DESC:FIELD OF THE INVENTION
The present invention relates to novel 3-oxobutanenitrile derivatives and processes for their preparation.

BACKGROUND OF THE INVENTION
Polycyclic carbamoylpyridone derivatives having HIV integrase inhibitory activity are described in PCT application WO 2006/116764.

Dolutegravir (I) and cabotegravir (II) are polycyclic carbamoylpyridone derivatives. Dolutegravir (I) is used against HIV infections as a single drug or fixed-dose combination with abacavir sulphate and lamivudine under the trade names Tivicay® and Triumeq® respectively. These commercial products contain dolutegravir as its sodium salt. It is chemically known as (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate having chemical structure of formula I.

Cabotegravir (II) is in phase II clinical trials and is chemically known as (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo-[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide having following chemical structure of formula II.

I II

SUMMARY OF THE INVENTION
The present invention provides 2-aminomethylene-3-oxobutanenitrile compounds of formula III
III
wherein,
P is hydroxy protecting group;
R1 is –CHO, –CH(OR2)(OR3), –CH(OH)CH2OH or–CH=CH2;
R2 and R3 are H or lower alkyl;
and
a wavy line means E form, Z form or a mixture thereof.

The present invention provides a process for the preparation of compound of formula III
III
wherein,
P and R1 are as defined above;
comprising:
reacting 3-oxobutanenitrile compound of formula IV
IV
wherein,
P is as defined above;
R4 is -N(R5)2, or –OR5;
R5 is lower alkyl;
and
a wavy line means E form, Z form or a mixture thereof;
with a compound of formula V
V
wherein,
R1 is as defined above.

The present invention further provides3-oxobutanenitrile compound of formulaIV
IV
wherein,
P and R4 are as defined above.

The present invention further provides a process for the preparation of compound of formulaIV
IV
wherein,
P and R4 are as defined above
comprising
reacting a compound of formula VI
VI
wherein,
P is as defined above
with a compound of formula VII
VII
wherein,
R4 is as defined above;
R6is lower alkyl.

The present invention further relates to the use of compound of formula III and IVfor the synthesis of carbamoylpyridone derivatives such as dolutegravir and cabotegravir.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel 3-oxobutanenitrile derivatives and processes for their preparation. These 3-oxobutanenitrile derivatives are important novel intermediates for the synthesis of HIV integrase inhibitors such as dolutegravir and cabotegravir.

Hereinafter, the terms used in the present specification are described.

Hydroxy protecting groupmay be selected from groups known to those skilled in the art, including protecting groups disclosed in Greene, Theodora W.; Wuts, Peter G. M. Protective Groups in Organic Synthesis. 3rd Ed. (1999).

Examples of a hydroxy protecting group (P) include lower alkyl, aralkyl (e.g. benzyl), acyl (e.g. acetyl, pivaloyl, benzoyl), alkoxyalkyl (e.g. methoxymethyl, methoxyethyl), lower alkylsulfonyl (e.g. methanesulfonyl), arylsulfonyl (e.g. benzenesulfonyl, toluenesulfonyl), alkoxycarbonyl (e.g. methoxycarbonyl) and the like.

The term "lower alkyl" encompasses linear or branched alkyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, most preferably 1 or 2 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl. Examples of preferred embodiments of "lower alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Examples of more preferred embodiments thereof include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

The production method of the present invention is described below.

Step A
This step involves reacting compound of formula VI with compound of formula VII to obtain a compound of formula IV, as shown below

wherein each symbol is as defined above.

The compound of formula VI and VIImay be commercially available reagent or can be obtained by a methods known in the literature.

The reaction solvent used in step A is preferably an aprotic solvent. Examples thereof include toluene,acetonitrile, tetrahydrofuran, dioxane, diethyl ether, dichloromethane, chloroform, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylimidazolidinone, and mixed solvents thereof.

The amount of the compound VII used is approximately 1.0 to 3.0 molar equivalents with respect to compound VI.

The reaction temperature is usually 0° C to reflux temperature, preferably room temperature.

The reaction time is usually 30 minutes to 50 hours, preferably 2 to 8 hours.

The compound IV may be isolated by a general purification method (extraction, distillation, column chromatography, crystallization, etc.) or can also be used in the next reaction without being isolated.

Step B
This step involves reacting compound of formula IV with compound of formula V to obtain a compound of formula III, as shown below

wherein each symbol is as defined above.

The compound of formula Vmay be commercially available reagent or can be obtained by a methods known in the literature.

The reaction solvent used in step Bis selected from the group consisting of hydrocarbons,alcohols, ethers, amides and mixtures thereof; preferably toluene,methanol, tetrahydrofuran, dimethyl formamide and mixtures thereof; more preferably toluene, dimethyl formamide and mixtures thereof.

The amount of the compound V used is approximately 1.0 to 3.0 molar equivalents with respect to compound IV.

