DESC:FIELD OF THE INVENTION
The present invention provides a process for the preparation of (1R, 3S)-3-aminocyclopentan-1-ol which is used in the preparation of various Active Pharmaceutical Ingredients (API’s). In particular (1R, 3S)-3-aminocyclopentan-1-ol is used in the preparation of Bictegravir or its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Bictegravir is chemically know as (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b] [1,3]oxazepine-10-carboxamide, and is structurally represented by Formula A.

(A)

Bictegravir is a potent HIV integrase inhibitor that causes a rapid reduction of HIV viral load in humans. It is developed by Gilead Sciences and combined with Emtricitabine & Tenofovir alafenamide fumarate for the treatment of HIV-1 infection in adults who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 3 months. Combination of Bictegravir/Emtricitabine/ Tenofovir alafenamide fumarate was approved in the United States on Feb 7, 2018 under the brand name Biktarvy®.

US 9216996 B2 discloses Bictegravir or a pharmaceutically acceptable salt as compound 42, its preparation, pharmaceutical composition and pharmaceutical use for the treatment of HIV infection.

(1R, 3S)-3-aminocyclopentan-1-ol or its hydrochloride is a useful intermediate in preparation of various Active Pharmaceutical Ingredients (API’s) such as Bictegravir. Preparation of this intermediate is disclosed in WO 2015/195656 A2.

The present invention relates to a process for the preparation of (1R, 3S)-3-aminocyclopentan-1-ol or its hydrochloride intermediate and its conversion to Bictegravir or its pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION
In one aspect the present invention relates to a process for the preparation of (1R, 3S)-3-aminocyclopentan-1-ol or its hydrochloride salt thereof, comprising the steps:
i) reacting freshly prepared cyclopentadiene with tert-butyl N-hydroxycarbamate in suitable alcoholic solvent using sodium metaperiodate in water to afford tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (1);

ii) preparing tert-butyl (3-hydroxycyclopentyl)carbamate (2) by a ring opening of tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate intermediate in a suitable solvent using suitable reagent;

iii) deprotecting tert-butyl (3-hydroxycyclopentyl)carbamate (2) using acetyl chloride in suitable alcoholic solvent to obtain 3-aminocyclopentan-1-ol hydrochloride (3);

iv) separating a racemic intermediate of 3-aminocyclopentan-1-ol hydrochloride (3) using mandelic acid as resolving agent in presence of sodium methoxide in suitable solvent to afford mandelic acid salt of (1R,3S)-3-aminocyclopentan-1-ol (4);

v) treating the mandelic acid salt with a base in presence of suitable solvent to obtain (1R,3S)-3-aminocyclopentan-1-ol;

vi) optionally converting (1R,3S)-3-aminocyclopentan-1-ol to its hydrochloride by treating with aqueous HCl.

In another aspect the present invention relates to a process for the preparation of (1R, 3S)-3-aminocyclopentan-1-ol or its hydrochloride salt thereof which is further converted to Bictegravir or its pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION
Thus one embodiment of the present invention provides a process for the preparation of (1R, 3S)-3-aminocyclopentan-1-ol or its hydrochloride salt (I) comprising the steps:
i) reacting freshly prepared cyclopentadiene with tert-butyl N-hydroxycarbamate in suitable alcoholic solvent using sodium metaperiodate in water to afford tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (1);

ii) preparing tert-butyl (3-hydroxycyclopentyl)carbamate (2) by a ring opening of tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate intermediate in a suitable solvent using suitable reagent;

iii) deprotecting tert-butyl (3-hydroxycyclopentyl)carbamate (2) using acetyl chloride in suitable alcoholic solvent to obtain 3-aminocyclopentan-1-ol hydrochloride (3);

iv) separating a racemic intermediate of 3-aminocyclopentan-1-ol hydrochloride (3) using mandelic acid as resolving agent in presence of sodium methoxide in suitable solvent to afford mandelic acid salt of (1R,3S)-3-aminocyclopentan-1-ol (4);

v) treating the mandelic acid salt with a base in presence of suitable solvent to obtain (1R,3S)-3-aminocyclopentan-1-ol ;

vi) optionally converting (1R,3S)-3-aminocyclopentan-1-ol to its hydrochloride by treating with aqueous HCl;
vii) optionally, the mandelic acid salt of (1R,3S)-3-aminocyclopentan-1-ol (4) can be used directly in the preparation of Bictegravir.

