A process for the preparation of polycyclic carbamoyl pyridinone compounds

Abstract

The application provides a preparation method of a polycyclic carbamoyl pyridinone compound suitable for industrialization. The polycyclic carbamoyl pyridinone compound is prepared from 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid as a starting material through condensation, deprotection, cyclization and dealkylation.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing a polycyclic carbamoylpyridinone compound. Background Technology

[0002] Polycyclic carbamoylpyridinone derivatives are used as antiviral drugs, antiretroviral drugs, anti-HIV drugs, anti-HTLV-1 (human T-cell leukemia virus type 1) drugs, anti-FIV (feline immunodeficiency virus) drugs, or anti-SIV (simian immunodeficiency virus) drugs, especially anti-HIV or anti-AIDS drugs. Dolutegravir, a polycyclic carbamoylpyridinone derivative developed by ViiV Healthcare (a subsidiary of GlaxoSmithKline), and bicitiravir, developed by Gilead Sciences, are used to treat HIV and are recommended as first-line treatment options in combination therapy regimens for treatment-naïve HIV patients by most international treatment guidelines.

[0003] US8129385 first disclosed a method for preparing dolutegravir, but this method has a long route and uses an oxidant, posing a high safety risk for scale-up production. US8217034 later improved this method, but it still uses ultra-low temperature reactions, catalytic carbonylation, and palladium-on-carbon hydrogenation, requiring specialized high-pressure equipment, making scale-up production difficult. Subsequent CN102933080 and CN106565747 disclosed another improved method for preparing dolutegravir. This method requires vacuum concentration, extraction and washing, and recrystallization after the reaction, making the operation cumbersome and the preparation cycle long. Literature reports that cyclization of methoxy substrates yields intermediates with an isomer ratio of approximately 9:1-10:1, resulting in numerous isomers. Removing isomers in post-processing is difficult and yields are low.

[0004] WO2014 / 100323 and WO2018 / 229798 disclose methods for preparing bicteravir, which also suffer from cumbersome post-processing of intermediates, as well as the presence of numerous isomers in the cyclization step and the difficulty in removing isomers during post-processing.

[0005] Dolutegravir and bicitiravir have the following structures:

[0006]

[0007] Structures of dolutegravir and bicitiravir cyclization step isomers:

[0008] Summary of the Invention

[0009] This invention provides a method for preparing polycyclic carbamoylpyridinone compounds, which has the following main advantages:

[0010] (1) Cycloning with ethoxy substrates can effectively reduce the content of isomers in the intermediates obtained by cyclization.

[0011] (2) The intermediate was prepared by adding an inert solvent to crystallize after the reaction, which simplified the post-processing operation, effectively separated the intermediate, and ensured the quality of the intermediate.

[0012] The main technical solutions of this invention are as follows:

[0013] This invention provides a method for preparing a polycyclic carbamoylpyridinone compound, comprising the following steps:

[0014] 1) Compound I reacts with Compound II under the action of a condensing agent to give Compound III;

[0015] 2) Compound III reacts under the action of acid, and after the reaction is complete, an inert solvent is added to obtain compound IV;

[0016] 3) Compound IV and Compound V react in an organic solvent under acid catalysis. After the reaction is complete, an inert solvent is added to obtain Compound VII; or Compound IV and Compound VI react in an organic solvent under acid catalysis. After the reaction is complete, an inert solvent is added to obtain Compound IX.

[0017] 4) Compound VII or Compound IX reacts with Lewis acids to give Compound VIII and Compound X, respectively;

[0018]

[0019] In the above methods, R1 is F or H; R2 is C. 1-4 The alkyl group, preferably methyl; n1 is 1 or 2, preferably n1 is 2; n2 is 1 or 2, preferably n2 is 2.

[0020] Specifically, the preparation method of the present invention includes the following steps:

[0021] 1) Compound I reacts with Compound II under the action of a condensing agent to give Compound III;

[0022] 2) Compound III reacts under the action of acid, and after the reaction is complete, an inert solvent is added to obtain compound IV;

[0023] 3) Compound IV and compound V react in an organic solvent under acid catalysis. After the reaction is complete, an inert solvent is added to obtain compound VII.

[0024] 4) Compound VII reacts with Lewis acids to give compound VIII;

[0025] Where R1 is F or H; R2 is C 1-4 Alkyl group, preferably methyl group; n1 is 1 or 2, preferably n1 is 2;

[0026]

[0027] Or it may include the following steps:

[0028] 1) Compound I and Compound II react under the action of a condensing agent to obtain Compound III;

[0029] 2) Compound III reacts under the action of acid, and after the reaction is complete, an inert solvent is added to obtain compound IV;

[0030] 3) Compound IV and compound VI react in an organic solvent under acid catalysis. After the reaction is complete, an inert solvent is added to obtain compound IX.

[0031] 4) Compound IX reacts with Lewis acids to give compound X;

[0032] Wherein, R1 is F or H; n2 is 1 or 2, preferably n2 is 2;

[0033]

[0034] In the above method, the molar ratio of compound I to compound II in step 1) is 1:1.0-1:2.0, preferably 1:1.1-1:1.3; the condensing agent used is one or more of carbonyl diimidazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, preferably carbonyl diimidazole; the molar ratio of compound I to the condensing agent is 1:1.0-1:3.0, preferably 1:1.1-1:1.3; the amidation reaction temperature is -20 to 80°C, preferably -10 to 20°C.

[0035] In the above method, the acid used in step 2) is selected from one or more combinations of formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, and sulfuric acid, with formic acid being preferred; the mass ratio of compound III to acid is 1:1.0-1:10.0, preferably 1:4.0-1:5.0.

[0036] In the above method, the inert solvent added in step 2) is selected from one or more combinations of water, n-heptane, methyl tert-butyl ether, isopropyl ether, and petroleum ether, preferably water; the volume ratio of the inert solvent to the organic acid is 1:1-10:1, preferably 2:1-4:1.

[0037] In the above method, the reaction temperature in step 3) is 70-120℃, preferably 95-105℃; the acid used includes formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, etc., preferably acetic acid; the molar ratio of compound IV to acid is 1:1.0-1:8.0, preferably 1:1.3-1:1.5.

[0038] In the above method, in step 3), the molar ratio of compound IV to compound V is 1:1.0-1:3.0, preferably 1:1.1-1:1.3; or the molar ratio of compound IV to compound VI is 1:1.0-1:8.0, preferably 1:1.1-1:1.3.

