US2015315114A1PendingUtilityA1
Methods of Synthesizing a Prostacyclin Analog
Est. expiryDec 7, 2032(~6.4 yrs left)· nominal 20-yr term from priority
Inventors:Kirk Willam HeringGilles ChambournierGregory William EndresVictor FedijThomas James Krell, IiHussein Mahmoud Mahmoud
A61P 9/12C07D 301/00C07C 51/412C07C 51/347C07C 41/26C07C 45/29C07D 301/32C07D 317/22C07D 303/16C07C 51/09C07C 2603/14C07D 303/14C07C 41/44C07C 205/57C07F 7/1804C07F 7/1856C07F 7/1852
56
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Claims
Abstract
The present invention provides processes for preparing a prostacyclin analogue of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 10 is a linear or branched C 1-6 alkyl. The processes of the present invention comprise steps that generate improved yields and fewer byproducts than traditional methods. The processes of the present invention employ reagents (e.g., the oxidizing reagent) that are less toxic that those used in the traditional methods (e.g., oxalyl chloride). Many of the processes of the present invention generate intermediates with improved e.e. and chemical purity; thereby eliminating the need of additional chromatography steps. And, the processes of the present invention are scalable to generate commercial quantities of the final compound.
Claims
exact text as granted — not AI-modified1 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent in the presence of an organic solvent to generate a compound of Formula 10
wherein R 1 is C 1-6 alkyl and the oxidizing agent comprises MnO 2 or Dess-Martin periodinane;
ii) reacting the compound of Formula 10 with a compound of Formula 5 in the presence of a base and an organic solvent to generate a compound of Formula 11, wherein each R 2 is independently selected from C 1-6 alkyl or phenyl; and
iii) converting the compound of Formula 11 to the compound of Formula I.
2 . The method of claim 1 , wherein the organic solvent of step i) comprises a halogenated organic solvent.
3 . The method of claim 2 , wherein the halogenated organic solvent comprises dichloromethane, chloroform, or any combination thereof.
4 . The method of claim 1 , wherein the base of step ii) comprises an alkyllithium reagent.
5 . The method of claim 4 , wherein the alkyllithium reagent is sec-butyllithium.
6 . The method of claim 1 , wherein the organic solvent of step ii) comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or any combination thereof.
7 . The method of claim 6 , wherein the organic solvent of step ii) comprises methyl-tert-butylether.
8 . The method of claim 1 , further comprising the steps of:
iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%;
v) reacting the compound of Formula 1 with SiCl(R 2 ) 3 under basic conditions to generate the compound of Formula 2;
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generate the compound of Formula 3; and
vii) converting the compound of Formula 3 to the compound of Formula 5.
9 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
viii) reacting a compound of Formula 11 with an oxidizing agent in the presence of an organic solvent to generate a compound of Formula 12
wherein R 1 is C 1-6 alkyl, each R 2 is independently selected from C 1-6 alkyl or phenyl, and the oxidizing agent comprises MnO 2 ; and
ix) converting the compound of Formula 12 to the compound of Formula I.
10 . The method of claim 9 , wherein each of the —OSi(R 2 ) 3 groups in the compounds of Formulae 11 and 12 is independently selected from
11 . The method of claim 9 , wherein the organic solvent of step viii) comprises a halogenated organic solvent.
12 . The method of claim 11 , wherein the halogenated organic solvent comprises dichloromethane, chloroform, or any combination thereof.
13 . The method of claim 9 , further comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent in the presence of an organic solvent to generate a compound of Formula 10
wherein R 1 is C 1-6 alkyl and the oxidizing agent comprises MnO 2 or Dess-Martin periodinane; and
ii) reacting the compound of Formula 10 with a compound of Formula 5
in the presence of a base and an organic solvent to generate a compound of Formula 11.
14 . The method of claim 13 , wherein the base of step ii) comprises an alkyllithium reagent.
15 . The method of claim 14 , wherein the alkyllithium reagent is sec-butyllithium.
16 . The method of claim 13 , wherein the organic solvent of step ii) comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or any combination thereof.
17 . The method of claim 16 , wherein the organic solvent of step ii) comprises methyl-tert-butylether.
