This application claims priority to this Indian patent application number 4980/CHE/2012 filed on November 29, 2012.

FIELD OF INVENTION

The present invention relates to the process for the preparation of 3-amino-3-cyclobutylmethyl-2-hydroxypropionamide or an acid addition salt thereof and its further conversion into Boceprevir.

BACKGROUND OF THE INVENTION

Boceprevir, (lR,5S)-N-[3-Amino-l-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-
[[[(1,1 -dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1 -oxobutyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexan-2(S)-carboxamide, having formula I is a hepatitis C virus ("HCV") protease inhibitor, developed by Merck & Co and marketed under the brand nameofVICTRELIS.

Intermediate I, 3-amino-3-cyclobutylmethyl-2-hydroxypropionamide or an acid addition salt thereof, having the following structure is one of the key intermediate for the synthesis of Boceprevir.

US patent 6992220 claims a process for the synthesis of Intermediate I and is represented in below scheme 1.

The processes exemplified above employ hazardous reagents and are difficult to handle in an industrial scale. There is a need in the art to provide a process which is not hazardous, cost effective with enhanced purity and yields.
The present invention provides a commercially viable and easy to handle process with simple reagents and with enhanced purity and yield of intermediate I or an acid addition salt thereof.

OBJECT AND SUMMARY OF THE INVENTION

The principle object of the present invention is to provide an improved process for preparing 3-amino-3-cyclobutylmethyl-2-hydroxypropionamide of Intermediate I or an acid addition salt thereof.

Another object of the present invention is to provide a novel intermediate of formula E.

Formula E P- Amine protecting group.

In one aspect, the present invention provides a process for preparing 3-amino-3-cyclobutyImethyl-2-hydroxypropionamide of Intermediate I or an acid addition salt thereof comprising the steps of:

a) reacting a benzophenone imine compound of formula A with a compound of formula B to give a compound of formula C,
c) reacting compound of formula D with a morpholine to give compound of formula E,

d) reducing compound of formula E to give compound of formula F,
e) reacting compound of formula F with a cyanohydrin compound to give compound of formula G,
f) hydrolyzing compound of formula G to give compound of formula H, and
g) deprotecting compound of formula H and optionally isolating Intermediate I as its acid addition salt.

In another aspect, the Intermediate I is converted into Boceprevir of formula I.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides an improved process for preparing 3-amino-3-cyclobutylmethyl-2-hydroxypropionamide or an acid addition salt thereof of Intermediate I. It also provides a novel intermediate of formula E.
The schematic representation of the present invention has given in scheme 4.
Scheme-4 As used herein, R- refers to an alkyl group straight or branched CI-9 alkyl, includes methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, s-butyl, t-butyl.

L refers to a leaving groups known in the art includes, halides, sulphonate groups such as alkylsulphonates arylsulphonates.

P refers a protecting group known in the art includes Di t-Butyl dicarbamate (Boc), Benzyl carbamate, acetamide, trifiuoroacetamide, phthalimide, benzylchloride, benzoyl chloride, tritylamine, benzylideneamine, tosylamide, methoxyethxoxymethyl, tetrahydropyaranyl (THP), and tertiary butyl.
Halide refers to F, CI, Br and I.

In one aspect, the present invention provides a process for preparing 3-amino-3-cyclobutylmethyl-2-hydroxypropionamide or an acid addition salt thereof of Intermediate I comprising the steps of:

a) reacting a benzophenone imine compound of formula A with compound of formula B to give a compound of formula C,
b) protecting and hydrolyzing the compound of formula C to give a compound of formula D,
c) reacting the compound of formula D with a morpholine to give a compound of formula E,
d) reducing the compound of formula E to give a compound of formula F,
e) reacting the compound of formula F with a cyanohydrin compound to give a compound of formula G,
f) hydrolyzing compound of formula G to give compound of formula H,
g) deprotecting the compound of formula H and optionally isolating Intermediate I as its acid addition salt

R- alkyl group; L-Leaving group; P-Protecting group.