The reaction temperature is usually 0° C to reflux temperature, preferably room temperature.

The reaction time is usually 30 minutes to 50 hours, preferably 1 to 8 hours.

The compound III may be isolated by a general purification method (extraction, distillation, column chromatography, crystallization, etc.).

The present invention is described in the following examples, however it should be noted that the scope of present invention is not limited by the examples.

Experimental
Example 1
Preparation of 4-(benzoyloxy)-2-[(dimethylamino)methylene]-3-oxobutanenitrile [IVa: P = -CH2Ph; R4 = -N(CH3)2]
4-(benzoyloxy)-3-oxobutanenitrile (VI: P = CH2Ph; 2 g, 0.01 mol) was dissolved in toluene (20 ml). N,N-dimethylformamide dimethyl acetal (3.1 g, 0.026 mol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was poured in water (20 ml) and the organic layer was separated. The organic layer was washed with 5 % HCl solution and water in this order. The solvent was distilled off and the obtained oil was purified by silica gel column chromatography (20 % ethyl acetate in hexane) to obtain IVa (0.2 g) as solid.
IR (in KBr) cm-1: 3011, 2956, 2923, 2857, 2815, 2193, 1731, 1676, 1608, 1497, 1466, 1456, 1427, 1397, 1367, 1351, 1306, 1268, 1202, 1178, 1143, 1057, 1041, 1025, 989, 856, 798, 738, 695.
1HNMR (CDCl3) d:3.25 (3H, s), 3.39 (3H, s), 4.45 (2H, s), 4.64 (2H, s), 7.26-7.39 (5H, m), 7.87 (1H, s).
Mass (m/z): 245.1 (M+1)+, 267.2 (M+Na)+.

Example 2
Preparation of 4-(benzoyloxy)-2-{[(2,2-dimethoxyethyl)amino]methylene}-3-oxobutanenitrile [IIIa: P = CH2Ph; R1 = –CH(OR2)(OR3); R2 = R3 = CH3]
Compound IVa (0.5 g, 0.002 mol) was dissolved in toluene (5 ml). Aminoacetaldehyde dimethylacetal (0.43 g, 0.004 mol) was added at 0-5 °C. The mixture was stirred at room temperature for 2 hours. The mixture was poured in water (10 ml) and extracted with ethyl acetate (15 ml). The organic layer was washed with water followed by brine solution. The solvent was distilled off to get IIIa (0.3 g) as oil.
1HNMR (CDCl3) d:3.37 (2H, d), 3.39-3.42 (6H, s), 4.37 (1H, m), 4.38 (2H, s), 4.64 (2H, s), 7.28-7.40 (6H, m).
Mass (m/z): 305.2 (M+1)+, 303.1(M-1)+.
,CLAIMS:1. A compound of formula III
III
wherein,
P is hydroxy protecting group;
R1 is –CHO, –CH(OR2)(OR3), –CH(OH)CH2OH or –CH=CH2;
R2 and R3 are H or lower alkyl;
and
a wavy line means E form, Z form or a mixture thereof.
2. A process for the preparation of compound of formula III
III
wherein,
P is hydroxy protecting group;
R1 is –CHO, –CH(OR2)(OR3), –CH(OH)CH2OH or –CH=CH2;
R2 and R3 are H or lower alkyl;
comprising:
reacting 3-oxobutanenitrile compound of formula IV
IV
wherein,
P is as defined above;
R4 is -N(R5)2, or –OR5;
R5 is lower alkyl;
and
a wavy line means E form, Z form or a mixture thereof;
with a compound of formula V
V
wherein,
R1 is as defined above.
3. The process as claimed in claim 2 wherein, the reaction solvent is selected from toluene, methanol, tetrahydrofuran, dimethyl formamide and mixtures thereof.
4. The process as claimed in claim 2 wherein, the amount of the compound V is approximately 1.0 to 3.0 molar equivalents with respect to compound IV.
5. A compound of formula IV
IV
wherein,
P is hydroxy protecting group;
R4 is -N(R5)2, or –OR5;
R5 is lower alkyl;
6. A process for the preparation of compound of formula IV
IV
wherein,
P is hydroxy protecting group;
R4 is -N(R5)2, or –OR5;
R5 is lower alkyl;
comprising
reacting a compound of formula VI
VI
wherein,
P is as defined above
with a compound of formula VII
VII
wherein,
R4 is as defined above;
R6 is lower alkyl.
7. The process as claimed in claim 6 wherein, the reaction solvent is selected from toluene, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, dichloromethane, chloroform, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylimidazolidinone and mixed solvents thereof.
8. The process as claimed in claim 6 wherein, the amount of the compound VII is 1.0 to 3.0 molar equivalents with respect to compound VI.
9. Use of compound of formula III and IV for the synthesis of dolutegravir.