Field of Invention :
The present invention relates to an improved process for the preparation of methyl 5-((2,4-difluorobenzyl)carbamoyl)-l-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-l,4-dihydropyridine-2-carboxylate, a key intermediate for the synthesis of commercially useful HIV Integrase inhibitors

Background of the Invention :
Polycyclic carbamoyl pyridone derivatives such as Dolutegravir and Cabotegravir are emerging as important therapeutics in treating Human immunodeficiency virus (HIV) infection. They act by inhibiting the HIV integrase, a key enzyme mediating the integration of viral DNA into the host cell genome. Dolutegravir was approved for the treatment of HIV infection by US FDA in 2013. Cabotegravir is an investigational new drug under development.

A key intermediate in the synthesis of carbamoyl pyridone derivatives such as Cabotegravir (XIHa), and Dolutegravir (XIHb) is the methyl 5-((2,4-difluorobenzyl)carbamoyl)-l-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (I).

The preparation of (I) described in the prior art involves selective hydrolysis of diester (II) to obtain a mono carboxylicacid (III), followed by condensation with 2,4-difluorobenzylamine (IV) using a suitable condensing agent (Scheme 1).

Hydrolysis of (II) at C-5 ester using lithium hydroxide is described in US 9,120,817 and in Organic Letters20\5, 17, 564-567. Although, use of lithium hydroxide resulted in selective hydrolysis of C-5 ester, about 10% hydrolysis of C-2 ester was also observed. When sodium hydroxide or potassium hydroxide was used the selectivity was much lower (Organic Letters.20\5, 17, 564-567).

The condensation of free carboxylic acid (III) with 2,4-difluorobenzylamine using a coupling agent is also reported. The use of 2-(l H-7-Azabenzotriazol-l-yl)-1,1,3,3-tetramethyl uronium hexafluoro phosphate (HATU) or l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) as coupling agent is described in WO 2014/100323 and alky I chloro formates such as ethyl chloro formate or isobutyl chloro formate in WO 2015177537A1 and in Organic Letters.20\5, 17, 564-567.

The preparation of the starting compound (II) by condensing methyl 4-methoxy acetoacetate with dimethyl formamide dimethyl acetal (DMF.DMA), followed by reaction with amino acetaldehyde dimethyl acetal and cyclization with dimethyl oxalate in the presence of a base is described in Organic Letters,2015, 17, 564-567 (Scheme 2).

A simple and less expensive alternative process for compound (I), a key intermediate for several carbamoyl pyridone derivatives useful as HIV integrase inhibitors, is desirable.

Summary of the Invention :
The literature method for the preparation of (I) involves coupling of the monocarboxylic acid (III) with the difluorobenzyl amine (IV). The required monocarboxylic acid (III) is obtained by selective hydrolysis of C-5 ester of the diester (II). Selective hydrolysis is difficult and achieved only by using lithium hydroxide. An alternative new route for the preparation of (III) was envisaged through a benzyl ester (V), followed by debenzylation by hydrogenation (Scheme 3). A scheme was designed to prepare benzyl ester (V) from benzyl 4-methoxyacetoacetate (VI) (Scheme 4): Although the scheme 4 proceeded smoothly up to. the intermediate (X), its reaction with dimethyl oxalate did not result in the benzyl ester (V). Surprisingly a trans-esterification was observed resulting in the dimethyl ester (II). The reaction of benzyl vinylogousamide (X) with dimethyl oxalate offers a new process for the preparation of the diester (II). Furthermore, interestingly the diester (II) on reacting with benzyl alcohol, underwent selective. transesterification at C-5, to give the expected benzyl ester (V). The benzyl ester (V) on hydrogenation resulted in the desired mono acid (III). Thus the benzyl ester (V) offers a new process for the preparation of the monoacid (III). The facile manner in which the diester (II) underwent selective trans-esterification with benzyl alcohol, prompted us to study direct amidation of (II) with 2,4-difluorobenzyl amine (IV). It was a pleasant surprise to find that, indeed (II) underwent direct amidation with (IV) to give the crucial intermediate (I) (Scheme 5). Thus, another aspect of the present invention is the development of a novel process for the preparation of (I) directly in one step from (II) without the need for any selective hydrolysis and coupling agent.