18 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
x) reacting a compound of Formula 12 with a reducing agent in the presence of an organic solvent to generate a compound of Formula 13
wherein the organic solvent comprises THF, R 1 is C 1-6 alkyl, and each R 2 is independently selected from C 1-6 alkyl or phenyl; and
xi) converting the compound of Formula 13 to the compound of Formula I.
19 . The method of claim 18 , wherein the reducing agent of step x) comprises a chiral borane compound.
20 . The method of claim 19 , wherein the chiral borane compound is selected from
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole, (4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any combination thereof.
21 . The method of claim 18 , wherein the organic solvent of step x) further comprises toluene.
22 . The method of claim 18 , further comprising the step of:
viii) reacting a compound of Formula 11 with an oxidizing agent to generate the compound of Formula 12, wherein the oxidizing agent comprises MnO 2
23 . The method of claim 22 , further comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent to generate a compound of Formula 10; and
ii) reacting the compound of Formula 10 with a compound of Formula 5 in the presence of a base and an organic solvent to generate a compound of Formula 11
24 . The method of claim 23 , wherein the oxidizing agent comprises MnO 2 or Dess-Martin periodinane.
25 . The method of claim 23 , wherein the base of step ii) comprises an alkyllithium reagent.
26 . The method of claim 25 , wherein the alkyllithium reagent is sec-butyllithium.
27 . The method of claim 23 , wherein the organic solvent of step ii) comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or any combination thereof.
28 . The method of claim 27 , wherein the organic solvent of step ii) comprises methyl-tert-butylether.
29 . The method of claim 23 , further comprising the steps of:
iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%;
v) reacting the compound of Formula 1 with SiCl(R 2 ) 3 under basic conditions to generate the compound of Formula 2;
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generate the compound of Formula 3; and
vii) converting the compound of Formula 3 to the compound of Formula 5.
30 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
xii) hydrogenating a compound of Formula 15 in the presence of an alcohol (e.g., methanol or ethanol), optionally substituted THF (e.g., THF or 2-Me-THF), or any combination thereof to generate the compound of Formula 16
wherein R 1 is C 1-6 alkyl, and each R 2 is independently selected from C 1-6 alkyl or phenyl; and
xiii) converting the compound of Formula 16 to the compound of Formula I.
31 . The method of claim 30 , further comprising the steps of:
x) reacting a compound of Formula 12 with a reducing agent in the presence of an organic solvent to generate a compound of Formula 13
wherein the organic solvent comprises THF; and
xiv) converting the compound of Formula 13 to the compound of Formula 15.
32 . The method of claim 31 , wherein the reducing agent of step x) comprises a chiral borane compound.
33 . The method of claim 32 , wherein the chiral borane compound is selected from
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole, (4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any combination thereof.
34 . The method of claim 31 , further comprising the steps of:
viii) reacting a compound of Formula 11 with an oxidizing agent to generate the compound of Formula 12, wherein the oxidizing agent comprises MnO 2
35 . The method of claim 34 , further comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent to generate a compound of Formula 10; and
ii) reacting the compound of Formula 10 with a compound of Formula 5 in the presence of a base and an organic solvent to generate a compound of Formula 11
36 . The method of claim 35 , wherein the oxidizing agent of step i) comprises MnO 2 or Dess-Martin periodinane.
37 . The method of claim 35 , wherein the base of step ii) comprises an alkyllithium reagent.
38 . The method of claim 37 , wherein the alkyllithium reagent is sec-butyllithium.
39 . The method of claim 35 , wherein the organic solvent of step ii) comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or any combination thereof.
40 . The method of claim 39 , wherein the organic solvent of step ii) comprises methyl-tert-butylether.
41 . The method of claim 35 , further comprising the steps of:
iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%;
v) reacting the compound of Formula 1 with SiCl(R 2 ) 3 under basic conditions to generate the compound of Formula 2;
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generate the compound of Formula 3; and
vii) converting the compound of Formula 3 to the compound of Formula 5.
42 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
xv) reacting a compound of Formula 21 with n-butyllithium in the presence of an organic solvent and a transition metal catalyst to generate a compound of Formula 22
wherein R 3 is C 1-6 alkyl or phenyl; and
xvi) converting the compound of Formula 22 to the compound of Formula I.