In one embodiment, a benzophenone imine compound of formula A is reacted with cyclobutyl methyl derivative of formula B to give amine compound of formula C in the presence of a suitable base and solvent. The suitable base is selected from metal hydroxide includes potassium hydroxide (KOH), sodium hydroxide (NaOH), metal carbonate includes sodium carbonate and potassium carbonate, preferably metal hydroxide potassium hydroxide; the suitable solvent is selected from polar aprotic solvent such as dimethyl sulfoxide (DMSO), dimethylacetamide, tetrahydrofuran (THF), acetone, dimethyl formamide (DMF) and acetonitrile; preferably DMSO. The reaction between compound of formula A and cyclobutyl methyl derivative of formula B can optionally be carried out in presence of a phase transfer catalyst such as tetrabutyl ammonium bromide (TBAB) and crown ethers to give amine compound of formula C.

In US 6992220 and US 20050249702, the reaction of a benzophenone imine compound of formula A with cyclobutyl methyl halide of formula B is carried out in presence of potassium tertiary butoxide, wherein in the present invention said reaction is performed in presence of alkaline metal hydroxide such as KOH which results into cost effective and less time cycled.

In another embodiment, the amine compound of formula C is protected with protecting group P by treating with a protecting agent in a suitable solvent includes hexane, diethyl ether and methylene chloride (MDC), preferably methylene chloride. The protection can be carried out by following the procedures as described in Theodora W. Greene and Peter G. M. Wuts, "Protecting Groups In Organic Synthesis," third edition, John Wiley and Sons, New York. N.Y.
In another embodiment, the amine protected compound of formula C is hydrolysed to obtain formula D by treating with a base and suitable solvent, wherein the suitable base is selected from alkaline metal hydroxide, preferably NaOH in a suitable solvent selected from polar solvents such as methanol, ethanol, isopropyl alcohol (IPA) and propanol, and butanol, preferably ethanol.

In one more embodiment, the acid compound of formula D is converted into a morpholine amide of formula E by treating formula D with a morpholine in presence of a suitable solvent and coupling agent. The suitable solvent includes methylene chloride (MDC), toluene, xylene and carbon tetrachloride (CCI4), preferably methylene chloride. The suitable coupling agent includes l-ethyI-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride (EDC.HC1), N,N'-Dicyclohexylcarbodiimide (DCC), 1,1'-

Carbonyldiimidazole (CDI). The said reaction is optionally carried out in presence of an activator like 1-hydroxybenzotraizole.

Compound of formula E can also be prepared by reacting alkylchloroformates such as ethylchloroformate, isobutylchloroformate with a compound of formula D followed by a morpholine. Alternatively compound of formula E can also be prepared directly from amino protected compound of formula C by reacting with a morpholine.

In another embodiment of the present invention, formula E is also prepared by converting compound of formula D to its acid halide derivative such as acid chloride and further reacting with a morpholine to yield compound of formula E.
In another embodiment, the morpholine amide compound of formula E is reduced into aldehyde compound of formula F by treating formula E with suitable reducing agent and suitable solvent, wherein the suitable reducing agent includes lithium aluminium hydride (LAH), diisobutylaluminum hydride (DIBAL-H) and sodium bis(2-methoxyethoxy) aluminumhydride (vitride). The suitable solvent includes ether solvents such as toluene, tetrahydrofuran (THF), diethyl ether.

In comparison with the prior art processes, the present invention provides a novel and simple process by replacing compound of formula J with the morpholine amide of formula E and further it is successfully established the reduction of compound of Formula J into corresponding aldehyde in process of preparing Intermediate I by employing commercially feasible reagent such as vitride solution instead of hazardous metallic hydride such as Lithium aluminium hydride.
In one more embodiment, the aldehyde compound of formula F is reacted with a cyanohydrin compound in presence of a suitable base and suitable solvent such as toluene, dichloromethane to obtain cyano compound of formula G. The cyanohydrin compound for the reaction is selected from ketone cyanohydrin, preferably acetone cyanohydrin. The base is selected from diisopropyl ethyl amine, dimethylamine, triethyl amine (TEA), trimethyl amine, methylamine, ethanolamine, triphenylamine, pyridine and piperidine, preferably TEA.