Detailed Description of the Invention :
The present invention provides a novel process for the preparation of the carbamoyl pyridine compound of formula (I): The diester (II) is prepared by reacting the vinylogousamide (X) with dimethyl oxalate, and the vinylogousamide (X) itself is prepared from benzyl 4-methoxyacetoacetate (VI) (Scheme 4).The preparation of the starting compound, benzyl 4-methoxyacetoacetate (VI) from ethyl 4-chloro acetoacetate is described in US 6,855,716. It is reacted with dimethyl formamide dimethyl acetal (DMF.DMA) in 1,4-dioxane at room temperature to obtain (VIII) in good yield and purity. The compound (VIII) reacts with amino acetaldehyde dimethyl acetal (IX) at about 0°C to give the vinylogous amide (X). The reaction of (X) with dimethyl oxalate in methanol using sodium methoxide as base resulted in the diester (II). The 'methyl' source for the trans esterification of the benzyl to methyl ester is likely to be from dimethyl oxalate. When sodium methoxide is replaced with potassium tert-butoxide or sodium hydride, the same diester (II) is obtained eliminating the possibility of sodium methoxide contributing the methyl group. Other bases such as triethyl amine, DIPEA, pyridine, give poor yield. Similarly, methanol as solvent seems to play

an important role. Very little product is obtained when other solvents such as ethanol, isopropanol and dimethyl formamide are used.

The diester (II) reacts with benzyl alcohol in toluene at reflux temperature and gives the benzyl ester (V)." The crude benzyl ester (V) dissolved in methanol undergoes deprotection on hydrogenation using Pd/C at room temperature to give the mono acid (III) as solid in high purity. The compound (III) can be converted to (I) by reacting with 2,4-difluorobenzylamine (IV) in the presence of a coupling agent such as alkyl chloro formate to give (I) as known in prior art. The diester (II) also reacts with 2,4-difluorobenzylamine (IV) and undergoes amidation to give (I). The reaction can be conducted neat without any solvent or in solvent such as toluene at room temperature. The obtained solid (I) shows high purity.

In some of the reactions, especially involving benzyl alcohol, the purity is low because of the presence of benzyl alcohol. Higher purity can be obtained if the benzyl alcohol is removed from intermediates such as (V). However, it is economical to take the crude product for further reaction without purification as the final product (I) is anyhow obtained in pure form.
Another aspect of the invention is the significant cost advantage in preparing (I) or (II) or (III) compared to prior art methods. It is mainly because of the starting compound for the present invention (VI), which is prepared from ethyl 4-chloro acetoacetate while prior art methods use methyl 4-methoxy acetoacetate. The price of ethyl 4-chloro acetoacetate according to Sigma-Aldrich (2016) Catalog is Rs.1644 for 50.0g (about $'24.9/50 g), whereas methyl 4-methoxy acetoacetate price is Rs. 12892 for 25.0 g (about $ 195.3/25 g). The commercial price of ethyl 4-chloro acetoacetate is Rs. 450/kg (about $ 6.84/kg) and that of methyl 4-methoxy acetoacetate is Rs. 6200/kg (about $ 93.94/kg).

Another aspect of the invention is the conversion of (I) to either Cabotegravir or Dolutegravir by known methods as in Scheme 6: Preparation of Cabotegravir from (I) is described in the Organic Letters, 2015, 17, 564-567. The acetal deprotection is carried out by reacting the acetal amide (I) with formic acid at 60° C for 3 hours to obtain the aldehyde (XI). The aldehyde (XI) underwent smooth ring closure with (2S)-2-amino-l-propanol (alaninol) in the presence of magnesium triflate resulting in the oxazolidine derivative (Xlla). After the ring closure, addition of sodium bromide resulted in demethylation of the methoxy group to give Cabotegravir (XHIa).

Similarly, reaction of the aldehyde (XI) with (3 R)-3-amino-l-butanol gives the cyclized product (XHb). Demethylation of (Xllb) gives Dolutegravir (XHIb). The US patent 9,120,817 describes . demethylation of (XHb) using magnesium halide or lithium halide to obtain Dolutegravir. The US patent 9,321,789 describes the use of trimethylsilyl iodide or boron trifluoride diethyl etherate for the demethylation of (Xllb) to obtain Dolutegravir (XIHb).
The embodiments of the present invention are illustrated in the following examples, which are not intended in any way to limit the scope of the invention. One skilled in the art can modify the details to suit the inputs and desired outcomes without affecting the present invention.