43 . The method of claim 42 , wherein the transition metal catalyst of step xv) comprises a compound or complex either of which comprises Cu having a +1 oxidation state.
44 . The method of claim 43 , wherein the transition metal catalyst of step xv) comprises CuX, wherein X is selected from halogen, acetate, benzoate, cyanide, hydroxide, nitrate, or any combination thereof.
45 . The method of claim 44 , wherein the transition metal catalyst of step xv) comprises CuI.
46 . The method of claim 42 , further comprising the steps of:
xvii) reacting a compound of Formula 19 with R 4 -substituted benzenesulfonyl chloride under basic conditions to generate a compound of Formula 20, wherein each R 4 is independently selected from —H or C 1-3 alkyl; and
xviii) reacting the compound of Formula 20 with methanol under basic conditions to generate the compound of Formula 21.
47 . The method of claim 46 , further comprising the steps of
xix) reacting a compound of Formula 16 with a reducing agent to generate a compound of Formula 17;
xx) reacting the compound of claim Formula 17 with Si(R 3 ) 3 Cl under basic conditions to generate a compound of Formula 18; and
xxi) selectively deprotecting the compound of Formula 18 to generate the compound of Formula 19.
48 . The method of claim 47 , further comprising the steps of:
xii) hydrogenating a compound of Formula 15
in the presence of an alcohol or optionally substituted THF to generate the compound of Formula 16.
49 . The method of claim 48 , further comprising the steps of:
x) reacting a compound of Formula 12 with a reducing agent to generate a compound of Formula 13; and
xiv) converting the compound of Formula 13 to the compound of Formula 15.
50 . The method of claim 49 , wherein the reducing agent of step x) comprises a chiral borane compound.
51 . The method of claim 50 , wherein the chiral borane compound is selected from
(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole, (4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any combination thereof.
52 . The method of claim 49 , further comprising the step of:
viii) reacting a compound of Formula 11
with an oxidizing agent to generate the compound of Formula 12, wherein the oxidizing agent comprises MnO 2 .
53 . The method of claim 52 , further comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent to generate a compound of Formula 10; and
ii) reacting the compound of Formula 10 with a compound of Formula 5 in the presence of a base and an organic solvent to generate a compound of Formula 11
54 . The method of claim 53 , wherein the oxidizing agent of step i) comprises MnO 2 or Dess-Martin periodinane.
55 . The method of claim 53 , wherein the base of step comprises an alkyllithium reagent.
56 . The method of claim 55 , wherein the alkyllithium reagent is sec-butyllithium.
57 . The method of claim 53 , wherein the organic solvent of step ii) comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or any combination thereof.
58 . The method of claim 57 , wherein the organic solvent of step comprises methyl-tert-butylether.
59 . The method of claim 53 , further comprising the steps of:
iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having greater than about 99% e.e.;
v) reacting the compound of Formula 1 with SiCl(R 2 ) 3 under basic conditions to generate the compound of Formula 2;
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generate the compound of Formula 3; and
vii) converting the compound of Formula 3 to the compound of Formula 5.
60 . The method of claim 59 , further comprising the steps of:
xxii) reacting a compound of Formula 7 with a 3-haloprop-1-ene in the presence of a base and an organic solvent to generate a compound of Formula 8; and
xxiii) deprotecting the compound of Formula 8 to generate the compound of Formula 9.
61 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
xxii) reacting a compound of Formula 7, wherein R 1 is C 1-6 alkyl and each R 2 is independently selected from C 1-6 alkyl or phenyl, with a 3-haloprop-1-ene in the presence of a base and an organic solvent to generate a compound of Formula 8;
xxiii) deprotecting the compound of Formula 8 to generate the compound of Formula 9, and
xxiv) converting the compound of Formula 9 to the compound of Formula I, wherein the base of step xxii) comprises sec-butyl lithium.
62 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent in the presence of an organic solvent to generate a compound of Formula 10
wherein R 1 is C 1-6 alkyl and the oxidizing agent comprises MnO 2 or Dess-Martin periodinane;
ii) reacting the compound of Formula 10 with a compound of Formula 5a in the presence of a base and an organic solvent to generate a compound of Formula 11a; and
iii) converting the compound of Formula 11a to the compound of Formula I.