[0039] In the above method, the organic solvent used in step 3) is one or more of n-butanol, tert-butanol, ethanol, propanol, isopropanol, and trifluoroethanol, preferably n-butanol.

[0040] In the above method, the inert solvent added in step 3) is selected from one or more combinations of water, n-heptane, n-hexane, cyclohexane, methyl tert-butyl ether, isopropyl ether, and petroleum ether, preferably n-heptane; the volume ratio of inert solvent 2 to solvent is 1:1-10:1, preferably 4:1-6:1.

[0041] In the above method, the Lewis acid used in step 4) is selected from one or more of anhydrous magnesium bromide, anhydrous lithium chloride, anhydrous magnesium chloride, and anhydrous lithium bromide, preferably anhydrous lithium bromide; the molar ratio of compound VII or IX to anhydrous lithium bromide is 1:2.0-1:10.0, preferably 1:4.5-1:5.5.

[0042] This invention also provides a method for preparing polycyclic carbamoylpyridinone compounds, comprising the following steps: reacting compound IV and compound V in an organic solvent under acid catalysis, and adding an inert solvent after the reaction to obtain compound VII; or reacting compound IV and compound VI in an organic solvent under acid catalysis, and adding an inert solvent after the reaction to obtain compound IX;

[0043]

[0044] Where R1 is F or H; R2 is C 1-4 Alkyl group; n1 is 1 or 2; n2 is 1 or 2;

[0045] Specifically, the preparation method of the present invention includes the following steps:

[0046] Compound IV and compound V react in an organic solvent under acid catalysis. After the reaction is complete, an inert solvent is added to obtain compound VII.

[0047]

[0048] Where R1 is F or H; R2 is C 1-4 Alkyl group, preferably methyl group; n1 is 1 or 2, preferably n1 is 2;

[0049] Or it may include the following steps:

[0050] Compound IV and compound VI react in an organic solvent under acid catalysis. After the reaction is complete, an inert solvent is added to give compound IX.

[0051]

[0052] Wherein, R1 is F or H; n2 is 1 or 2, preferably n2 is 2;

[0053] In the above method, the molar ratio of compound IV to compound V is 1:1.0-1:3.0, preferably 1:1.1-1:1.3;

[0054] In the above methods, the molar ratio of compound IV to compound VI is 1:1.0-1:3.0, preferably 1:1.1-1:1.3;

[0055] In the above methods, the organic solvent is selected from one or more combinations of n-butanol, tert-butanol, ethanol, propanol, isopropanol, and trifluoroethanol, with n-butanol being preferred;

[0056] In the above methods, the reaction temperature is 70-120℃, preferably 95-105℃; the acid used is selected from one or more combinations of formic acid, acetic acid, trifluoroacetic acid, and methanesulfonic acid, more preferably acetic acid; the molar ratio of compound IV to acid is 1:1.0-1:8.0, preferably 1:1.3-1:1.5;

[0057] In the above methods, the inert solvent is selected from one or more combinations of water, n-heptane, n-hexane, cyclohexane, methyl tert-butyl ether, isopropyl ether, and petroleum ether, preferably n-heptane; the volume ratio of the inert solvent to the organic solvent is 1:1-10:1, preferably 4:1-6:1.

[0058] The present invention also provides the following compounds:

[0059]

[0060] Where R1 is F or hydrogen; R2 is C 1-4 Alkyl group; n1 is 1 or 2; n2 is 1 or 2;

[0061] The following compounds are preferred:

[0062]

[0063] The beneficial effects of this invention are as follows:

[0064] (1) This invention uses 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid as the starting material. The isomer impurity content in the intermediate obtained by cyclization is 50:1 to 100:1, which is significantly lower than the isomer content in the intermediate of existing preparation methods. This avoids the need for multiple purification operations to remove this impurity and improves the yield.

[0065] (2) It eliminates the need for extraction, washing and concentration, saving production time and avoiding the risk of impurities that may be generated during high-temperature operation; the method is low-cost, simple to operate and has a short process cycle. Attached Figure Description

[0066] Figure 1 HPLC chromatogram of dolutegravir cyclization intermediate prepared from methoxy raw material (related substances)

[0067] Figure 2 HPLC chromatogram of dolutegravir cyclized intermediate (isomer) prepared from methoxy raw material.

[0068] Figure 3 HPLC chromatogram of the biclotipravir cyclized intermediate prepared from methoxy raw materials (related substances).

[0069] Figure 4 HPLC chromatogram of the biclotipravir cyclized intermediate (isomer) prepared from methoxy raw materials.

[0070] Figure 5 HPLC chromatogram of dolutegravir cyclization intermediate prepared from ethoxylated raw material (related substances)

[0071] Figure 6 HPLC chromatogram of dolutegravir cyclization intermediate (isomer) prepared from ethoxylated starting material.

[0072] Figure 7 HPLC chromatogram of the biclotivir cyclization intermediate prepared from ethoxylated raw material (related substances)

[0073] Figure 8 HPLC chromatogram (isomers) of the biclotivir cyclized intermediate prepared from ethoxylated raw materials. Detailed Implementation

[0074] The 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid used in this invention is manufactured by Shanghai Shenghua Pharmaceutical Technology Co., Ltd.; other reaction reagents and raw materials can be purchased commercially. The contents of related substances and isomers were detected using high-performance liquid chromatography (HPLC).

[0075] The following specific embodiments further illustrate the above-mentioned content of the present invention. These embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the invention in any way. All technologies implemented based on the above-mentioned content of the present invention fall within the scope of the present invention. Unless otherwise stated, the materials and operating methods used in the present invention are well known in the art. The raw materials and solvents used in the present invention are commercially available products or can be prepared by known methods.

[0076] Comparative Example 1: Preparation of dolutegravir from 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

[0077] Step 1: Methyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate

[0078]

[0079] 35.0 g of 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (111.01 mmol, 1.0 eq) was added to 350 ml of tetrahydrofuran, and 23.4 g of CDI (144.31 mmol, 1.3 eq) was added with stirring. The mixture was refluxed for 3 hours, cooled to 0–10°C, and 19.1 g of 2,4-difluorobenzylamine (133.44 mmol, 1.2 eq) was added. After addition, the mixture was stirred at 0–10°C for 0.5 hours, washed successively with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain the crude oil compound methyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate. No further purification was required; the oil was used directly in the next step.