EXAMPLES:
Example-l: Preparation of benzyl (Z)-2-((dimethyIamino) methyIene)-4-methoxy-3-oxobutanoate (VIII): Benzyl 4-methoxy-3-oxobutanoate (VI) (25.0 gm, 0.112 mole) was dissolved in 45.0 mL 1,4-dioxane. DMF-DMA (VII) (26.8 gm, 0.225 mole) was added dropwise at 0°C. Reaction mixture was stirred for 4 hrs at room temperature. Evaporation of reaction mixture under reduced pressure at 45-50°C resulted in benzyl (Z)-2-((dimethyl aminq)methylene)-4-methoxy-3-oxobutanoate (VIII) (31.0 gm, yield: 99.3%, GC :94.1%). IR (NaCl):3480.97, 2930.43, 2820.85, 1655.38, 1586.19, 1423.09, 1385.99, 1280.77, 1195.77, 1113.84, 1039.83,970.86,929.63,845.10,755.44, 700.14, 658.48 Cm"1; ]HNMR:(300MHz,CDCb), 57.76 (s, 1H), 7.40-.26(m,5H), 5.19-5.18(s,2H), 4.37(s,2H), 3.36(s,3H), 3.21(br.s,3H), 2.98(br.s,3H); ,3CNMR:(300MHz,CDCI3) 5194.10, 167.14, 158.43, 136.37, 128.50, 128.29, 128.08, 127.84,99.26,77.45,65.88,58.86,47.73,42.54:

Example-2: Preparation of benzyl (E)- 2-((2, 2-dimethoxyethyl) amino) methylene)-4-methoxy-3-oxobutanoate (X): Benzyl (Z)-2-((dimethyl amino) methylene)-4-methoxy-3-oxobutanoate (VIII) (31.0 gm, 0.111 mole) was dissolved in 100.0 mL methanol at room temperature. Amino acetaldehyde dimethyl acetal (IX) (12.6 gm, 0.120 mole) was added dropwise at 0°C and stirred for 90 min at 0°C. Evaporation of reaction mixture under reduced pressure at 45-50°C resulted in benzyl (E)-2-((2, 2-dimethoxyethyI)amino)methylene)-4-methoxy-3-oxobutanoate (X) (36.1 gm, yield:95.8%, HPLC: 87.6%). IR (NaCl): 3487.25, 3209.74, 2999.76, 2939.17, 2834.36, 1694.64, 1645.94, 1592.76, 1497.42, 1448.43, 1424.90, 1374.37, 1301.16, 1265.16, 1239.74, 1.199.24, 1112.04, 1076.14, 1045.49, 974.77, '931.61, 803.70, 753.15, 699.04, 665.43 Cm"1; 1 HNMR:(300MHz,CDCl3), 511.0(br.s, 1H), 8.01 -7.96(d, 1H), 7.40-7.30(m,5H), 5.17(s,2H), 4.58(s,2H),4.42-4.38(1,1 H),3.48(s,3H),3.42(s,6H),3.44-3.38(m,2H); l3CNMR:(300MHz,CDCl3) 5196.92, 166.24, 160.96,136.8,128.52, 128.08, 102.69,98.2,65.42, 59.07,54.82,51.73.

Example-3: Preparation of dimethyl l-(2, 2-dimethoxyethyI)-3-methoxy-4-oxo-l, 4-dihydropyridine-2, 5-dicarboxylate (II): Benzyl (E)- 2-((2,2-dimethoxyethyl) amino) methylene)-4-methoxy-3-oxobutanoate(X) (25.0 gm, 0.074 mole) was dissolved in 250.0 mL methanol at room temperature. Dimethyl oxalate (32.3 gm, 0.273 mole) was added lot wise at room temperature, followed by addition of 28% NaOMe solution (57.2 gm,0.296 mole) dropwise at room temperature. Reaction mixture was stirred for 7 hrs at 50-55°C. Evaporation of reaction mixture under reduced pressure at 45-50°C resulted in brown colour semi solid. Ethyl acetate (200.0 mL) was added and stirred for 30 min at room temperature, filtered to remove the salts, filtrate evaporated under reduced pressure at 45-50°C and 100.0 mL ethyl acetate added. The above process was repeated to get brown colour crude. Diisopropyl ether (50.0 mL) was added, stirred for 20 min at room temperature and the diisopropyl ether layer decanted. The above process was repeated. Evaporation of the remaining crude under reduced pressure at 45-50°C resulted in dimethyl 1 -(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (II) (19.7 gm , yield: 81%, HPLC: 80%). IR(NaCl): 3455.62, 3016.68, 2954.45, 2938.99, 2846.96, 2401.39, 1732.32, 1699.25, 1625.79, 1604.99, 1543.27, 1494.89, 1435.88, 1345.39, 1315.86, 1253.98, 1216.40, 1193.98, 1155.93, 1125.90, 1090.79, 1034.89, 979.17, 924.10, 880.56, 846.29, 809.76, 767.84, 666.97Cm-'; lH NMR:(300 MHz, CDC13), 58.14(s,lH),4.52-4.48(t,lH), 3.98(s,6H), 3.94(d,2H), 3.90(s.3H), 3.40(s,6H); 13CNMR: (300MHz,CDCl3) 5171.04, 165.41, 162.38, 150.32, 146.05, 133.80, 118.28, 102.78,60.52,56.67, 55.78,53.31,52.24.