The freshly prepared cyclopentadiene is used for the present invention and it is prepared by a distillation of diclyclopentadiene at reflux temperature 150-160°C.

The suitable alcoholic solvent in step i) is selected from methanol, ethanol, isopropanol or tert-butanol.

The intermediate tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (1) is then converted to tert-butyl (3-hydroxycyclopentyl)carbamate (2) intermediate by ring opening using a suitable reagent selected from Raney Nickel under hydrogen pressure, Pd/C under hydrogen pressure, NiCl2 in presence of NaBH4 and a suitable solvent selected from methanol, ethanol, isopropanol or tert-butanol.

The tert-butyl (3-hydroxycyclopentyl)carbamate (2) intermediate is then deprotected using acetyl chloride in suitable alcoholic solvent selected from methanol, ethanol, isopropanol or tert-butanol to obtain 3-aminocyclopentan-1-ol hydrochloride (3) intermediate as racemic mixture.

Racemic intermediate 3-aminocyclopentan-1-ol hydrochloride is then subjected to resolution using suitable resolving agent such as S(+)mandelic acid in presence of sodium methoxide in suitable solvent selected from methanol, ethanol, isopropanol or tert-butanol to afford Mandelic acid salt of (1R,3S)-3-aminocyclopentan-1-ol (4).

The Mandelic acid salt of (1R,3S)-3-aminocyclopentan-1-ol is then treated with a base in presence of suitable solvent selected from dichloromethane, acetone, ethyl acetate, methanol, ethanol, isopropanol; followed by treatment with aqueous HCl to obtain (1R,3S)-3-aminocyclopentan-1-ol hydrochloride (I). The base is organic base or inorganic base; preferably the organic base such as triethylamine is used.
The intermediate (1R,3S)-3-aminocyclopentan-1-ol or its hydrochloride salt prepared by the process of the present invention is then converted to Bictegravir or its pharmaceutically acceptable salts by any of the methods known in the art.

EXAMPLES:
Following experimental procedure set forth is only to understand invention and is not intended and should not be interpreted as a limitation thereon. Modifications to reaction conditions, for example, temperature, duration of the reaction or combination thereof, are envisioned as part of the invention.

Example 1: Preparation of (1R,3S)-3-aminocyclopentan-1-ol hydrochloride

Step -1: tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (1)
Diclyclopentadiene (12 g) was charged into a flask and was heated to 160-170°C distilling to get freshly prepared cyclopentadiene at 0-5°C in the receiver till the residue remains in the flask. In a cooled temperature 0-5°C freshly distilled cyclopentadiene (10 g) and tert-butyl N-hydroxycarbamate (10 g) and methanol (200 ml) were charged in the Round-bottom flask. A solution of sodium metaperiodate (12.8 g in 100 ml water) was added at 0-10°C. After completion of reaction, water (100 ml) was added and product extracted into ethyl acetate (250 ml). Ethyl acetate layer washed with 10% sodium thiosulphate solution and distilled, degassed to get tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate as oily residue (10.0 g).