[0080] Step 2: Methyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate

[0081]

[0082] 220.0 g of formic acid (4.5 M, 180 ml) was added to the oily substance obtained in step 1 (theoretical amount 48.9 g, 1.0 M). The mixture was stirred at 75–85 °C for 2 hours. After the reaction was completed, the temperature was lowered, and 660 ml of purified water was added at 10–20 °C. The mixture was stirred, filtered, washed with purified water, and dried to obtain 34.4 g of compound methyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate (yield 75.2%).

[0083] 1 H-NMR (600MHz, DMSO-d6): δ3.81(s,3H),3.93(s,3H),3.95(d,J=4.8Hz, 2H),4.53(d,J=6.0Hz,2H),4.94-4.98(m,1H),6.39(d,J=5.4Hz,2H),7.06-7.09(m ,1H),7.23-7.27(m,1H),7.39-7.43(m,1H),8.46(s,1H),10.34(t,J=12.0Hz,1H).

[0084] Step 3: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-methoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide

[0085]

[0086] 30.0 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate (72.75 mmol, 1.0 eq), 7.8 g of (R)-3-aminobutanol (87.50 mmol, 1.2 eq), and 6.1 g of acetic acid (101.58 mmol, 1.4 eq) were added to 135 ml of n-butanol. The mixture was stirred at 95–105 °C for 12 hours. After the reaction was completed, the temperature was lowered, and 540 ml of n-heptane was added at -10–0 °C. The mixture was stirred for 2–3 hours, filtered, purified, and dried to obtain 25.6 g of compound (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-methoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (yield: 81.2%, HPLC: related substances: 96.07%). Figure 1Product content: Main component: 90.29%, isomers: 9.71%, such as... Figure 2 。).

[0087] 1 H-NMR (400MHz, DMSO-d6): δ = 1.28 (d, J = 7.2Hz, 3H), 1.51 (dd, J = 1.6Hz, 1H), 1.91-2.00 (m, 1H), 3.78 (s, 3H), 3.85-3.88 (m, 1 H),3.97(dd,J=10.0Hz,1H),4.34(dd,J=6.0Hz,1H),4.54-4.57(m,3H),4.74-4.80(m,1H),5.34-5.36(m,1H),7.05-7.10(m, 1H),7.23-7.28(m,1H),7.38-7.44(m,1H),8.57(s,1H).

[0088] Step 4: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide

[0089]

[0090] 20.0 g of compound (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-methoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (46.15 mmol, 1.0 eq) and 20.0 g of anhydrous lithium bromide (230.31 mmol, 5.0 eq) were added to 240 ml of tetrahydrofuran. The mixture was refluxed for 8 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. 80 ml of ethanol was added at 20-30 °C and stirred to dissolve the mixture. 7.7 ml of concentrated hydrochloric acid was added for acidification. 460 ml of purified water was added, and the mixture was stirred at 0-10 °C for 110-130 minutes. The mixture was filtered, purified, and dried to obtain 16.2 g of compound (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (yield: 83.7%).

[0091] 1H-NMR (400MHz, DMSO-d6): δ = 1.36 (t, J = 7.2Hz, 3H), 1.58 (d, J = 14.0Hz, 1H), 2.00-2.06 (m, 1H), 3.91 (t, J = 9.6Hz, 1H), 4.06 (t, J = 24.0Hz, 1H), 4.38 (dd, J=4.4Hz,1H),4.56(t,J=17.6Hz,3H),4.82(t,J=13.2Hz,1H),5.46(d,J=3.6Hz,1H ),7.08(t,J=16.8Hz,1H),7.23-7.27(m,1H),7.41(dd,J=6.8Hz,1H),8.50(s,1H), 10.36(t,J=9.2Hz,1H),12.52(s,1H).

[0092] Comparative Example 2: Preparation of bicteravir from 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

[0093] Step 1: Methyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate

[0094]

[0095] Add 30.0 g of 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (95.15 mmol, 1.0 eq) to 300 ml of tetrahydrofuran, and then add 20.1 g of CDI (123.96 mmol, 1.3 eq) while stirring. The mixture was refluxed for 3 hours, cooled to 0–10°C, and 18.4 g of 2,4,6-trifluorobenzylamine (114.19 mmol, 1.2 eq) was added. After addition, the mixture was stirred at 0–10°C for 0.5 hours, washed successively with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain the crude oil compound methyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate. No further purification was required; the oil was used directly in the next step.

[0096] Step 2: Methyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate

[0097]

[0098] Add 196.0 g of formic acid (4.5 M, 160 ml) to the oily substance obtained in step 1 (theoretical amount 43.6 g, 1.0 M). Stir the mixture at 75–85 °C for 2 hours. After the reaction is complete, cool the mixture and add 436 ml of purified water at 10–20 °C. Stir, filter, wash with purified water, and dry to obtain 33.4 g of compound methyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate (yield 81.6%).

[0099] 1 H-NMR (600MHz, DMSO-d6): δ3.82 (s, 3H), 3.91 (s, 3H), 3.96 (d, J = 5.4Hz, 2H), 4.53 (d, J = 6.0Hz, 2H), 4.96-5.01 (m, 1H), 6.41 (d, J = 5.4Hz, 2H), 7.22 (t, J = 17.4Hz, 2H), 8.46 (s, 1H), 10.36 (t, J = 12.0Hz, 1H).

[0100] Step 3: (2R,5S,13aR)-8-methoxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0101]

[0102] 30 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate (69.71 mmol, 1.0 eq), 8.5 g of (1R,3S)-3-aminocyclopentanol (84.03 mmol, 1.2 eq), and 5.9 g of acetic acid (98.25 mmol, 1.4 eq) were added to 135 ml of n-butanol. The mixture was stirred at 95–105 °C for 12 hours. After the reaction was completed, the temperature was lowered to -10–0 °C, 540 ml of n-heptane was added, and the mixture was stirred for 2–3 hours. After filtration and purification, 26.3 g of compound (2R,5S,13aR)-8-methoxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-Formamide (yield: 81.4%, HPLC: related substances: 96.68%, such as...) Figure 3 Product content: Main component: 91.04%, isomers: 8.96%, such as... Figure 4 。).

