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US 10,155,716 B2Granted
Amine salts of a prostacyclin analog
AssigneeCayman Chemical Company, Incorporated
InventorsGilles Chambournier, Gregory William Endres, Kirk William Hering, Victor Fedij, Hussein Mahmoud Mahmoud
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Abstract
The present invention provides amine salts of the prostacyclin analogue of Formula I and processes for generating these amine salts.
Claims99
A method of generating an N-methyldiethanolamine salt compound of Formula I
- comprising the steps of:
- i) 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 R1 is C1-6 alkyl, each R2 is independently selected from C1-6 alkyl or phenyl, and the oxidizing agent comprises MnO2;
- and
- ii) converting the compound of Formula 12 to the N-methyldiethanolamine salt of the compound of Formula I.
2 more elements
A method of generating an N-methyldiethanolamine salt of the compound of Formula I
- comprising the steps of:
- iii) 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, R1 is C1-6 alkyl, and each R2 is independently selected from C1-6 alkyl or phenyl;
- and
- iv) converting the compound of Formula 13 to the N-methyldiethanolamine salt of the compound of Formula I.
2 more elements
A method of generating an N-methyldiethanolamine salt of the compound of Formula I
- comprising the steps of:
- v) hydrogenating a compound of Formula 15 in the presence of an organic solvent to generate the compound of Formula 16
- wherein R1 is C1-6 alkyl, and each R2 is independently selected from C1-6 alkyl or phenyl;
- and
- vi) converting the compound of Formula 16 to the N-methyldiethanolamine salt of the compound of Formula I.
2 more elements
A method of generating an N-methyldiethanolamine salt of the compound of Formula I
- comprising the steps of:
- viii) 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 R3 is C1-6 alkyl or phenyl;
- and
- xvi) converting the compound of Formula 22 to the N-methyldiethanolamine salt of the compound of Formula I.
2 more elements
A method of generating an N-methyldiethanolamine salt of the compound of Formula I
- comprising the steps of:
- xxii) reacting a compound of Formula 7, wherein R1 is C1-6 alkyl and each R2 is independently selected from C1-6 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.
1 more element
A method of generating an N-methyldiethanolamine salt of the compound of Formula I
- 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 R1 is C1-6 alkyl and the oxidizing agent comprises MnO2 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 1a and
- iii) converting the compound of Formula IIa to the N-methyldiethanolamine salt of the compound of Formula I.
2 more elements
A method of generating an N-methyldiethanolamine salt of the compound of Formula I
- 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 R1 is C1-6 alkyl and the oxidizing agent comprises MnO2;
- and
- ix) converting the compound of Formula 12a to the N-methyldiethanolamine salt of the compound of Formula I.
2 more elements
A method of generating an N-methyldiethanolamine salt of the compound of Formula I
- 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, R1 is C1-6 alkyl, and each R2 is independently selected from C1-6 alkyl or phenyl;
- and
- xi) converting the compound of Formula 13 to the N-methyldiethanolamine salt of the compound of Formula I.
2 more elements
A method of generating an N-methyldiethanolamine salt of the compound of Formula I
- comprising the steps of:
- xii) hydrogenating a compound of Formula 15a in the presence of an organic solvent to generate the compound of Formula 162
- wherein R1 is C1-6 alkyl;
- and
- xiii) converting the compound of Formula 16a to the N-methyldiethanolamine salt of the compound of Formula I.
2 more elements
A method of generating an N-methyldiethanolamine salt of the compound of Formula I
- 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 R1 is C1-6 alkyl;
- and
- xvi) converting the compound of Formula 22a to the N-methyldiethanolamine salt of the compound of Formula I.
2 more elements
A method of generating an N-methyldiethanolamine salt of the compound of Formula I
- 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 MnO2;
- 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 or THF 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.
16 more elements
Dependencies are inferred from the claim text.