63 . The method of claim 62 , wherein the organic solvent of step i) comprises a halogenated organic solvent.
64 . The method of claim 63 , wherein the halogenated organic solvent comprises dichloromethane, chloroform, or any combination thereof.
65 . The method of claim 62 , wherein the base of step ii) comprises an alkyllithium reagent.
66 . The method of claim 65 , wherein the alkyllithium reagent is sec-butyllithium.
67 . The method of claim 62 , wherein the organic solvent of step comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or any combination thereof.
68 . The method of claim 67 , wherein the organic solvent of step comprises methyl-tert-butylether.
69 . The method of claim 62 , further comprising the steps of:
iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%;
v) reacting the compound of Formula 1 with TBSCl under basic conditions to generate the compound of Formula 2a;
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generate the compound of Formula 3a; and
vii) converting the compound of Formula 3a to the compound of Formula 5a.
70 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
viii) reacting a compound of Formula 11a with an oxidizing agent in the presence of an organic solvent to generate a compound of Formula 12a
wherein R 1 is C 1-6 alkyl and the oxidizing agent comprises MnO 2 ; and
ix) converting the compound of Formula 12a to the compound of Formula I.
71 . The method of claim 70 , wherein the organic solvent of step viii) comprises a halogenated organic solvent.
72 . The method of claim 71 , wherein the halogenated organic solvent comprises dichloromethane, chloroform, or any combination thereof.
73 . The method of claim 70 , further comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent in the presence of an organic solvent to generate a compound of Formula 10
wherein the oxidizing agent comprises MnO 2 or Dess-Martin periodinane; and
ii) reacting the compound of Formula 10 with a compound of Formula 5a
in the presence of a base and an organic solvent to generate a compound of Formula 11a.
74 . The method of claim 73 , wherein the base of step ii) comprises an alkyllithium reagent.
75 . The method of claim 74 , wherein the alkyllithium reagent is sec-butyllithium.
76 . The method of claim 73 , wherein the organic solvent of step ii) comprises pentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane, diethyl ether, petro ether, methyl-tert-butylether, or any combination thereof.
77 . The method of claim 76 , wherein the organic solvent of step ii) comprises methyl-tert-butylether.
78 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
x) reacting a compound of Formula 12a with a reducing agent in the presence of an organic solvent to generate a compound of Formula 13a
wherein the organic solvent comprises THF, R 1 is C 1-6 alkyl, and each R 2 is independently selected from C 1-6 alkyl or phenyl; and
xi) converting the compound of Formula 13 to the compound of Formula I.
79 . The method of claim 78 , wherein the reducing agent of step x) comprises a chiral borane compound.
80 . The method of claim 79 , wherein the chiral borane compound is selected from (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, (R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole, (4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any combination thereof.
81 . The method of claim 80 , wherein the organic solvent of step x) further comprises toluene.
82 . The method of claim 78 , further comprising the step of:
viii) reacting a compound of Formula 11a with an oxidizing agent to generate the compound of Formula 12a, wherein the oxidizing agent comprises MnO 2
83 . The method of claim 81 , further comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent to generate a compound of Formula 10; and
ii) reacting the compound of Formula 10 with a compound of Formula 5a in the presence of a base and an organic solvent to generate a compound of Formula 11a
84 . The method of claim 83 , wherein the oxidizing agent comprises MnO 2 or Dess-Martin periodinane.
85 . The method of claim 83 , further comprising the steps of:
iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%;
v) reacting the compound of Formula 1 with TBSCl under basic conditions to generate the compound of Formula 2a;
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generate the compound of Formula 3a; and
vii) converting the compound of Formula 3a to the compound of Formula 5a.
86 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
xii) hydrogenating a compound of Formula 15a in the presence of methanol, ethanol, THF, 2-methyl-THF, or any combination thereof to generate the compound of Formula 16a
wherein R 1 is C 1-6 alkyl; and
xiii) converting the compound of Formula 16a to the compound of Formula I.
87 . The method of claim 86 , further comprising the steps of:
x) reacting a compound of Formula 12a with a reducing agent in the presence of an organic solvent to generate a compound of Formula 13a
wherein the organic solvent comprises THF; and
xiv) converting the compound of Formula 13a to the compound of Formula 15a.
