4-alkoxy-3-(trifluoromethyl)benzyl alcohol production method
The present invention relates to a production method of 4-alkoxy-3-trifluoromethylbenzyl alcohol at a high conversion ratio, which can strictly suppress production of a byproduct by using DIBAL as a reducing agent.
1. A production method for making a compound of formula (II), the method comprising reducing a compound of formula (I) by using diisobutylaluminum hydride:
wherein R is alkyl having 1 to 10 carbon atoms, wherein the byproduct of formula (IIa′):
is not detected by HPLC using a C18 column and a mobile phase of 50 mM NaClO 4 buffer (pH 2.5) and acetonitrile.
2. A production method for making a compound of formula (IV) or a pharmaceutically acceptable acid addition salt thereof, the method comprising:
reducing a compound of formula (I) by using diisobutylaluminum hydride to provide a compound of formula (II):
converting the compound of formula (II) to a compound of formula (V):
reacting the compound of formula (V) with a compound of formula (III):
to produce a compound of formula (VI):
and
hydrolyzing and reducing the compound of formula (VI) to produce a compound of formula (IV):
wherein R is alkyl having 1 to 10 carbon atoms, and R′ is alkyl having 1 to 3 carbon atoms, wherein the byproduct of formula (IIa′):
is not detected by HPLC using a C18 column and a mobile phase of 50 mM NaClO 4 buffer (pH 2.5) and acetonitrile.
3. The production method according to claim 1 , wherein R is a heptyl group.
4. The production method according to claim 2 , wherein R is a heptyl group, and the compound represented by the formula (IV) or a pharmaceutically acceptable acid addition salt thereof is 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol.
5. The production method according to claim 2 , wherein R is a heptyl group, and the compound represented by the formula (IV) or a pharmaceutically acceptable acid addition salt thereof is 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride.
6. The production method according to claim 2 , wherein R is a heptyl group.
7. A production method for making a compound of formula (IV) or a pharmaceutically acceptable acid addition salt thereof, the method comprising:
reducing a compound of formula (I) by using diisobutylaluminum hydride to provide a compound of formula (II):
and
converting the compound of formula (II) to a compound of formula (IV):
wherein R is alkyl having 1 to 10 carbon atoms,
wherein the byproduct of formula (IIa′):
is not detected by HPLC using a C18 column and a mobile phase of 50 mM NaClO 4 buffer (pH 2.5) and acetonitrile.
8. The production method according to claim 7 , wherein R is a heptyl group.
9. The production method according to claim 7 , wherein R is a heptyl group, and the compound represented by the formula (IV) or a pharmaceutically acceptable acid addition salt thereof is 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol.
10. The production method according to claim 7 , wherein R is a heptyl group, and the compound represented by the formula (IV) or a pharmaceutically acceptable acid addition salt thereof is 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride.
11. The production method according to claim 2 , wherein the compound of formula (II) is provided at a high conversion ratio.
12. The production method according to claim 11 , wherein the compound of formula (II) is provided at a conversion ratio of greater than 98%.
13. The production method according to claim 7 , wherein the compound of formula (II) is provided at a high conversion ratio.
14. The production method according to claim 13 , wherein the compound of formula (II) is provided at a conversion ratio of greater than 98%.
15. The production method according to claim 1 , further comprising HPLC conditions having (i) a column temperature of 40° C., (ii) a linear concentration gradient of NaClO 4 buffer/acetonitrile from an initial concentration of 40/60 to a final concentration of 10/90 for the mobile phase, (iii) a mobile phase flow rate of 1.0 mL/min, and (iv) an analysis time of 40 minutes.
16. The production method according to claim 2 , further comprising HPLC conditions having (i) a column temperature of 40° C., (ii) a linear concentration gradient of NaClO 4 buffer/acetonitrile from an initial concentration of 40/60 to a final concentration of 10/90 for the mobile phase, (iii) a mobile phase flow rate of 1.0 mL/min, and (iv) an analysis time of 40 minutes.
17. The production method according to claim 7 , further comprising HPLC conditions having (i) a column temperature of 40° C., (ii) a linear concentration gradient of NaClO 4 buffer/acetonitrile from an initial concentration of 40/60 to a final concentration of 10/90 for the mobile phase, (iii) a mobile phase flow rate of 1.0 mL/min, and (iv) an analysis time of 40 minutes.