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US 10,208,003 B2Granted
Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
AssigneeKnopp Biosciences LLC
InventorsWeirong Chen, Michael Humora, Daw-Iong Albert Kwok, William F. Kiesman, Erwin Ayandra Irdam
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Abstract
The present invention is related to an improved process for the preparation of amino-substituted 4,5,6,7-tetrahydrobenzothiazole compounds of formula I, such as the compound 2-amino-4,5,6,7-tetrahydro-6-(n-propylamino)benzothiazole. The invention further relates to an improved synthesis of (R)-2-amino-4,5,6,7-tetrahydro-6-(n-propylamino)benzothiazole. The invention also relates to the methods and intermediates associated with the synthetic process.
Claims65
A process for preparing a compound of formula I(HOTs)
- wherein R1 and R2 are each independently hydrogen or C1-6 alkyl, wherein each C1-6 alkyl is optionally and independently substituted with up to 3 occurrences of C1-6 alkyl, aryl or heteroaryl;
- the process comprising contacting a mixture, which comprises a compound of formula II
- and a solvent, with a compound having the formula
- in the presence of a base, to provide a compound of formula I(HOTs), wherein the solvent is acetonitrile, a mixture of acetonitrile and water, IPA, a mixture of IPA and water, a mixture of acetonitrile and IPA, or a mixture of acetonitrile, IPA and water;
- isolating the compound of formula I(HOTs),
- a) forming a mixture comprising the compound of formula I(HOTs), IPA and water, and heating the mixture to about 70° C. to about 85° C.;
- b) cooling the mixture to about 5° C. to about 15° C.;
- and
- c) isolating the solid compound of formula I(HOTs) formed during step b).
6 more elements
A process for preparing Compound 1(2 HCl-H2O)
- wherein the process comprises the steps of:
- a) contacting a mixture comprising Compound 2
- and a solvent, with n-PrOTs and DIPEA to provide Compound 1(HOTs)
- wherein the solvent is acetonitrile, a mixture of acetonitrile and water, IPA, a mixture of IPA and water, a mixture of acetonitrile and IPA, or a mixture of acetonitrile, IPA and water;
- b) isolating the solid Compound 1(HOTs) formed in step a);
- c) forming a mixture comprising Compound 1(HOTs), IPA and water, and heating the mixture to a temperature of about 60° C. to about 90° C.;
- d) cooling the mixture to a temperature of about −5° C. to about 15° C.;
- e) isolating the solid Compound 1(HOTs) formed in step d);
- f) forming a biphasic mixture comprising Compound 1(HOTs), 2-methyltetrahydrofuran and brine, wherein the brine has a salt content of about 2-20% by weight;
- g) contacting the mixture with sodium hydroxide to form Compound 1
- h) forming a mixture comprising Compound 1, 2-methyltetrahydrofuran and IPA;
- i) contacting the mixture with HCl;
- and
- j) isolating the solid Compound 1(2 HCl-H2O) produced in step i).
11 more elements
A process for preparing Compound 1(2HCl-H2O)
- wherein the process comprises the steps of:
- a) contacting a mixture comprising Compound 2
- and a solvent, with n-PrOTs and DIPEA to provide Compound 1(HOTs)
- wherein the solvent is a mixture of acetonitrile and water;
- b) isolating the solid Compound 1(HOTs) formed in step a);
- c) forming a mixture comprising Compound 1(HOTs), IPA and water, and heating the mixture to a temperature of about 75° C., wherein the ratio of IPA to water is about 2.5:1;
- d) cooling the mixture to a temperature from about 0° C. to about 10° C.;
- e) isolating the solid Compound 1(HOTs) formed in step d);
- f) forming a biphasic mixture comprising Compound 1(HOTs), 2-methyltetrahydrofuran and brine, wherein the brine has a salt content of about 12% by weight and wherein the ratio of 2-methyltetrahydrofuran to brine is about 1:1;
- g) contacting the mixture with sodium hydroxide to form Compound 1
- h) forming a mixture comprising Compound 1, 2-methyltetrahydrofuran and IPA;
- i) contacting the mixture with HCl;
- and
- j) isolating the solid Compound 1(2HCl-H2O) produced in step i).
11 more elements
Dependencies are inferred from the claim text.