[0103] 1 H-NMR (600MHz, DMSO-d6): δ=1.53-1.57(m,1H),1.77-1.82(m,2H), 1.90-1.94(m,3H),3.78(s,3H),4.05-4.09(m,1H),4.54(d,J=6.6Hz,3H),4.61-4.64(m, 1H),5.12(d,J=4.2Hz,1H),5.39(dd,J=3.6Hz,1H),7.21(t,J=17.4Hz,2H),8.53(s,1H), 10.40(t,J=11.4Hz,1H).

[0104] Step 4: (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0105]

[0106] 25.0 g of compound (2R,5S,13aR)-8-methoxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza 10-Formamide (53.95 mmol, 1.0 eq) and 23.4 g of anhydrous lithium bromide (269.46 mmol, 5.0 eq) were added to 300 mL of tetrahydrofuran. The mixture was refluxed for 8 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, dissolved by adding 100 mL of ethanol at 20–30 °C, acidified by adding 9.0 mL of concentrated hydrochloric acid, and then added to 575 mL of purified water. The mixture was stirred at 0–10 °C for 110–130 minutes, filtered, purified, and dried to give 20.0 g of compound 1 (yield: 82.5%).

[0107] 1H-NMR (600MHz, DMSO-d6): δ = 1.58 (dd, J = 3.6Hz, 1H), 1.84 (d, J = 12.6Hz, 1H),1.91(t,J=18.0Hz,4H),4.01(dd,J=9.0Hz,1H),4.52(dd,J=6.0Hz,1H),4.57-4.60(m,2H),4.69(dd,J=4.8Hz,1 H), 5.11 (s, 1H), 5.45 (dd, J = 4.2Hz, 1H), 7.21 (t, J = 17.4Hz, 2H), 8.46 (s, 1H), 10.38 (t, J = 11.4Hz, 1H), 12.45 (s, 1H).

[0108] Example 1: Ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate

[0109]

[0110] 30.0 g of 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (87.38 mmol, 1.0 eq) was added to 300 mL of tetrahydrofuran, and 15.6 g of CDI (96.21 mmol, 1.1 eq) was added with stirring. The mixture was refluxed for 3 hours, cooled to -10 to 0 °C, and 13.8 g of 2,4-difluorobenzylamine (96.41 mmol, 1.1 eq) was added. After the addition was complete, the mixture was stirred at -10 to 0 °C for 0.5 hours, washed with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain the crude oil compound ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid. No further purification is required; the oily substance can be used directly in the next step.

[0111] Example 2: Ethyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate

[0112]

[0113] 164.0 g of formic acid (4.0 M, 134 ml) was added to the oily substance obtained in Example 1 (theoretical amount 40.9 g, 1.0 M). The mixture was stirred at 75-85 °C for 2 hours. After the reaction was completed, the temperature was lowered, and 269 ml of purified water was added at 10-20 °C. The mixture was stirred, filtered, washed with purified water, and dried to obtain 37.6 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (yield 97.8%).

[0114] Example 3: Ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate

[0115]

[0116] 30.0 g of 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (87.38 mmol, 1.0 eq) was added to 300 mL of tetrahydrofuran, and 18.4 g of CDI (113.48 mmol, 1.3 eq) was added with stirring. The mixture was refluxed for 3 hours, cooled to 5–15 °C, and 16.3 g of 2,4-difluorobenzylamine (113.87 mmol, 1.3 eq) was added. After the addition was complete, the mixture was stirred at 5–15 °C for 0.5 hours, washed with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain the crude oil compound ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid. No further purification is required; the oily substance can be used directly in the next step.

[0117] Example 4: Ethyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate

[0118]

[0119] 204.0 g of methanesulfonic acid (5.0 M, 138 ml) was added to the oily substance obtained in Example 1 (theoretical amount 40.9 g, 1.0 M). The mixture was stirred at 75-85 °C for 2 hours. After the reaction was completed, the temperature was lowered, and 552 ml of purified water was added at 10-20 °C. The mixture was stirred, filtered, washed with purified water, and dried to obtain 35.8 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (yield 93.1%).

[0120] Example 5: Ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate

[0121]

[0122] 20.0 g of 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (58.25 mmol, 1.0 eq) was added to 200 mL of tetrahydrofuran, and 24.4 g of HATU (64.17 mmol, 1.1 eq) was added with stirring. The mixture was stirred at 20–40 °C for 3 hours, cooled to 10–20 °C, and 10.0 g of 2,4-difluorobenzylamine (69.86 mmol, 1.2 eq) was added. After the addition was complete, the mixture was stirred at 10–20 °C for 1 hour, washed with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain the crude oil compound ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid. No further purification is required; the oily substance can be used directly in the next step.

[0123] Example 6: Ethyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate

[0124]

[0125] 136.0 g of trifluoroacetic acid (5.0 M, 88 ml) was added to the oily substance obtained in Example 1 (theoretical amount 27.3 g, 1.0 M). The mixture was stirred at 75–85 °C for 2 hours. After the reaction was completed, the temperature was lowered, and 352 ml of isopropyl ether was added at 10–20 °C. The mixture was stirred, filtered, washed with isopropyl ether, and dried to obtain 23.9 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (yield 93.2%).

[0126] Example 7: Ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate

[0127]

[0128] 3.50 kg of 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (10.19 mol, 1.0 eq) was added to 35.00 L of tetrahydrofuran, and 2.15 kg of CDI (13.26 mol, 1.3 eq) was added with stirring. The mixture was refluxed for 3 hours, cooled to 0–10 °C, and 1.75 kg of 2,4-difluorobenzylamine (12.23 mol, 1.2 eq) was added. After the addition was complete, the mixture was stirred at 0–10 °C for 0.5 hours, washed with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain the crude oil compound ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid. No further purification is required; the oily substance can be used directly in the next step.

[0129] Example 8: Ethyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylate

[0130]

[0131] 21.00 kg of formic acid (4.5 M, 17.21 L) was added to the oily substance obtained in Example 1 (theoretical amount 4.78 kg, 1.0 M). The mixture was stirred at 75–85 °C for 2 hours. After the reaction was completed, the temperature was lowered, and 48.00 L of purified water was added at 10–20 °C. The mixture was stirred, filtered, washed with purified water, and dried to obtain 4.44 kg of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (yield 98.9%).

[0132] 1 H-NMR (400MHz, DMSO-d6): δ = 1.22 (t, J = 14.0Hz, 3H), 1.34 (t, J = 14.4Hz, 3H),3.32(d,J=11.6Hz,6H),4.14(dd,J=7.2Hz,2H),4.23(d,J=4.4Hz,2H),4.40 (dd,J=7.2Hz,2H),4.54(t,J=9.6Hz,3H),7.05-7.10(m,1H),7.22-7.28(m,1H), 7.40-7.46(m,1H),8.47(s,1H),10.33(t,J=11.6Hz,1H).