88 . The method of claim 87 , further comprising the steps of:
viii) reacting a compound of Formula 11a with an oxidizing agent to generate the compound of Formula 12a, wherein the oxidizing agent comprises MnO 2
89 . The method of claim 87 , further comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent to generate a compound of Formula 10; and
ii) reacting the compound of Formula 10 with a compound of Formula 5a in the presence of a base and an organic solvent to generate a compound of Formula 11a
90 . The method of claim 89 , further comprising the steps of:
iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%;
v) reacting the compound of Formula 1 with TBSCl under basic conditions to generate the compound of Formula 2a;
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generate the compound of Formula 3a; and
vii) converting the compound of Formula 3a to the compound of Formula 5a.
91 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
xv) reacting a compound of Formula 21a with n-butyllithium in the presence of an organic solvent and a transition metal catalyst to generate a compound of Formula 22a
wherein R 1 is C 1-6 alkyl; and
xvi) converting the compound of Formula 22a to the compound of Formula I.
92 . The method of claim 91 , wherein the transition metal catalyst comprises a compound or complex either of which comprises copper having a +1 oxidation state.
93 . The method of claim 92 , wherein the transition metal catalyst comprises CuI.
94 . The method of claim 91 , further comprising the steps of:
xvii) reacting a compound of Formula 19a with triisopropylbenzenesulfonyl chloride under basic conditions to generate a compound of Formula 20a; and
xviii) reacting the compound of Formula 20a with methanol under basic conditions to generate the compound of Formula 21a.
95 . The method of claim 94 , further comprising the steps of
xix) reacting a compound of Formula 16a with a reducing agent to generate a compound of Formula 17a;
xx) reacting the compound of Formula 17a with TBDPSCl under basic conditions to generate a compound of Formula 18a; and
xxi) selectively deprotecting the compound of Formula 18a to generate the compound of Formula 19a.
96 . The method of claim 95 , further comprising the steps of:
xii) hydrogenating a compound of Formula 15a
in the presence of an alcohol, optionally substituted THF, or any combination thereof to generate the compound of Formula 16a.
97 . The method of claim 96 , further comprising the steps of:
x) reacting a compound of Formula 12a with a reducing agent to generate a compound of Formula 13a; and
xiv) converting the compound of Formula 13a to the compound of Formula 15a.
98 . The method of claim 97 , further comprising the step of:
viii) reacting a compound of Formula 11a
with an oxidizing agent to generate the compound of Formula 12a, wherein the oxidizing agent comprises MnO 2 .
99 . The method of claim 97 , further comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent to generate a compound of Formula 10; and
ii) reacting the compound of Formula 10 with a compound of Formula 5a in the presence of a base and an organic solvent to generate a compound of Formula 11a
100 . The method of claim 99 , further comprising the steps of:
iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%;
v) reacting the compound of Formula 1 with TBSCl under basic conditions to generate the compound of Formula 2a;
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generate the compound of Formula 3a; and
vii) converting the compound of Formula 3a to the compound of Formula 5a.
101 . The method of claim 100 , further comprising the steps of:
xxii) reacting a compound of Formula 7a with a 3-haloprop-1-ene in the presence of a base and an organic solvent to generate a compound of Formula 8a; and
xxiii) deprotecting the compound of Formula 8a to generate the compound of Formula 9.
102 . A method of generating a compound of Formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
i) reacting a compound of Formula 9 with an oxidizing agent to generate a compound of Formula 10;
ii) reacting the compound of Formula 10 with a compound of Formula 5a in the presence of a base and an organic solvent to generate a compound of Formula 11a;
iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%;
v) reacting the compound of Formula 1 with TBSCl under basic conditions to generate the compound of Formula 2a;
vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generate the compound of Formula 3a;
vii) converting the compound of Formula 3a to the compound of Formula 5a;
viii) reacting a compound of Formula 11a with an oxidizing agent to generate the compound of Formula 12a, wherein the oxidizing agent comprises MnO 2 ;
x) reacting a compound of Formula 12a with a reducing agent to generate a compound of Formula 13a;
xiv) converting the compound of Formula 13a to the compound of Formula 15a;
xii) hydrogenating a compound of Formula 15a in the presence of methanol, ethanol, THF, 2-methyl-THF, or any combination thereof to generate the compound of Formula 16a;
xix) reacting a compound of Formula 16a with a reducing agent to generate a compound of Formula 17a;
xx) reacting the compound of Formula 17a with TDPSCl under basic conditions to generate a compound of Formula 18a;
xxi) selectively deprotecting the compound of Formula 18a to generate the compound of Formula 19a;
xvii) reacting a compound of Formula 19a with triisopropylbenzenesulfonyl chloride under basic conditions to generate a compound of Formula 20a;
xviii) reacting the compound of Formula 20a with methanol under basic conditions to generate the compound of Formula 21a;
xv) reacting a compound of Formula 21a with n-butyllithium in the presence of an organic solvent and a transition metal catalyst to generate a compound of Formula 22a; and
xvi) converting the compound of Formula 22a to the compound of Formula I.
