FIELD OF INVENTION
The present invention relates to an improved process for the preparation of (Z?)-3-amino-l-butanol (I). CH3 1 Formula I The compound of Formula I is a key precursor in the preparation of integrase inhibitor, Dolutegravir of Formula II.
CH3 O OH r^N^Y^f° F"Y^YF Formula II

BACKGROUND OF THE INVENTION

Dolutegravir (I) is chemically known as (4i?,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2//-pyrido[r,2':4,5]pyrazino [2,1 -b] [ 1,3]oxazine-9-carboxamide. Dolutegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Dolutegravir is being marketed under the trade name Tivicay®. (i?)-3-Amino-l-butanol (I) is a key precursor used in the preparation of Dolutegravir of Formula II. 2 Journal of Organic Chemistry 1977, 42(9), 1650-1652 reported a process for the preparation of (i?)-3-amino-l-butanol (I) by reacting ethyl crotonate (III) with (-)-l-(S)-phenylethylamine (IV) to produce ethyl-3(^)-N-[l(5)-methylbenzyl]amino butyrate (V), which is further undergoes reduction with LiAlKt to produce 3(i?)-N-[l(S)-methylbenzyl]aminobutan-I-ol (VI). Compound (VI) is further hydrogenating with Pd/C in ethanol to produce C#)-3-amino-l-butanol (I). The process is as shown in scheme-I below: O
^5s
H
OC2H5 +
(III)
H
Ph
(IV)
CH* CH, O
OC2H5
CH*
CH3 CH3
HjIV^^^OH
H2 /Pd/C / Ethanol
AH
(I)
H
(VI)
Scheme-I

The major disadvantage of above process is that it involves large number of steps for the manufacture of (i?)-3-amino-l-butanol (I). In the chemical synthesis, the number of steps is not advisable for the commercialization of the product. The number of steps is more in a chemical process means the lowering of the overall yield and the time cycle of the production is more. This does not make the suitable chemical process. US 8,288,575 discloses a process for the preparation of (#)-3-amino-l-butanoI (I), wherein methyl (i?)-3-aminobutanoate (VII) is hydrogenated using ruthenium complex in a solvent.

The process is as shown in scheme-II below:

H ,----, H
/ N I / >----1 Ru

BH,
3
THF (I)
Scheme-II
The major disadvantage with the above process is that the sensitivity and the use of more expensive catalyst such as ruthenium complex, which is not easier to handle on commercial scale, and this process is not suitable for commercial scale production of (/?)-3 -amino-1 -butanol (I).
US 2011/0275855 Al discloses a process for the resolution of (i?,5)-3-amino-l-butanol (VIII), wherein racemic 3-amino-l -butanol undergoes resolution with (S^-mandelic acid in the presence of an acid different from (5)-mandelic acid to produce (i?)-3-amino-l-butanol (S)-mandelic acid salt (Ila), which is further neutralized with sodium methoxide to produce (i?)-3-amino-1 -butanol (I). The process is as shown in scheme-Ill below:
OH
CH
3
H2rr ^^ "OH
(VIII)
(S) -mandelic acid / 9Hj
other acid H.NA^nH. 1