Process for preparation of aldehyde scavenger and intermediates

A method of preparing a compound of Formula IV:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is H, D, halogen, —NH2, —CN, —OR, —SR, or optionally substituted C1-6 aliphatic;
• R2 is absent or is selected from —R, halogen, —CN, —OR, —SR, —N(R)2, —N(R)C(O)R, —C(O)N(R)2, —N(R)C(O)N(R)2, —N(R)C(O)OR, —OC(O)N(R)2, —N(R)S(O)2R, —SO2N(R)2, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —S(O)2R;
• R3 is absent or is selected from —R, halogen, —CN, —OR, —SR, —N(R)2, —N(R)C(O)R, —C(O)N(R)2, —N(R)C(O)N(R)2, —N(R)C(O)OR, —OC(O)N(R)2, —N(R)S(O)2R, —SO2N(R)2, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —S(O)2R;
• R4 is absent or is selected from —R, halogen, —CN, —OR, —SR, —N(R)2, —N(R)C(O)R, —C(O)N(R)2, —N(R)C(O)N(R)2, —N(R)C(O)OR, —OC(O)N(R)2, —N(R)S(O)2R, —SO2N(R)2, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —S(O)2R;
• Ra is C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms;
• Rb is C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms;
• or Ra and Rb, taken together with the carbon atom to which they are attached, form a 3- to 8-membered cycloalkyl or heterocyclyl ring containing 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur;
• and
• each R is independently selected from hydrogen, deuterium, or an optionally substituted group selected from C1-6 aliphatic;
• a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring;
• phenyl;
• an 8- to 10-membered bicyclic aryl ring;
• a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• a 6- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• or a 7- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• the method comprising:
• step 1) treating pyruvate starting material,
• wherein Z is a halogen, and R9 is an C1-6aliphatic with a heterocycle to form Compound IV-A1′:
• step 2) treating Compound IV-A1′ with an Ring A of structure
• wherein each of R1, R2, R3 and R4 is a defined for Formula VI to form Compound IV-A2′:
• step 3) treating Compound IV-A2′ with a suitable heterocycle to form Compound IV-A3′:
• step 4) treating Compound IV-A3′ with a Grignard reagent or methyl anion to produce compound of Formula IV;
• wherein one or more of the following conditions are satisfied:
• a) the compound of Formula IV produced in step 4) is crude and is not purified by chromatography;
• or
• b) the compound of Formula IV produced in step 4) is slurried with a mixture comprising ethanol acetate, SiO2 and charcoal, followed by solvent exchange and crystallization;
• or
• c) Compound IV-A1′ is isolated and purified prior to treatment with Ring A;
• or
• d) Compound IV-A2′ is isolated and purified prior to its treatment with a heterocycle;
• wherein at least one of b), c) and d) is satisfied.

A method of preparing Compound A, 6-chloro-3-amino-2-(2-hydroxypropyl)-1-azanaphthalene:

• or a pharmaceutically acceptable salt thereof, comprising:
• step 1) treating an alkylhalopyruvate (AHP)
• wherein Z is halogen and R9 is a C1-6aliphatic, with pyridine to form Compound A1′:
• step 2) treating Compound A1′ with 2-amino-5-chloro-benzaldehyde (ACB)
• and pyridine to form Compound A2′:
• step 3) treating Compound A2′ with a suitable heterocycle to form Compound A3′:
• and
• step 4) treating Compound A3′ with a Grignard reagent to form Compound A;
• wherein one or more of the following conditions are satisfied:
• a) Compound A formed in step 4) is crude and is not purified by chromatography;
• b) Compound A formed in step 4) is slurried with a mixture comprising ethanol acetate, SiO2 and charcoal, followed by solvent exchange and crystallization;
• c) Compound A1′ is isolated and purified prior to treatment with ACB;
• and
• d) Compound A2′ is isolated and purified prior to its treatment with a heterocycle;
• and
• wherein at least one of b), c) and d) is satisfied.

A method of preparing Compound B, 3-amino-2-(2-hydroxypropyl)-1-azanapthalene,

• or a pharmaceutically acceptable salt thereof, comprising:
• step 1) treating an alkylhalopyruvate,
• wherein Z is halogen and R9 is a C1-6aliphatic with pyridine to form Compound B1′:
• step 2) treating Compound B1′ with 2-amino-benzaldehyde (AB) and pyridine to form Compound B2′:
• step 3) treating Compound B2′ with a suitable heterocycle to form Compound B3′:
• step 4) treating Compound B3′ with a Grignard reagent or methyl anion to form Compound B.