Example-4: Preparation of 5-benzyl 2-methyl l-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-l, 4-dihydropyridine-2,5-dicarboxylate (V):Dimethyl l-(2, 2-dimethoxyethyl)-3-methoxy-4-oxo-l, 4-dihydropyridine-2, 5-dicarboxylate (II) (3.0 gm, 0.009 mole) was dissolved in 30.0 mL toluene, followed by benzyl alcohol (1.0 gm,0.0092 mole) at room temperature. Reaction mixture was heated to reflux temperature and maintained for 2 hrs at reflux temperature. Evaporation of reaction mixture under reduced pressure at 65-70°C resulted in 5-benzyl 2-methyl l-(2, 2-dimethoxyethyl)-3-methoxy-4-oxo-l, 4-dihydropyridine-2, 5-dicarboxylate (V) (3.5 gm, yield: 95%, HPLC: 65%). The low purity by HPLC is because of the presence of dibenzyl ester and residual benzyl alcohol and the crude can be taken for the next reaction without further purification. IR (NaCI): 3018.63,1732.10,1625.96, 1452.81, 1309.26, 1253.99, 1215.92, 752.12, 667.85Cm-'; 'H NMR:(300 MHz, CDCb), 58.11(s,lH), 7.49-7.27(m.5H), 5.36(s,2H), 4.50-4.47(t,lH), 3.98(s,3H), 3.97(s,3H), 3.38(s,6H); l3CNMR:(300MHz,CDCI3): 5170.99, 164.21, 162.31, 150.10, 145.96, 133.92, 128.42, 127.92, 127.88, 118.18, 102.75, 66.39, 60.46, 56.48, 55.68, 53.23.

ExampIe-5: Preparation of l-(2, 2-dimethoxyethyI)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1, 4-dihydropyridine-3-carboxylic acid (III): 5-Benzyl-2-methyI-l-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-l-4-dihydropyridine-2,5-dicarboxylate (V) (8.6 gm, 0.0212 mole, 65% HPLC purity) was dissolved in 80.0 mL methanol at room temperature, followed by 0.6 gm of 5% Pd/C. Hydrogen gas was passed through reaction mixture for 1 hr at room temperature. Reaction mixture was filtered through hyflow bed, filtrate was evaporated under reduced pressure at 45-50°C to get pale orange crude. Crystallization from methanol and water resulted in pale brown solid of l-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l,4-dihydropyridine-3-carboxylic acid (III). (3.0 gm, yield:45%, HPLC:99.1%). IR (KBr): 3065.82, 2939.58, 2841.54, 1737.68, 1622.36,1533.05,1432.16, 1350.42, 1260.96, 1212.68, 1171.7, 1087.31, 977.77, 925.97, 851.50, 778.49, 709.33, 639.06, 587Cm-'; 'H NMR:(300 MHz, CDCI3), 68.39 (s,lH), 4.54-4.5 l(t,lH), 4.10-4.09(d,2H) , 4.028(s,3H), 4.02(s,3H), 3.41(s,6H); l3CNMR: (300MHz, CDCb) 5174.81, 165.82, 161.55, 148.65, 145.29, 136.42, 116.60, 102.29, 60.89, 57.26, 55.85, 53.64.