Yet in another embodiment, the cyanohydrin compound of formula G is hydrolyzed with a base in a suitable solvent such as DMSO and in presence H2O2 to obtain amide compound of formula H, wherein the base is selected from potassium carbonate, sodium carbonate, preferably potassium carbonate.
In one embodiment, the cyanohydrin compound of formula G is converted into Intermediate I or an acid addition salt thereof as per the process disclosed in US 20050249702 depicted in scheme 3.

In one embodiment, the amide compound of formula H is deprotected by treating with an acid in suitable solvent to give Intermediate I or an acid addition salt thereof. The acid is selected from hydrochloric acid (HC1), hydrobromic acid (HBr), sulfuric acid (H2S04), trifluoro acetic acid (TFA), phosphoric acid (H3PO4), paratoluene sulfonic acid (pTSA) and the like, preferably HC1. The suitable solvent is selected from polar solvents such as methanol, ethanol, n-propanol, isopropyl alcohol (IPA) and butanol preferably IPA.

Yet another embodiment, the amide compound of formula H is converted into Intermediate I by the conventional methods.

In another aspect, present invention provides an improved process for preparing an aldehyde compound of formula F by reducing compound of formula J as represented in scheme 5.

In US 20050249702 the conversion of compound of formula J into aldehyde compound of formula F is carried out by employing LAH. Present invention provides conversion of compound of formula J into aldehyde compound of formula F by substituting hazardous reducing agents like LAH with vitride solution to offer a commercially viable process.

According to the present invention, the reduction of the compound of formula J into compound of formula F is carried out by treating compound of formula J with sodium bis(2-methoxyethoxy)aluminumhydride (Vitride) in a suitable solvent selected from polar aprotic solvent includes, tetrahydrofuran (THF); preferably THF.

In another aspect, the present invention provides novel intermediate of formula E.
In one embodiment, the novel morpholine compound of formula E is converted into Boceprevir of formula I.

In one more embodiment, the aldehyde compound of formula J is further converted into Boceprevir by the conventional methods.

In another embodiment, the Intermediate I is converted into Boceprevir of formula I as per the process disclosed in US 7012066, US 20050249702, WO 2008079216 and WO2002008244.

The following non-limiting examples illustrate specific embodiments of the present invention. The examples are not intended to be limiting the scope of present invention in any way.

Examples:

Example -1: Synthesis of Benzophenone imine

129.8 g of Benzophenone, 50 g of glycine ethyl ester hydrochloride (0.5 moles), 3.38 g of j9-toluenesulfonic acid (0.05 moles) and 205 ml toluene were taken in to RBF equipped with dean-stark apparatus. To the reaction mixture was added 96.59 g ofNJJ-diisopropyl ethyl amine and was heated to 110-119 °C and maintained at same temperature with stirring for six hours. During the reaction, water was removed from the reaction azeotropically. After completion of the reaction, the reaction mixture was cooled to 20 °C and the reaction mixture was washed with water and layers were separated. The organic layer was concentrated under reduced pressure to get the product as an oily residue (169 g).

Example -2: Preparation of formula C (R = ethyl)

(N-diphenylmethylene)glycine ethyl ester (17.9 g, Example 1) was dissolved in 50 ml of DMSO and cooled to 0 °C. To this 11.27 g of potassium hydroxide was added and stirred for 10 min. To the reaction mixture 10 g of Cyclobutyl methyl bromide (Formula B-Leaving group is halide, preferably Br) was added at 0 °C and continued stirring for one hour at 0 °C. After completion of the reaction, toluene was added to the reaction mass and filtered through Hyflo bed. Water was added to the filtrate and extracted with toluene. The organic layers were combined and washed with brine solution; dried over anhydrous Na2SC>4 and concentrated under reduced pressure to get oily residue. The resulting oily residue was dissolved in diisopropyl ether and added 50%