Step-2: tert-butyl (3-hydroxycyclopentyl)carbamate (2)
tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (10 g) and methanol (50 ml) were charged into the autoclave followed by Raney-Ni (2 g) and applied hydrogen pressure at room temperature. After reaction completion, the reaction mass was filtered through celite and filtrate was distilled off and degassed to get tert-butyl (3-hydroxycyclopentyl)carbamate as oily compound (2) (10.0 g).
Step-3: 3-aminocyclopentan-1-ol hydrochloride (3)
tert-butyl (3-hydroxycyclopentyl)carbamate (10 g) and isopropanol (50 ml) were charged into the round-bottom flask followed by acetyl chloride (20 ml) at 0-10°C. The reaction mixture was raised to room temperature and maintained till reaction completion. Solvent was removed and degassed to get 3-aminocyclopentan-1-ol hydrochloride as oily compound (5.0 g).
Step-4: (1R, 3S)-3-aminocyclopentan-1-ol S (+) mandelic acid salt (4)
To a mixture of 3-aminocyclopentan-1-ol hydrochloride (10 g) and methanol (50 ml) in Round-bottom flask added 1 mole eq. of sodium methoxide solution (30%) at 20-30°C. Solid inorganic material filtered and filtrate distilled out under vacuum to get oily product. To this oily mass, isopropanol (100 ml) and 0.5 mole eq. of S (+) Mandelic acid were added. The reaction mixture was stirred and filtered the solid and dried to get (1R, 3S)-3-aminocyclopentan-1-ol S (+) mandelic acid salt (8.0 g).
Step-5: (1R, 3S)-3-aminocyclopentan-1-ol hydrochloride (I)
(1R, 3S)-3-aminocyclopentan-1-ol S(+) mandelic acid salt (10 g) and dichloromethane (50 ml) was charged into the Round-bottom flask followed by 1 mole eq. of triethylamine at 20-30°C. Reaction mass was filtered and layer was separated and aqueous layer was treated with aqueous HCl (5 ml) and distilled, degassed under vacuum to get oily product. n–Heptane was added to the oily mass and stirred, filtered and dried to get (1R, 3S)-3-aminocyclopentan-1-ol hydrochloride (5.0 g).
,CLAIMS:
1) A process for the preparation of (1R, 3S)-3-aminocyclopentan-1-ol or its hydrochloride salt thereof, comprising the steps:
vii) reacting cyclopentadiene with tert-butyl N-hydroxycarbamate in suitable alcoholic solvent using sodium metaperiodate in water to afford tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (1);

viii) preparing tert-butyl (3-hydroxycyclopentyl)carbamate (2) by a ring opening of tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate intermediate in a suitable solvent using suitable reagent;

ix) deprotecting tert-butyl (3-hydroxycyclopentyl)carbamate (2) using acetyl chloride in suitable alcoholic solvent to obtain 3-aminocyclopentan-1-ol hydrochloride (3);

x) separating a racemic intermediate of 3-aminocyclopentan-1-ol hydrochloride (3) using mandelic acid as resolving agent in presence of sodium methoxide in suitable solvent to afford mandelic acid salt of (1R,3S)-3-aminocyclopentan-1-ol (4);

xi) treating the mandelic acid salt with a base in presence of suitable solvent to obtain (1R,3S)-3-aminocyclopentan-1-ol;

xii) optionally converting (1R,3S)-3-aminocyclopentan-1-ol to its hydrochloride by treating with aqueous HCl.
2) The process according to claim 1, step i) and step iii), wherein suitable alcoholic solvent is selected from methanol, ethanol, isopropanol or tert-butanol.
3) The process according to claim 1, step ii) and step iv), wherein suitable solvent is selected from methanol, ethanol, isopropanol or tert-butanol.
4) The process according to claim 1, step ii), wherein suitable reagent is selected from Raney Nickel, Pd/C, NiCl2 in presence of NaBH4.
5) The process according to claim 1, step v), wherein base is triethylamine.

6) The process according to claim 1, step v), wherein suitable solvent is selected from dichloromethane, acetone, ethyl acetate, methanol, ethanol or isopropanol.
7) The process according to claim 1, wherein intermediate (1R,3S)-3-aminocyclopentan-1-ol or its hydrochloride salt is further converted to Bictegravir or its pharmaceutically acceptable salts.