Methods of preparing phosphonamidate compounds

Abstract

The present invention relates to methods of preparing phosphonamidate compounds of, for example, formulae (I) and (II), or solvates or salts thereof: (I) (I*) wherein: - is a triple bond; or - is a double bond; - is absent when is a triple bond; or V is H or (C1-C8)alkyl when is a double bond; X is R3-C when is a triple bond; or X is R4-R5-C when is a double bond; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is selected from the group consisting of H, –Si(RSi)3 and (C1-C8)alkyl, wherein RSi is, each independently, (C1-C8)alkyl; R4 is H or (C1-C8)alkyl; R5 is H or (C1-C8)alkyl; R6 is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group. The present invention also relates to phosphonamidate compounds of, for example, formulae (I) and (I*) or solvates or salts thereof.

Description

Abstract This invention relates to a method for preparing, for example, phosphoramide compounds of formula (I) and (II) or their solvates or salts: (I) (I*) wherein: - is a triple bond; or - is a double bond; - is absent when it is a triple bond; or V is H or (C1-C8) alkyl when it is a double bond; X is R3-C when it is a triple bond; or X is R4-R5-C when it is a double bond; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is selected from the group consisting of: H, –Si(RSi)3 and (C1-C8) alkyl, wherein each RSi is independently (C1-C8) alkyl; R4 is H or (C1-C8) alkyl; R5 is H or (C1-C8) alkyl; R6 is H or (C1-C8) alkyl; A is a spacer group; and PG is a protecting group. The present invention also relates to phosphoramide compounds of, for example, formulas (I) and (I*) or their solvates or salts.

Claims

CLAIMS What is claimed is:

1. A method of preparing a compound of formula (I) or a salt or solvate thereof, comprising: (i) reacting a compound of formula (VIII) or a salt or solvate thereof:, wherein: R21, R22, R23and R24are, each independently, H or optionally substituted (C1-C8)alkyl; optionally R21and R22may together form a ring; and / or optionally R23and R24may together form a ring; and / or optionally one of R21and R22may form a ring together with one of R23and R24; and LG is a leaving group with a compound of formula (VII):, wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; is R3 X Cis a triple bond; orR5 X is R4 C when is a double bond; R3is selected from the group consisting of H, –Si(RSi)3and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; andM is a metal-containing group capable of transferring the group V to the phosphorus atom to replace the leaving group LG; (ii) reacting the product obtained in step (i) with a compound of formula (V) or a salt or solvate thereof:(V); wherein: R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group; (iii) reacting the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: R1 OH (III), wherein: R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iv) reacting the product obtained in step (iii) with an oxidizing agent to give a compound of formula (I) or a salt or solvate thereof:(I), wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; 3 X is R Cis a triple bond; or R5 X is R4 Cis a double bond; R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3is selected from the group consisting of H, –Si(RSi)3 and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group.

