O)R 18 , wherein R 18 is C 1 to about C 20 hydrocarbyl.
292 . The method of claim 291 wherein the source of halide is selected from the group consisting of a source of HBr and a source of HI.
293 . The method of claim 292 wherein the source of halide is a source of HBr.
294 . A method for the preparation of a substituted propionaldehyde compound having the structure of Formula 12
wherein the method comprises the steps of:
(a) reacting a diol compound having the structure of Formula 37
in the presence of a carbonyl compound having the structure of Formula 38
and a source of halide to form an acid ester having the structure of Formula 36
(b) solvolyzing the acid ester to form a substituted propanol compound having the structure of Formula 35
(c) oxidizing the substituted propanol compound to form the substituted propionaldehyde compound;
wherein:
R 1 , R 2 , R 10 , and R 18 independently are C 1 to about C 20 hydrocarbyl;
X 4 is a nucleophilic substitution leaving group; and
X 6 is selected from the group consisting of hydroxy, halo, and —OC(O)R 18 .
295 . The method of claim 294 wherein the carboxylic acid equivalent is a carbonyl compound having the structure of Formula 38
wherein X 6 is selected from the group consisting of hydroxy, halo, and —OC(O)R 18 .
296 . The method of claim 295 wherein R 1 , R 2 , R 10 , and R 11 independently are C 1 to about C 10 hydrocarbyl.
297 . The method of claim 296 wherein R 1 , R 2 , R 10 , and R 18 independently are C 1 to about C 5 hydrocarbyl.
298 . The method of claim 297 wherein one of R 1 and R 2 is ethyl and the other of R 1 and R 2 is butyl.
299 . The method of claim 297 wherein both R 1 and R 2 are butyl.
300 . The method of claim 299 wherein R 10 is methyl.
301 . The method of claim 297 wherein R 18 is methyl.
302 . The method of claim 301 wherein X 4 is halo.
303 . The method of claim 302 wherein X 4 is bromo.
304 . The method of claim 303 wherein X 6 is hydroxy.
305 . A crystalline form of a tetrahydrobenzothiepine compound having the structure of Formula 71
or an enantiomer thereof wherein the crystalline form has a melting point or a decomposition point of about 278° C. to about 285° C.
306 . The crystalline form of claim 305 wherein the tetrahydrobenzothiepine compound has an absolute configuration predominantly of (4R,5R).
307 . The crystalline form of claim 305 having a melting point or a decomposition point of about 280° C. to about 283° C.
308 . The crystalline form of claim 307 having a melting point or a decomposition point of about 282° C.
309 . The crystalline form of claim 305 having an X-ray powder diffraction pattern with peaks at about 9.2 degrees 2 theta, about 12.3 degrees 2 theta, and about 13.9 degrees 2 theta.
310 . The crystalline form of claim 309 wherein the X-ray powder diffraction pattern substantially lacks peaks at about 7.2 degrees 2 theta and at about 11.2 degrees 2 theta.
311 . The crystalline form of claim 305 having an X-ray powder diffraction pattern substantially as shown in plot (b) of FIG. 6.
312 . The crystalline form of claim 305 having an IR spectrum with a peak at 10 about 3245 cm −1 to about 3255 cm −1 .
313 . The crystalline form of claim 312 having an IR spectrum with a peak at about 1600 cm −1 .
314 . The crystalline form of claim 312 having an IR spectrum with a peak at about 1288 cm −1 .
315 . The crystalline form of claim 312 having an IR spectrum substantially as shown in plot (b) of FIG. 7.
316 . The crystalline form of claim 305 having a solid state carbon-13 NMR spectrum with peaks at about 142.3 ppm, about 137.2 ppm, and about 125.4 ppm.
317 . The crystalline form of claim 305 having a solid state carbon-13 NMR spectrum substantially as shown in plot (b) of FIG. 8.
318 . The crystalline form of claim 305 that after an essentially dry sample of the crystalline form is equilibrated under about 80% relative humidity air at 25° C. gains less than 1% of its own weight.
319 . The crystalline form of claim 305 that is essentially nonhygroscopic.
320 . A crystalline form of a tetrahydrobenzothiepine compound wherein the tetrahydrobenzothiepine compound has the structure of Formula 71
and that after a sample of the crystalline form is dried at essentially 0% relative humidity at about 25° C. under a purge of essentially dry nitrogen until the sample exhibits essentially no weight change as a function of time, the sample gains less than 1% of its own weight when equilibrated under about 80% relative humidity air at about 25° C.
321 . A crystalline form of a tetrahydrobenzothiepine compound wherein the tetrahydrobenzothiepine compound has the structure of Formula 71
and wherein the crystalline form is produced by crystallizing the tetrahydrobenzothiepine compound from a solvent comprising methyl ethyl ketone.
322 . A method for the preparation of a crystalline form of a tetrahydrobenzothiepine compound having the structure of Formula 63
wherein the method comprises crystallizing the tetrahydrobenzothiepine compound from a solvent comprising methyl ethyl ketone, and wherein:
R 1 and R 2 independently are C 1 to about C 20 hydrocarbyl;
R 3 , R 4 , and R 5 independently are selected from the group consisting of H and C 1 to about C 20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R 3 , R 4 , and R 5 taken together with the atom to which they are attached form a cyclic structure;
R 9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR 3 , NR 3 R 4 , N + R 3 R 4 R 5 A − , SR 3 , S(O)R 3 , SO 2 R 3 , SO 3 R 3 , oxo, CO 2 R 3 , CN, halogen, NCO, CONR 3 R 4 , SO 2 OM, SO 2 NR 3 R 4 , PO(OR 23 )OR 24 , P + R 3 R 4 R 5 A − , S + R 3 R 4 A − , and C(O)OM;
R 23 and R 24 are independently selected from the substituents constituting R 3 and M;
n is a number from 0 to 4;
A − and Z − independently are pharmaceutically acceptable anions; and
M is a pharmaceutically acceptable cation.
323 . The method of claim 322 wherein the tetrahydrobenzothiepine compound has the structure of Formula 64
324 . The method of claim 323 wherein the tetrahydrobenzothiepine compound has the structure of Formula 41
325 . A method for the preparation of a product crystal form of a tetrahydrobenzothiepine compound having the compound structure of Formula 41
wherein the product crystal form has a melting point or a decomposition point of about 278° C. to about 285° C., wherein the method comprises applying heat to an initial crystal form of the tetrahydrobenzothiepine compound wherein the initial crystal form has a melting point or a decomposition point of about 220° C. to about 235° C., thereby forming the product crystal form.
326 . The method of claim 325 wherein the initial crystal form is heated to a temperature from about 20° C. to about 150° C.
327 . The method of claim 326 wherein the initial crystal form is heated to a temperature from about 50° C. to about 125° C.
328 . The method of claim 327 wherein the initial crystal form is heated to a temperature from about 60° C. to about 100° C.
329 . The method of claim 325 wherein the method further comprises a cooling step after the step in which the initial crystal form is heated.
330 . The method of claim 325 further comprising mixing the initial crystal form with a solvent.
331 . The method of claim 330 wherein the solvent comprises a ketone.
332 . The method of claim 331 wherein the ketone is selected from the group consisting of methyl ethyl ketone, acetone, and methyl isobutyl ketone.
333 . The method of claim 332 wherein the ketone is methyl ethyl ketone.
334 . The method of claim 332 wherein the ketone is acetone.
335 . The method of claim 332 wherein the ketone is methyl isobutyl ketone.
336 . The method of claim 330 wherein the method further comprises a cooling step after the step in which the initial crystal form is heated.Join the waitlist — get patent alerts
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