[0133] Example 9: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide

[0134]

[0135] 25.0 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (56.77 mmol, 1.0 eq), 5.6 g of (R)-3-aminobutanol (62.82 mmol, 1.1 eq), and 8.2 g of methanesulfonic acid (85.32 mmol, 1.5 eq) were added to 113 ml of n-butanol. The mixture was stirred at 110–120 °C for 8 hours. After the reaction was completed, the temperature was lowered to -10–0 °C, 452 ml of purified water was added, and the mixture was stirred for 2–3 hours. After filtration and purification, 21.3 g of compound (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide was obtained (yield: 83.8%, HPLC: related substances: 99.90%; product content: main component: 98.44%, isomers: 1.56%).

[0136] Example 10: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide

[0137]

[0138] 30.0 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (68.12 mmol, 1.0 eq), 7.3 g of (R)-3-aminobutanol (81.89 mmol, 1.2 eq), and 10.1 g of trifluoroacetic acid (88.58 mmol, 1.3 eq) were added to 135 ml of trifluoroethanol. The mixture was stirred at 70–80 °C for 18 hours. After the reaction was completed, the temperature was lowered to -10–0 °C, and 810 ml of methyl tert-butyl ether was added. The mixture was stirred for 2–3 hours, filtered, purified, and dried to obtain 25.2 g of compound (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (yield: 82.7%, HPLC: related substances: 99.87%; product content: main component: 98.34%, isomers: 1.66%).

[0139] Example 11: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide

[0140]

[0141] 4.34 kg of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (9.85 mol, 1.0 eq), 1.05 kg of (R)-3-aminobutanol (11.78 mol, 1.2 eq), and 0.83 kg of acetic acid (13.82 mol, 1.4 eq) were added to 19.50 L of n-butanol. The mixture was stirred at 95–105 °C for 12 hours. After the reaction was completed, the temperature was lowered to -10–0 °C, and 78.00 L of n-heptane was added. The mixture was stirred for 2–3 hours, filtered, purified, and dried to obtain 3.77 kg of compound (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (yield: 85.5%, HPLC: related substances: 99.91%). Figure 5 Product content: Main component: 98.50%, isomers: 1.50%, such as... Figure 6 。).

[0142] 1 H-NMR (400MHz, DMSO-d6): δ = 1.28 (d, J = 7.2Hz, 3H), 1.39-1.47 (m, 4H), 2.08-2.14(m,1H),3.89(t,J=9.6Hz,2H),4.06(dd,J=6.0Hz,1H),4.15-4.22(m,3H), 4.55(d,J=6.0Hz,2H),4.92-4.96(m,1H),5.12(dd,J=4.0Hz,1H),6.69-6.76(m,2H), 7.20-7.31(m,1H),8.32(s,1H),10.31(t,J=10.4Hz,1H).ESI(+):m / z=448.25 [M+H] + .

[0143] Example 12: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide

[0144]

[0145] 20.0 g of compound (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (44.70 mmol, 1.0 eq) and 37.0 g of anhydrous magnesium bromide (200.94 mmol, 4.5 eq) were added to 240 ml of tetrahydrofuran. The mixture was refluxed for 8 hours. After the reaction was completed, it was concentrated under reduced pressure. 80 ml of ethanol was added at 20-30 °C and stirred to dissolve. 7.5 ml of concentrated hydrochloric acid was added for acidification. 460 ml of purified water was added. The mixture was stirred at 0-10 °C for 110-130 minutes. After filtration, purification and drying, 15.7 g of dolutegravir was obtained (yield: 83.8%).

[0146] Example 13: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide

[0147]

[0148] 30.0 g of compound (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (67.05 mmol, 1.0 eq) and 32.0 g of anhydrous lithium bromide (368.49 mmol, 5.5 eq) were added to 360 ml of tetrahydrofuran. The mixture was refluxed for 8 hours. After the reaction was completed, it was concentrated under reduced pressure. 120 ml of ethanol was added at 20-30 °C and stirred to dissolve. 11.2 ml of concentrated hydrochloric acid was added for acidification. 690 ml of purified water was added and stirred at 0-10 °C for 110-130 minutes. The mixture was filtered, purified, and dried to obtain 23.7 g of dolutegravir (yield: 84.3%).

[0149] Example 14: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide

[0150]

[0151] 3.35 kg of compound (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (1.0 eq) and 3.25 kg of anhydrous lithium bromide (5.0 eq) were added to 40.00 L of tetrahydrofuran. The mixture was refluxed for 8 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, dissolved by stirring in 13.40 L of ethanol at 20–30 °C, acidified by adding 1.25 L of concentrated hydrochloric acid, and then added to 77.00 L of purified water. The mixture was stirred at 0–10 °C for 110–130 minutes, filtered, purified, and dried to give 2.67 kg of dolutegravir (yield: 85.0%).

[0152] 1H-NMR (400MHz, DMSO-d6): δ1.34(t,J=6.8Hz,3H),1.56(d,J=13.6Hz,1H),1.99-2.06(m,1H),3.90(t,J=9.2Hz,1H),4.04 (t,J=24.0Hz,1H),4.36(dd,J=4.4Hz,1H),4.56(t,J=17.6Hz,3H),4.80(t,J=12.8Hz,1H),5.45(d,J=3.6Hz,1H),7.06(t, J=16.8Hz,1H),7.22-7.27(m,1H),7.40(dd,J=6.8Hz,1H),8.50(s,1H),10.36(t,J=9.2Hz,1H),12.51(s,1H).

[0153] Example 15: Ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate

[0154]

[0155] 30.0 g of 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (87.38 mmol, 1.0 eq) was added to 300 ml of tetrahydrofuran, and 15.6 g of CDI (96.21 mmol, 1.1 eq) was added with stirring. The mixture was refluxed for 3 hours, cooled to 10–20°C, and 15.5 g of 2,4,6-trifluorobenzylamine (96.20 mmol, 1.1 eq) was added. After addition, the mixture was stirred at 10–20°C for 0.5 hours, washed with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain the crude oil compound 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylic acid ethyl ester. No further purification was required; the oil was used directly in the next step.