103 . The method of claim 102 , further comprising the step of:
xxiv) reacting the compound of Formula I with diethanolamine in the presence of an organic solvent to generate the diethanolamine salt of the compound of Formula I.
104 . A compound of Formula 21
wherein R 1 is C 1-6 alkyl and each R 3 is independently C 1-6 alkyl or phenyl.
105 . The compound of claim 104 , wherein R 1 is methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, or tert-butyl.
106 . The compound of claim 104 , wherein the —OSi(R 3 ) 3 group is selected from
107 . The compound of claim 104 , wherein R 1 is methyl and the —OSi(R 3 ) 3 group is
108 . A compound of Formula 1a
109 . A method of purifying a compound of Formula 1 comprising:
xxx) reacting a compound of Formula 1 with a derivatizing reagent to generate a precipitate that is substantially insoluble in dichloromethane or mixtures thereof;
xxxi) collecting the precipitate and refluxing the precipitate in a solvent comprising an alcohol to generate the compound of Formula 1 having a chemical purity of about 98% or greater and an e.e. of about 98% or greater;
wherein the method excludes the use of any column chromatography.
110 . The method of claim 109 , wherein the derivitizing reagent comprises 3,5-dinitrobenzoyl chloride and the alcohol comprises methanol.
111 . A method of purifying a compound of Formula 9 comprising:
xl) reacting a compound of Formula 9, wherein R 1 is C 1-6 alkyl, with 3,5-dinitrobenzoyl chloride to generate a precipitate comprising a compound of Formula 9A; and
xli) collecting the precipitate and treating the precipitate with a base in the presence of an alcohol to generate the compound of Formula 9 having a chemical purity of about 95% or greater;
wherein the method excludes the use of any column chromatography.
112 . The method of claim 111 , further comprising the step:
xlii) recrystallizing the precipitate of step xli).
113 . A method of generating a compound of Formula 5
wherein each R 2 is independently selected from a C 1-6 alkyl or phenyl, comprising
iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%;
v) reacting the compound of Formula 1 with SiCl(R 2 ) 3 , wherein each R 2 is independently selected from C 1-6 alkyl or phenyl, under basic conditions to generate the compound of Formula 2;
vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generate the compound of Formula 3;
l) deprotecting the compound Formula 3 under basic condition to generate a compound of Formula 4, wherein each of R 4 and R 5 are H or —OSi(R 2 ) 3 ; and
li) reacting the compound of Formula 4 with SiCl(R 2 ) 3 under basic conditions to generate the compound of Formula 5,
wherein the compound of Formula 5 has a chemical purity of about 98% or greater and an e.e. of about 98% or greater.
114 . A compound of Formula 5
wherein each of R 2 is independently selected from a C 1-6 alkyl or phenyl.
115 . A compound of Formula 9a
wherein R 1 is C 1-6 alkyl.
116 . A compound of Formula 13
wherein R 1 is C 1-6 alkyl and each R 2 is independently selected from C 1-6 alkyl or phenyl.
117 . A method of generating a compound of Formula 13
wherein R 1 is C 1-6 alkyl and each R 2 is independently selected from C 1-6 alkyl or phenyl, comprising
x) reacting a compound of Formula 12 with (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole in the presence of an organic solvent comprising THF and toluene to generate a compound of Formula 13
wherein the compound of Formula 13 has a chemical purity of about 97% or greater and a d.e. of about 97% or greater.Cited by (0)
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