aqueous HC1 solution. The reaction mass was maintained at room temperature with stirring for 3 hours. Separated the aqueous layer from reaction mass and neutralized with aqueous sodium carbonate solution. Extracted the product with dichloromethane and concentrated under reduced pressure to get product as an oily mass (7 g).
Example-3: Preparation of formula D (P = Boc)
To a solution of amine (7 g, Example-2) in 70 ml of dichloromethane, 9.39 g of ditert-butyl dicarbonate was added at 0 °C. The reaction mixture was stirred for 12 hrs at room temperature. After completion of the reaction, reaction mixture was concentrated under reduced pressure to get an oily residue. The oily residue was dissolved in 10 ml of methanol/ethanol and treated with sodium hydroxide solution (3g in 20 ml of water) and stirred for 3 hrs at room temperature. After completion of reaction, reaction mass was concentrated under reduced pressure and water was added and stirred for 10 min. The reaction mixture was cooled to 10-15 °C and pH was adjusted to 1-2 by using IN HC1 solution. The product was extracted with dichloromethane. The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to get the product as an oily mass (8 g).
Example-4: Preparation of formula E (P = Boc)
To a solution of BOC-acid (8 g, example-3) in 80 ml of dichloromethane, 5.18 g of 1-Hydroxybenzotraizole and 10 ml of morpholine were added under nitrogen atmosphere. To the above reaction mixture 7.56 g of l-ethyl-3-(3-

dimethylaminopropyl)carbodiimide) hydrochloride (EDC.HC1) was added and stirred for 4 hrs. After completion of reaction, reaction mixture was filtered and washed with dichloromethane. The filtrate was washed with 10% aqueous HC1 solution and separated the organic layer. The organic layer was washed with 5% sodium bicarbonate solution followed by brine solution. The organic layer was dried over Na2S04 and concentrated under reduced pressure to obtain 6 g product as solid.
ExampIe-5: Preparation of formula E (P = Boc):
To a solution of BOC-acid (10 g, example-3) in 100 ml of dichloromethane was added Triethylamine (13.74 gm) at -15 °C. Then added 5.95 gm of Pivaloyl chloride and stirred for one hour at -15 °C under nitrogen atmosphere. 4.47 gm of Morpholine was added to the above reaction mass at -15 °C and stirred for one hour. After completion of reaction, water was added and separated the layers. Organic layer washed with 10% aqueous HC1 solution followed by 5% Sodium bicarbonate solution. Finally washed the organic layer with brine solution and dried over Na2SC>4. Concentrated the organic layer under reduced pressure and recrystallized using hexane/heptane to get 11 gm product as white solid.
Example -6: Preparation of formula F (P = Boc).
A solution of morpholine-amide (3 g, Example-4) in 30 ml of Toluene was cooled to 0 °C and Vitride solution (8.3 ml, 70% solution in toluene) was added drop wise. The reaction mixture was slowly heated to room temperature and stirred for 3 hours. After

completion of the reaction, reaction mixture was cooled to 0-5 °C and quenched with aqueous ammonium chloride followed by 10% aqueous HC1 solution. Organic layer was separated and aqueous layer is extracted with toluene. The combined organic layers were washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to get the product as an oily mass (2.4 g).

Example-7: Preparation of formula J (P = Boc, R = ethyl)

To a solution of 5 g of BOC-acid (Example-3) in 100 ml of dichloromethane, 3.3 g of 1-Hydroxybenzotraizole, 9.11 ml of diisopropyl ethyl amine and 3 g of N,0-dimethylhydroxylamine hydrochloride were added under nitrogen atmosphere. To the reaction mixture 4.72 g of EDC.HC1 was added and stirred for 12 hrs. After completion of reaction, 100 ml of 20% aqueous HC1 solution was added, stirred and the layers were separated. Aqueous layer was extracted with dichloromethane and the organic layers were combined and were washed with saturated sodium bicarbonate solution, followed by brine solution. The organic layer was dried over Na2SC>4 and concentrated under reduced pressure to get 5 g of product as white solid.

Example-8: Preparation of formula F (P = Boc)

2 g of solution of compound of formula J (Example-6) in 20 ml of tetrahydrofuran was cooled to 0 °C and vitride solution (6.05 ml, 70% solution in toluene) was added drop wise. The reaction mixture was slowly heated to room temperature and stirred for 3 hours. After completion of reaction, the reaction mixture was cooled to 0-5 °C and quenched with ice water followed by 10% aqueous HC1 solution. Then, to the reaction mixture dichloromethane was added and filtered through hyflow bed and washed with dichloromethane. The layers were separated and aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine solution, dried over Na2SC>4 and concentrated under reduced pressure to get the product as an oily mass (1-5 g).