Example-6: Preparation of methyl 5-((2,4-difluorobenzyl)carbamoyl)-l-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-l,4-dihydropyridine-2-carboxylate (I) Dimethyl 1 -(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (II) . (5.0 gm, 0.015 mole) was dissolved in 2,4-difluorobenzyl amine (IV) (4.34 gm , 0.03 mole) and stirred for about 12 hrs at room temperature. Ethyl acetate (100.0 mL) was added to the reaction mixture. The.ethyl acetate layer was washed with water (100.0 mL X 3). The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum at 45-50°C to obtain a brown solid. On recrystallization from, MTBE, a white crystalline material is obtained (5.2 gm, Yield :78%, melting point: 118-119°C, HPLC: 98.8%) 'RNMRiQOO MHz, DMSO), 53.33(d,6H), 3.8 l(s, 3H), 3.93(s, 3H), 4.23(d, 2H), 4.53(t, 3H), 7.08(m, 1H), 7.28(m, 1H), 7.44(m, 1H), 8.5(s, 1H), 10.32(m, 1H); l3CNMR:(300 MHz, DMSO), 536.2, 53.9, 55.7, 56.1, 60.6, 102.7, 103.9, 104.2, 1.11.6, 111.7, 111.9, 118.7, 122.5,122.6, 122.7,122.8, 131.3, 131.4, 131.5, 135.7, 145.7, 148.5, 162.2, 163.6, 172.5, IR(KBr): 3742.85, 3456.15, 3069.74, 3054.79, 3016.22, 2988.78, 2937.11, 2845.52, 1888.78, 1737.13, 1671.34, 1619.01, 1550.82, 1534.59, 1503.33, 1442.07, 1350.50, 1337.82, 1298.19, 1256.56, 1169.00, 106901 Cm"1 : m/z(M+l): 441.15.

Example-7: Preparation of methyl 5-((2,4-difluorobenzyl)carbamoyl)-l-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-l,4-dihydropyridine-2-carboxylate (I) Dimethyl 1 -(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (II) (5.0 gm, 0.015 mole) was dissolved in 25.0 mL toluene. 2,4-difluoro benzyl amine (IV) (2.1 gm, 0.015 mole) and acetic acid (0.91 gm, 0.005 mole) were added and stirred at 90°C for about 12 hrs. The reaction mixture was washed with water (26.0 mL X 3). The toluene layer was dried over anhydrous sodium sulphate and concentrated under vacuum at 45-50°C to obtain a light brown solid. On recrystallization from, MTBE, a white crystalline material is obtained.5.8 gm, Yield :88%, HPLC 99.1% , melting point: 119-120°C.

I. A process for preparing the carbamoyl pyridone of the formula (I):
a) reacting the diester of the formula (II):
with benzyl alcohol to obtain the monobenzyl ester of the formula (V):
b) converting the benzyl ester (V) to a monoacid of the formula (III) and
c.) reacting the mdnoacid (III) with 2,4-difluorobenzylamine of the formula (IV):

2. The process according to claim 1, wherein at step (a) the diester (II):

3. The process according to claim I, wherein at step (a) the diester (II) is prepared by reacting the vinylogousamide of the formula (X):

4. The process according to claim 3, wherein the vinylogousamide (X) is prepared by a process comprising:

a) reacting benzyl-4-methoxyacetoacetate of the formula (VI):
b) reacting the compound (VIII) with aminoacetaldehyde dimethyl acetal (IX):

5. A monobenzyl ester compound having the structure shown in formula (V)

6. A process for the preparation of the monobenzyl ester compound according to claim 5 by reacting the dimethyl ester of the formula (II)

7. A vinylogousamide compound having the structure shown in the formula (X)

8. A process for preparing the mono benzyl ester having the structure shown in formula (V) comprising:
a) reacting benzyl-4-methoxyacetoacetate of the formula (VI):
with DMF.DMA of the formula (VII):
to obtain the compound of the formula (VIII):
b) reacting the compound (VIII) with amino acetaldehyde dimethyl acetal (IX):

9. A process for the preparation of Cabotegravir having the formula (XHIa), or Dolutegravir having the formula (XHIb) using the carbamoyl pyridone of formula (I), prepared from a process according to claim 1.

10. A process for the preparation of Cabotegravir having the formula (XHIa), or Dolutegravir having the formula (Xlllb) using the monobenzyl ester of formula (V) according to claim

11. A process for the preparation of Cabotegravir having the formula (XHIa), or Dolutegravir having the formula (Xlllb) using the vinylogous amide of formula (X), according to claim