[0156] Example 16: Ethyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate

[0157]

[0158] 170.0 g of 60% sulfuric acid (4.0 M, 113 ml) was added to the oily substance obtained in Example 1 (theoretical amount 42.5 g, 1.0 M). The mixture was stirred at 75-85 °C for 2 hours. After the reaction was completed, the temperature was lowered, and 226 ml of purified water was added at 10-20 °C. The mixture was stirred, filtered, washed with purified water, and dried to obtain 36.1 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (yield 90.1%).

[0159] Example 17: Ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate

[0160]

[0161] Add 30.0 g of 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (87.38 mmol, 1.0 eq) to 300 ml of tetrahydrofuran, and then add 18.4 g of CDI (113.48 mmol, 1.3 eq) while stirring. The mixture was refluxed for 3 hours, cooled to -10 to 0°C, and 18.3 g of 2,4,6-trifluorobenzylamine (113.57 mmol, 1.3 eq) was added. After addition, the mixture was stirred at -10 to 0°C for 0.5 hours, washed with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain the crude oil compound 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylic acid ethyl ester. No further purification was required; the oil was used directly in the next step.

[0162] Example 18: Ethyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate

[0163]

[0164] 213.0 g of formic acid (5.0 M, 174 ml) was added to the oily substance obtained in Example 1 (theoretical amount 42.5 g, 1.0 M). The mixture was stirred at 75-85 °C for 2 hours. After the reaction was completed, the temperature was lowered, and 698 ml of purified water was added at 10-20 °C. The mixture was stirred, filtered, washed with purified water, and dried to obtain 38.1 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (yield 95.1%).

[0165] Example 19: Ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate

[0166]

[0167] 20.0 g of 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (58.25 mmol, 1.0 eq) was added to 200 ml of tetrahydrofuran, and 24.4 g of HATU (64.17 mmol, 1.1 eq) was added with stirring. The mixture was stirred at 20–40°C for 3 hours, then cooled to 5–15°C. 11.3 g of 2,4,6-trifluorobenzylamine (70.13 mmol, 1.2 eq) was added. After addition, the mixture was stirred at 5–15°C for 1 hour. The mixture was washed with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain an oily crude compound, ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate. No further purification was required; the oily compound was used directly in the next step.

[0168] Example 20: Ethyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate

[0169]

[0170] 142.0 g of trifluoroacetic acid (5.0 M, 92 ml) was added to the oily substance obtained in Example 1 (theoretical amount 28.3 g, 1.0 M). The mixture was stirred at 75–85 °C for 2 hours. After the reaction was completed, the temperature was lowered, and 368 ml of methyl tert-butyl ether was added at 10–20 °C. The mixture was stirred, filtered, washed with methyl tert-butyl ether, and dried to obtain 24.6 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (yield 92.1%).

[0171] Example 21: Ethyl 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate

[0172]

[0173] Add 30.0 g of 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (87.38 mmol, 1.0 eq) to 300 ml of tetrahydrofuran, and then add 18.5 g of CDI (114.09 mmol, 1.3 eq) while stirring. The mixture was refluxed for 3 hours, cooled to 0–10°C, and 16.9 g of 2,4,6-trifluorobenzylamine (104.88 mmol, 1.2 eq) was added. After addition, the mixture was stirred at 0–10°C for 0.5 hours, washed successively with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain the crude oil compound 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylic acid ethyl ester. No further purification was required; the oil was used directly in the next step.

[0174] Example 22: Ethyl 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylate

[0175]

[0176] 191.0 g of formic acid (4.5 M, 156 ml) was added to the oily substance obtained in Example 1 (theoretical amount 42.5 g, 1.0 M). The mixture was stirred at 75-85 °C for 2 hours. After the reaction was completed, the temperature was lowered, and 425 ml of purified water was added at 10-20 °C. The mixture was stirred, filtered, washed with purified water, and dried to obtain 39.5 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (yield 98.6%).

[0177] 1 H-NMR (600MHz, DMSO-d6): δ = 1.20 (t, J = 13.8Hz, 3H), 1.32 (t, J = 13.8Hz, 3H), 3.92 (d, J = 4.8Hz, 2H), 4.11 (dd, J = 7.2Hz, 2H), 4.40 (dd, J = 7.2Hz, 2H), 4.54 (d, J = 6.0Hz, 2H), 4. 94-4.98(m,1H),6.37(d,J=6.0Hz,2H),7.21(t,J=16.8Hz,2H),8.43(s,1H),10.35(t,J=11.4Hz,1H).

[0178] Example 23: (2R,5S,13aR)-8-ethoxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0179]

[0180] 25.0 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (54.54 mmol, 1.0 eq), 6.6 g of (1R,3S)-3-aminocyclopentanol (65.25 mmol, 1.2 eq), and 4.9 g of acetic acid (81.60 mmol, 1.5 eq) were added to 113 ml of n-butanol. The mixture was stirred at 110–120 °C for 8 hours. After the reaction was completed, the temperature was lowered to -10–0 °C, 452 ml of n-heptane was added, and the mixture was stirred for 2–3 hours. The mixture was filtered, purified, and dried to obtain 21.6 g of compound (4R,12aS)-N-[(2,4,6-trifluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (yield: 82.9%, HPLC: related substances: 99.36%; product content: main component: 98.25%, isomers: 1.75%).

[0181] Example 24: (2R,5S,13aR)-8-ethoxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0182]

[0183] 30.0 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (65.45 mmol, 1.0 eq), 8.6 g of (1R,3S)-3-aminocyclopentanol (85.02 mmol, 1.3 eq), and 9.7 g of trifluoroacetic acid (85.07 mmol, 1.3 eq) were added to 135 ml of ethanol. The mixture was stirred at 70–80 °C for 18 hours. After the reaction was completed, the temperature was lowered to -10–0 °C, 810 ml of isopropyl ether was added, and the mixture was stirred for 2–3 hours. After filtration and purification, 25.9 g of compound (4R,12aS)-N-[(2,4,6-trifluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide was obtained (yield: 82.9%, HPLC: related substances: 99.46%; product content: main component: 98.19%, isomers: 1.81%).