2. A method of preparing a compound of formula (I) or a salt or solvate thereof, comprising: (a) (i) reacting a compound of formula (VIII) or a salt or solvate thereof:,wherein: R21, R22, R23and R24are, each independently, H or optionally substituted (C1-C8)alkyl; optionally R21and R22may together form a ring; and / or optionally R23and R24may together form a ring; and / or optionally one of R21and R22may form a ring together with one of R23and R24; and LG is a leaving group with a compound of formula (VII):, wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; 3 X is R Cis a triple bond; or R5 s R4 X i Cis a double bond; R3is selected from the group consisting of H, –Si(RSi)3 and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; andM is a metal-containing group capable of transferring the group V to the phosphorus atom to replace the leaving group LG; (ii) reacting the product obtained in step (i) with a compound of formula (III) or a salt or solvate thereof:R1 OH (III), wherein: R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; (iii) reacting the product obtained in step (ii) with a compound of formula (V) or a salt or solvate thereof:(V); wherein: R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group; and (iv) reacting the product obtained in step (iii) with an oxidizing agent to give a compound of formula (I) or a salt or solvate thereof: PG(I), wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; X is R3 Cis a triple bond; orR5 X is R4 C when is a double bond; R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3is selected from the group consisting of H, –Si(RSi)3 and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group; or (b) (ii) reacting a compound of formula (VI) or a salt or solvate thereof:, wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; 3 X is R Cis a triple bond; or Xis a double bond; R21, R22, R23and R24are, each independently, H or optionally substituted (C1-C8)alkyl; optionally R21and R22may together form a ring; and / or optionally R23and R24may together form a ring; and / or optionally one of R21and R22may form a ring together with one of R23and R24;R3is selected from the group consisting of H, –Si(RSi)3 and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; and R5is H or (C1-C8)alkyl with a compound of formula (V) or a salt or solvate thereof:(V), wherein: R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group; (iii) reacting the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: R1 OH (III), wherein: R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iv) reacting the product obtained in step (iii) with an oxidizing agent to give a compound of formula (I) or a salt or solvate thereof:(I), wherein:is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; 3 X is R Cis a triple bond; or R5 is R4 X Cis a double bond; R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3is selected from the group consisting of H, –Si(RSi)3 and (C1-C8)alkyl, wherein RSiis each, independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group; or (c) (ii) reacting a compound of formula (VI) or a salt or solvate thereof: R23(VI), wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond;s a triple bond; or X is when is a double bond; R21, R22, R23and R24are, each independently, H or optionally substituted (C1-C8)alkyl; optionally R21and R22may together form a ring; and / or optionally R23and R24may together form a ring; and / or optionally one of R21and R22may form a ring together with one of R23and R24; R3is selected from the group consisting of H, –Si(RSi)3 and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; and R5is H or (C1-C8)alkyl with a compound of formula (III) or a salt or solvate thereof: R1 OH (III), wherein: R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iii) reacting the product obtained in step (ii) with a compound of formula (V) or a salt or solvate thereof:(V), wherein: R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group; and (iv) reacting the product obtained in step (iii) with an oxidizing agent to give a compound of formula (I) or a salt or solvate thereof:(I), wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; X is R3 Cis a triple bond; or R5 X is R4 Cis a double bond; R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3is selected from the group consisting of H, –Si(RSi)3 and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group.

3. The method according to claim 1 or 2, wherein:is a triple bond; V is absent; X is R3 C ; and R3is selected from the group consisting of H, –Si(RSi)3and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; preferably R3is H or –Si(RSi)3, wherein RSiis, each independently, (C1-C8)alkyl; more preferably R3is H; or R5 is a double bond; V is H or (C1-C8)alkyl, preferably V is H; X is R4 C ; R4is H or (C1-C8)alkyl, preferably R4is H and R5is H or (C1-C8)alkyl, preferably R5is H.

4. The method according to any one of the preceding claims, wherein (a) the leaving group LG is selected from the group consisting of halogen (e.g., F, Cl, Br or I) and optionally substituted phenoxy; preferably wherein the leaving group LG is Cl; and / or (b) M is MgY, wherein Y is halogen, preferably wherein Y is Br; or M is Li; and / or (c) R6is H.

5. The method according to any one of the preceding claims, wherein the spacer A is selected from the group consisting of optionally substituted -(C6-C10)arylene-, optionally substituted - (C1-C10)alkylene-, optionally substituted -(C3-C8)carbocyclo-, optionally substituted -(C1- C10)alkylene-(C6-C10)arylene-, optionally substituted -(C6-C10)arylene-(C1-C10)alkylene-, optionally substituted -(C1-C10)alkylene-(C3-C8)carbocyclo-, optionally substituted -(C3- C8)carbocyclo-(C1-C10)alkylene-, optionally substituted -(C3-C8)heterocyclo-, optionally substituted -(C1-C10)alkylene-(C3-C8)heterocyclo- and optionally substituted -(C3- C8)heterocyclo-(C1-C10)alkylene-; preferably wherein the spacer A is optionally substituted -phenylene-.

6. The method according to any one of the preceding claims, wherein PG is optionally substituted (C1-C8)alkyl, preferably wherein PG is tert-butyl.

