Improved methods for production of cyclic guanosine-monophosphate analogues

Method for producing a cyclic guanosine-3′, 5′-monophosphate (cGMP) analogue or a synthetic intermediate thereof, the method comprising the steps of:

• i) providing a guanosine analogue of general formula (I) or a salt thereof:
• wherein:
• h is H, halogen, or Q;
• X1 and X2 are each independently chosen from H or p′;
• p′ is in each instance independently chosen from a hydroxyl protective group;
• R1 and R2 are each independently chosen from H, —(CH2)n—H, —(CH2)n—C3-9heterocyclyl, —(CH2)n-ar, and ar, wherein each instance of n is independently chosen from 0, 1, 2, 3, or 4, or R1 and R2 together form —CH═C(ar)- or —(CH2)1-4C(═O)—;
• ar is in each instance independently a 5- or 6-membered aromatic or heteroaromatic ring, p wherein each instance of ar is individually optionally substituted with halogen, —OH, —SH, —NH2, —NO2, —OCH3, —CH3, —CH2CH3, —CH(CH3)2, or —CF3, and is optionally fused with a second instance of ar;
• Q is —(CH2)n—S—(CH2)n—H, —S—(CH2)˜—OH, —S—(CH2)n—NH2, —(CH2)˜—O—(CH2)n—H, —O—(CH2)˜—OH, —O—(CH2)n—NH2, —O—C(CH3)3, —O—CH(CH3)2, —(CH2)n—N(—[CH2]nH)2, —NH—(CH2)nNH2, —NH—(CH2)˜—OH, —(CH2)n—Nc1c2 wherein c1 and c2 together with the N to which they are attached form a 3 to 8 membered heterocycle or wherein c1 is H and c2 is a 3 to 8 membered heterocycle, —(CH2)n—H, —N3, —CF3, —(CH2)n-ar, —O—(CH2)n-(ar), —NH—(CH2)n-(ar), —S—(CH2)n-(ar), —(CH2)n-amido-ar, —O—(CH2)n-amido-(ar), —NH—(CH2)n-amido-(ar), —S—(CH2)n-amido-(ar), or a linker moiety, wherein any —H may be optionally replaced by a halogen, wherein each instance of n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, or 8;
• ii) contacting the provided guanosine analogue with a phosphorous oxoacid derivative to obtain a guanosine 5′-monophosphorous oxoacid ester analogue;
• and
• iii) isolating the obtained guanosine 5′-monophosphorous oxoacid ester analogue by crystallization.