Exampl-9: Preparation of formula G (P = Boc)

To the 1 g solution of BOC-aldehyde (formula F- P is Boc) in 10 ml of toluene 1.5 g of acetone cyanohydrin and triethylamine (1.22 ml) were added and stirred for 24 h at room temperature. After completion of the reaction, 20 ml of 10% aqueous HC1 solution were added and stirred. The layers were separated and the aqueous layer was extracted with toluene and organic layers were combined. The combined organic layers were washed with water followed by brine solution, dried over Na2S04 and concentrated under reduced pressure to get the product as an oily mass (1 g).

Example-10: Preparation of formula H (P = Boc)

To the 1 g solution of BOC-cyano alcohol (Example-8) in 5 ml of DMSO 0.5 g of potassium carbonate was added and heated to 40-45 °C. To the reaction mixture 2 ml of 35% H2O2 solution was added drop wise over one hour and stirred at same temperature for 4 h. After completion of the reaction 15 ml of water was added and cooled to 0 °C and continued stirring for 5 h at same temperature. The reaction mixture was filtered. The obtained solid was washed with water and dried at 50-55 °C for 6 h give 0.4 g of product.

Example 11: Preparation of Intermediate I.

To the 0.5 g solution of BOC-hydroxy amide (Example-9) in 3 ml isopropyl alcohol IPA.HC1 solution (2 ml, 9% w/w) was added. The reaction mass temperature was heated to 40-45 °C and continued stirring for 6 hours. The reaction mass temperature was cooled to 0-5 °C and stirred for one hour. Filtered the obtained solid and dried at 60-65 °C for 6 hours to give 0.3 g of compound.

We Claim:

1. A process for preparing intermediate compound of formula I comprising the steps of:

b) reacting the compound of formula F with a cyanohydrin compound to give a compound of formula G,
c) hydrolyzing the compound of formula G to give a compound of formula H,
d) deprotecting the compound of formula H and optionally isolating Intermediate I as its acid addition salt R- alkyl group; L-Leaving group; P-Protecting group.

2. The process according to the claim 1, wherein the reducing step is carried out with a reducing agent selected from lithium aluminium hydride (LAH), diisobutylaluminum hydride (DIBAL-H) and sodium bis(2-methoxyethoxy) aluminumhydride (vitride).

3. The process according to the claim 1, wherein the compound of formula F is reacted with cyanohydrin in presence of a base and a solvent.

4. The process according to the claim 3, wherein the suitable base is selected from diisopropyl ethyl amine, dimethylamine, triethyl amine (TEA), trimethyl amine, methylamine, ethanolamine, triphenylamine, pyridine and piperidine and the like.

5. The process according to the claim 1, wherein the compound of formula G is hydrolyzed in presence of a base.

6. The process according to the claim 5, wherein the base is selected from potassium carbonate, sodium carbonate and the like.

7. The process according to the claim 1, wherein the compound of formula H is optionally deprotected by treating with an acid and a suitable solvent.

8. The process according to the claim 7, wherein the suitable acid is selected from hydrochloric acid (HC1), hydrobromic acid (HBr), sulfuric acid (H2SO4), trifluoro acetic acid (TFA), phosphoric acid (H3PO4), paratoluene sulfonic acid (pTSA) and the like.

9. The process according to the claim 1, wherein the compound of formula E is prepared comprising the steps of:

a) reacting a benzophenone imine compound of formula A with compound of formula B to give compound of formula C,
R- alkyl group ; L-Leaving group;
b) protecting and hydrolyzing the compound of formula C to give a compound of formula D,
c) reacting the compound of formula D with a morpholine to give the compound of formula E,

10. A process for preparing compound of formula F comprising reducing formula J with sodium bis(2-methoxyethoxy)aluminumhydride (Vitride) in a suitable solvent.

11. The process according to the claim 10, wherein the suitable solvent is tetrahydrofuran.

12. A Compound of formula E.

13. The use of compound of claim 12, in the preparation of Intermediate I.

14. The use of compound of claim 12, in the preparation of Boceprevir.

15. The process according to the proceeding claims, wherein the compound of formula I is further converted into Boceprevir.