7. The method according to any one of the preceding claims, wherein the compound of formula PG, wherein , X, V, R1and PG are as defined in any one of the preceding claims;PG preferably wherein the compound of formula ( , and the PGcompound of, wherein , X, V, R1and PG are as defined in any one of the preceding claims.

8. The method according to any one of the preceding claims, wherein R1is: KFo , wherein: indicates the position of the O; KFis selected from the group consisting of -H, a protecting group, -PO3H, -(C1-C10)alkyl, -(C1-C10)alkyl-SO3H, -(C2-C10)alkyl-CO2H, -(C2-C10)alkyl-OH, -(C2-C10)alkyl-NH2, -(C2- C10)alkyl-NH(C1-C3)alkyl and -(C2-C10)alkyl-N((C1-C3)alkyl)2; and o is an integer ranging from 1 to 100; preferably wherein KFis H; and / or preferably wherein o ranges from 8 to 30, more preferably wherein o ranges from 20 to 28.

9. The method according to any one of claims 1, 2 item (a) and 3 to 8, wherein the compoundof, the compound of formula (VII) , thecompound of formu , p I) is, wherein KFand o are as defined in claim 8; preferably wherein KFis H; and / or preferably wherein o is 24 or 12.

10. The method according to any one of claims 1, 2 item (a), and 3 to 9, wherein the compound of formula (III) is used in a substantially equimolar amount based on the amount of the compound of formula (VIII); preferably wherein the compound of formula (III) is used in an amount of from 0.5 to 1.5 molar equivalents based on 1.0 molar equivalent of the compound of formula (VIII); still more preferably wherein the compound of formula (III) is used in an amount of from 0.9 to 1.1 molar equivalents based on 1.0 molar equivalent of the compound of formula (VIII).

11. The method according to any one of the preceding claims, wherein the oxidizing agent is selected from the group consisting of hydrogen peroxide, meta-chloroperoxybenzoic acid (mCPBA), a urea-hydrogen peroxide adduct, (camphorsulfonyl)oxaziridine (CSO), iodine, tert-butylhydroperoxide (tBuOOH) and air; preferably wherein the oxidizing agent is selected from the group consisting of hydrogen peroxide, meta-chloroperoxybenzoic acid (mCPBA) and a urea-hydrogen peroxide adduct; more preferably wherein the oxidizing agent is hydrogen peroxide.

12. The method according to any one of the preceding claims, wherein steps (i) to (iv) are carried out as a one-pot process.

13. The method according to any one of the preceding claims, further comprising: (v) removing a protecting group PG from a compound of formula (I) or a salt or solvate thereof:(I) wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; X is R3 Cis a triple bond; or Xis a double bond; R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3is selected from the group consisting of H, –Si(RSi)3and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group to give a compound of formula (I*) or a salt or solvate thereof:(I*), wherein: is a triple bond; oris a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; X is R3 Cis a triple bond; or R5 X is R4 Cis a double bond; R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3is selected from the group consisting of H, –Si(RSi)3and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; R6is H or (C1-C8)alkyl; and A is a spacer.

14. A method of preparing a compound of formula (I*), comprising: removing a protecting group PG from a compound of formula (I) or a salt or solvate thereof:(I) wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; X is R3 Cis a triple bond; or R5 is R4 X Cis a double bond;R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3is selected from the group consisting of H, –Si(RSi)3 and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group to give a compound of formula (I*) or a salt or solvate thereof:(I*), wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; 3 X is R Cis a triple bond; or Xis a double bond; R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3is selected from the group consisting of H, –Si(RSi)3and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; R6is H or (C1-C8)alkyl; and A is a spacer.

5. A compound of formula (I) or a salt or solvate thereof:(I) wherein: is a triple bond; or is a double bond; V is absentis a triple bond; or V is H or (C1-C8)alkylis a double bond; 3 X is R Cis a triple bond; or Xis a double bond; R1is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3is selected from the group consisting of H, –Si(RSi)3and (C1-C8)alkyl, wherein RSiis, each independently, (C1-C8)alkyl; R4is H or (C1-C8)alkyl; R5is H or (C1-C8)alkyl; R6is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group.

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