[0184] Example 25: (2R,5S,13aR)-8-ethoxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0185]

[0186] 35.0 g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4,6-trifluorobenzoyl)pyridine-2-carboxylic acid ethyl ester (76.35 mmol, 1.0 eq), 9.3 g of (1R,3S)-3-aminocyclopentanol (91.94 mmol, 1.2 eq), and 6.4 g of acetic acid (106.58 mmol, 1.4 eq) were added to 158 ml of n-butanol. The mixture was stirred at 95–105 °C for 12 hours. After the reaction was completed, the temperature was lowered to -10–0 °C, 632 ml of n-heptane was added, and the mixture was stirred for 2–3 hours. After filtration and purification, 30.9 g of compound (2R,5S,13aR)-8-ethoxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-Formamide (yield: 84.8%, HPLC: related substances: 99.59%, such as...) Figure 7 Product content: Main component: 98.16%, isomers: 1.84%, such as... Figure 8 。).

[0187] 1 H-NMR (600MHz, DMSO-d6): δ = 1.28 (t, J = 13.8Hz, 3H), 1.52-1.55 (m, 1H), 1.77-1.81(m,2H),1.89-1.94(m,3H),3.95-4.02(m,2H),4.04-4.09(m,1H),4.54(d, J=6.0Hz,3H),4.61-4.64(m,1H),5.10(d,J=3.6Hz,1H),5.38(dd,J=3.6Hz,1H),7.21(t,J=17.4Hz,2H),8.51(s,1H),10.39(t,J=11.4Hz,1H).

[0188] Example 26: (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0189]

[0190] 20.0 g of compound (4R,12aS)-N-[(2,4,6-trifluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (41.89 mmol, 1.0 eq) and 34.7 g of anhydrous magnesium bromide (188.45 mmol, 4.5 eq) were added to 240 ml of tetrahydrofuran. The mixture was refluxed for 8 hours. After the reaction was completed, it was concentrated under reduced pressure. 80 ml of ethanol was added at 20-30 °C and stirred to dissolve. 7.2 ml of concentrated hydrochloric acid was added for acidification. 460 ml of purified water was added. The mixture was stirred at 0-10 °C for 110-130 minutes. After filtration, purification and drying, 15.3 g of dolutegravir was obtained (yield: 81.2%).

[0191] Example 27: (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0192]

[0193] 30.0 g of compound (4R,12aS)-N-[(2,4,6-trifluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (62.84 mmol, 1.0 eq) and 30.0 g of anhydrous lithium bromide (345.46 mmol, 5.5 eq) were added to 360 ml of tetrahydrofuran. The mixture was refluxed for 8 hours. After the reaction was completed, it was concentrated under reduced pressure. 120 ml of ethanol was added at 20-30 °C and stirred to dissolve. 10.7 ml of concentrated hydrochloric acid was added for acidification. 690 ml of purified water was added and stirred at 0-10 °C for 110-130 minutes. The mixture was filtered, purified, and dried to obtain 23.5 g of dolutegravir (yield: 83.2%).

[0194] Example 28: (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0195]

[0196] 22.0 g of compound (2R,5S,13aR)-8-ethoxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza 10-Formamide (1.0 eq) and 20.0 g anhydrous lithium bromide (5.0 eq) were added to 264 mL of tetrahydrofuran. The mixture was refluxed for 8 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, dissolved in 88 mL of ethanol at 20–30 °C, acidified with 8.0 mL of concentrated hydrochloric acid, and then added to 506 mL of purified water. The mixture was stirred at 0–10 °C for 110–130 minutes, filtered, purified, and dried to give 18.0 g of compound 1 (yield: 86.9%). 1 H-NMR (600MHz, DMSO-d6): δ = 1.57 (dd, J = 3.0Hz, 1H), 1.84 (d, J = 12.0Hz, 1H), 1.93 (t, J = 18.6Hz, 4H), 4.02(dd,J=9.6Hz,1H),4.52(dd,J=5.4Hz,1H),4.56-4.60(m,2H),4.67(dd,J=4.2Hz, 1H), 5.09 (s, 1H), 5.44 (dd, J = 4.2Hz, 1H), 7.20 (t, J = 17.4Hz, 2H), 8.44 (s, 1H), 10.36 (t, J = 11.4Hz, 1H), 12.44 (s, 1H).

Claims

1. A method for synthesizing polycyclic carbamoylpyridinone compounds, characterized in that, Includes the following steps: 1) Compound I reacts with Compound II under the action of a condensing agent to give Compound III; 2) Compound III reacts under the action of acid. After the reaction is completed, an inert solvent is added to obtain compound IV. The inert solvent is selected from one or more combinations of water, n-heptane, methyl tert-butyl ether, isopropyl ether, and petroleum ether. The volume ratio of the inert solvent to the acid is selected from 1:1 to 10:

1. 3) Compound IV and Compound V react in an organic solvent under acid catalysis, and after the reaction is complete, an inert solvent is added to obtain Compound VII; or Compound IV and Compound VI react in an organic solvent under acid catalysis, and after the reaction is complete, an inert solvent is added to obtain Compound IX, wherein the organic solvent is one or more combinations of n-butanol, tert-butanol, ethanol, propanol, isopropanol, and trifluoroethanol; the inert solvent is selected from one or more combinations of water, n-heptane, n-hexane, cyclohexane, methyl tert-butyl ether, isopropyl ether, and petroleum ether; the volume ratio of the inert solvent to the organic solvent is selected from 1:1 to 10:1; 4) Compound VII or Compound IX reacts with Lewis acids to give Compound VIII and Compound X, respectively; Where R1 is F or H; R2 is C 1-4 Alkyl group; n1 is 1 or 2; n2 is 1 or 2; 。 2. The method according to claim 1, characterized in that, It includes the following steps: 1) Compound I reacts with Compound II under the action of a condensing agent to give Compound III; 2) Compound III reacts under the action of acid, and after the reaction is complete, an inert solvent is added to obtain compound IV; 3) Compound IV and compound V react in an organic solvent under acid catalysis. After the reaction is complete, an inert solvent is added to obtain compound VII. 4) Compound VII reacts with a Lewis acid to give compound VIII; Where R1 is F or H; R2 is C 1-4 Alkyl group; n1 is 1 or 2; 。 3. The method according to claim 1, characterized in that, It includes the following steps: 1) Compound I reacts with Compound II under the action of a condensing agent to give Compound III; 2) Compound III reacts under the action of acid, and after the reaction is complete, an inert solvent is added to obtain compound IV; 3) Compound IV and compound VI react in an organic solvent under acid catalysis. After the reaction is complete, an inert solvent is added to obtain compound IX. 4) Compound IX reacts with a Lewis acid to give compound X; Where R1 is F or H; R2 is C 1-4 Alkyl group; n2 is 1 or 2; 。 4. The method according to any one of claims 1 to 3, characterized in that, The inert solvent in step 2) is selected from water.

5. The method according to any one of claims 1 to 3, characterized in that, The volume ratio of the inert solvent to the acid in step 2) is selected from 2:1 to 4:

1.

6. The method according to any one of claims 1 to 3, characterized in that, The inert solvent in step 3) is selected from n-heptane.

7. The method according to any one of claims 1 to 3, characterized in that, The volume ratio of the inert solvent to the organic solvent in step 3) is selected from 4:1 to 6:

1.

8. The method according to any one of claims 1 to 3, characterized in that, In step 1), the molar ratio of compound I to compound II is selected from 1:1.0 to 1:2.0; the condensing agent used is selected from one or more combinations of carbonyl diimidazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; the molar ratio of compound I to the condensing agent is selected from 1:1.0 to 1:3.0; and the amidation reaction temperature is selected from -20 to 80℃.

9. The method according to any one of claims 1 to 3, characterized in that, In step 1), the molar ratio of compound I to compound II is selected from 1:1.1 to 1:1.

3.

10. The method according to any one of claims 1 to 3, characterized in that, In step 1), the condensing agent is selected from carbonyl diimidazole.

11. The method according to any one of claims 1 to 3, characterized in that, In step 1), the molar ratio of compound I to the condensing agent is selected from 1:1.1 to 1:1.

3.

12. The method according to any one of claims 1 to 3, characterized in that, The amidation reaction temperature in step 1) is selected from -10 to 20℃.

13. The method according to any one of claims 1 to 3, characterized in that, The acid used in step 2) is selected from one or more combinations of formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, and sulfuric acid; the mass ratio of compound III to acid is selected from 1:1.0 to 1:10.

0.

14. The method according to any one of claims 1 to 3, characterized in that, The acid used in step 2) is formic acid.

15. The method according to any one of claims 1 to 3, characterized in that, In step 2), the mass ratio of compound III to acid is selected from 1:4.0 to 1:5.

0.

16. The method according to any one of claims 1 to 3, characterized in that, The reaction temperature in step 3) is selected from 70-120℃; the acid used is selected from one or more combinations of formic acid, acetic acid, trifluoroacetic acid, and methanesulfonic acid; the molar ratio of compound IV to acid is selected from 1:1.0-1:8.

0.

17. The method according to any one of claims 1 to 3, characterized in that, The reaction temperature in step 3) is selected from 95-105℃.

18. The method according to any one of claims 1 to 3, characterized in that, The acid used in step 3) is selected from acetic acid.

19. The method according to any one of claims 1 to 3, characterized in that, In step 3), the molar ratio of compound IV to acid is selected from 1:1.3 to 1:1.

5.

20. The method according to claim 1 or 2, characterized in that, In step 3), the molar ratio of compound IV and compound V is selected from 1:1.0 to 1:3.

0.

21. The method according to claim 1 or 2, characterized in that, In step 3), the molar ratio of compound IV and compound V is selected from 1:1.1 to 1:1.

3.

22. The method according to claim 1 or 3, characterized in that, In step 3), the molar ratio of compound IV and compound VI is selected from 1:1.0 to 1:3.

0.

23. The method according to claim 1 or 3, characterized in that, In step 3), the molar ratio of compound IV and compound VI is selected from 1:1.1 to 1:1.

3.

24. The method according to any one of claims 1 to 3, characterized in that, The Lewis acid used in step 4) is selected from one or more combinations of anhydrous magnesium bromide, anhydrous lithium chloride, anhydrous magnesium chloride, and anhydrous lithium bromide; the molar ratio of compound VII or IX to anhydrous lithium bromide is selected from 1:2.0 to 1:10.

0.

25. The method according to any one of claims 1 to 3, characterized in that, The Lewis acid used in step 4) is selected from anhydrous lithium bromide.

26. The method according to any one of claims 1 to 3, characterized in that, In step 4), the molar ratio of compound VII or IX to anhydrous lithium bromide is selected from 1:4.5 to 1:5.

5.

27. A method for synthesizing a polycyclic carbamoylpyridinone compound, comprising the following steps: in, R1 is F or H; R2 is C 1-4 Alkyl group; n1 is 1 or 2; n2 is 1 or 2; The steps include: reacting compound IV and compound V in an organic solvent under acid catalysis, and adding an inert solvent after the reaction to obtain compound VII; or reacting compound IV and compound VI in an organic solvent under acid catalysis, and adding an inert solvent after the reaction to obtain compound IX; The molar ratio of compound IV to compound V was selected from 1:1.0 to 1:3.0; The molar ratio of compound IV to compound VI was selected from 1:1.0 to 1:3.0; The organic solvent is selected from one or more combinations of n-butanol, tert-butanol, ethanol, propanol, isopropanol, and trifluoroethanol; The reaction temperature is selected from 70-120℃; the acid used is selected from one or more combinations of formic acid, acetic acid, trifluoroacetic acid, and methanesulfonic acid; the molar ratio of compound IV to acid is selected from 1:1.0 to 1:8.0; The inert solvent is selected from one or more combinations of water, n-heptane, n-hexane, cyclohexane, methyl tert-butyl ether, isopropyl ether, and petroleum ether; the volume ratio of the inert solvent to the organic solvent is selected from 1:1 to 10:

1.

28. The method according to claim 27, characterized in that, The molar ratio of compounds IV and V was selected from 1:1.1 to 1:1.

3.

29. The method according to claim 27, characterized in that, The molar ratio of compounds IV and VI was selected from 1:1.1 to 1:1.

3.

30. The method according to claim 27, characterized in that, The organic solvent is selected from n-butanol.

31. The method according to claim 27, characterized in that, The reaction temperature is selected from 95-105℃.

32. The method according to claim 27, characterized in that, The acid used is acetic acid.

33. The method according to claim 27, characterized in that, The molar ratio of compound IV to acid is selected from 1:1.3 to 1:1.

5.

34. The method according to claim 27, characterized in that, The inert solvent is selected from n-heptane.

35. The method according to claim 27, characterized in that, The volume ratio of inert solvent to organic solvent is selected from 4:1 to 6:

1.

36. The compounds shown in formula (VII) and formula (IX), 、 in, R1 is F or hydrogen; R2 is C. 1-4 Alkyl group; n1 is 1 or 2; n2 is 1 or 2.

37. Compounds 。

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