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CN111187200A - Synthesis method of lomitapide-D8 - Google Patents

Synthesis method of lomitapide-D8 Download PDF

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CN111187200A
CN111187200A CN202010271711.8A CN202010271711A CN111187200A CN 111187200 A CN111187200 A CN 111187200A CN 202010271711 A CN202010271711 A CN 202010271711A CN 111187200 A CN111187200 A CN 111187200A
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贲昊玺
于海涛
唐小航
孙爱学
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Nanjing Haolv Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/05—Isotopically modified compounds, e.g. labelled

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Abstract

The invention provides a synthesis method of lomitapide-D8, which comprises the following steps: 1) performing halogenation reaction on the compound 2a and hydrobromic acid to obtain a compound 2; 2) firstly, carrying out hydrogen abstraction reaction on the compound 1 and n-butyllithium, and then adding the compound 2 for substitution reaction to prepare a compound 3; 3) carrying out condensation reaction on the compound 3 and the compound 4 to obtain a compound 5; 4) carrying out condensation reaction on the compound 6 and the compound 7 to obtain a compound 8; 5) removing tert-butyloxycarbonyl protection from the compound 8 and trifluoroacetic acid to obtain a compound 9; 6) and carrying out substitution reaction on the compound 5 and the compound 9 to obtain the lomitapide-D8. The invention firstly uses the relatively low-cost deuterated tetrahydrofuran as the raw material to synthesize the deuterated 1, 4-dibromobutane-D8, successfully synthesizes the deuterated lomitapide-D8, changes the conventional synthetic route, and enables the difficultly obtained deuterated atoms to achieve the maximum atom economic effect.

Description

Synthesis method of lomitapide-D8
Technical Field
The invention relates to a synthesis method of lomitapide-D8, belonging to the technical field of organic chemical synthesis.
Background
Lomitapide is an oral small molecule microsomal triglyceride transfer protein (MTP) inhibitor that was approved by the FDA in the united states for marketing in 2012 for the treatment of hypercholesterolemia, including primary hypercholesterolemia and familial hypercholesterolemia. The action mechanism of the lometasapine is that the lometasapine can be retained in endoplasmic reticulum, is directly combined with MTP and has inhibition effect on the MTP, prevents the assembly and secretion of apolipoprotein in intestinal epithelial cells and liver cells, inhibits the synthesis of chylomicron and very low density lipoprotein, and reduces the level of plasma low density lipoprotein cholesterol.
Lomitapide-D8 can be used for clinical pharmacology and toxicology research. No report on the synthesis of Lomitapide-D8 exists at present.
The conventional synthetic route of lomitapide takes diphenylethanol as a raw material, N- (2, 2, 2-trifluoroethyl) -9- (4-bromobutyl) -9H-fluorenyl-9-formamide is obtained through Friedel-Crafts reaction, nucleophilic substitution and aminolysis, the N- (2, 2, 2-trifluoroethyl) -9- [4- (4-aminopiperidine-1-yl) -butyl ] -9H-fluorenyl-9-formamide is subjected to N-substitution reaction with amino piperidine protected by Boc, deprotection is carried out to obtain N- (2, 2, 2-trifluoroethyl) -9- [4- (4-aminopiperidine-1-yl) -butyl ] -9H-fluorenyl-9-formamide, and acyl chloride prepared from 4' -trifluoromethyl biphenyl-2-carboxylic acid is condensed to obtain the product.
Lomitapide-D8 cannot be synthesized by adopting the conventional synthetic route of Lomitapide.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provides a synthesis method of lomitapide-D8.
The technical scheme of the invention is as follows:
a method for synthesizing lometasai-D8, the structure of lometasai-D8 is shown as formula I,
Figure 492788DEST_PATH_IMAGE001
the synthetic route is as follows:
Figure 74948DEST_PATH_IMAGE002
the method comprises the following steps:
1) under the acidic condition, carrying out halogenation reaction on the compound 2a and hydrobromic acid to obtain a compound 2;
2) under the protection of nitrogen, firstly, carrying out hydrogen abstraction reaction on the compound 1 and n-butyllithium, and then adding the compound 2 for substitution reaction to prepare a compound 3;
3) carrying out condensation reaction on the compound 3 and the compound 4 in the presence of 1-hydroxybenzotriazole, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine to prepare a compound 5;
4) carrying out condensation reaction on a compound 6 and a compound 7 in the presence of 1-hydroxybenzotriazole, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine to prepare a compound 8;
5) removing tert-butyloxycarbonyl protection from the compound 8 and trifluoroacetic acid to obtain a compound 9;
6) carrying out substitution reaction on the compound 5 and the compound 9 in the presence of potassium carbonate to obtain lomitapide-D8;
in the step 1), the acid is concentrated sulfuric acid, the reaction temperature is 110 ℃, and the reaction time is 6 hours;
in the step 2), the reaction solvent is anhydrous tetrahydrofuran, the reaction condition of the compound 1 and n-butyllithium is 0 ℃ for 1 hour, and the reaction condition of adding the compound 2 is room temperature reaction for 24 hours;
in the step 3), the reaction solvent is N, N-dimethylformamide, the reaction temperature is room temperature, and the reaction time is 24 hours;
in the step 4), the reaction solvent is N, N-dimethylformamide, the reaction temperature is room temperature, and the reaction time is 24 hours;
in the step 5), the reaction solvent is dichloromethane, the reaction temperature is room temperature, and the reaction time is 1 hour;
in the step 6), the reaction solvent is N, N-methylformamide, the reaction temperature is 50 ℃, and the reaction time is 24 hours.
Preferably, the first and second electrodes are formed of a metal,
the method comprises the following steps:
1) under the ice bath condition, slowly adding concentrated sulfuric acid into an aqueous solution of hydrobromic acid, then slowly adding a compound 2a, and after completion, heating to 110 ℃ for reacting for 6 hours to obtain a compound 2;
2) dissolving compound 1 in anhydrous tetrahydrofuran under nitrogen protection at 0oSlowly adding n-butyllithium under the condition of C, preserving heat, reacting for 1 hour, then adding the compound 2, heating to room temperature, and reacting for 24 hours to obtain a compound 3;
3) adding the compound 3, the compound 4, the 1-hydroxybenzotriazole, the benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate and the N, N-diisopropylethylamine into the N, N-dimethylformamide in sequence, and reacting at room temperature for 24 hours to obtain a compound 5;
4) adding the compound 6, the compound 7, the 1-hydroxybenzotriazole, the benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate and the N, N-diisopropylethylamine into the N, N-dimethylformamide in sequence, and stirring at room temperature for reacting for 24 hours to obtain a compound 8;
5) dissolving the compound 8 in dichloromethane, slowly dropwise adding trifluoroacetic acid while stirring at room temperature, and reacting at room temperature for 1 hour to obtain a compound 9;
6) and sequentially adding the compound 5, the compound 9 and potassium carbonate into N, N-methylformamide, heating to 50 ℃ and reacting for 24 hours to obtain the lomitapide-D8.
More preferably still, the first and second liquid crystal compositions are,
in the step 1), the molar ratio of the compound 2a to the hydrobromic acid is 1.0: 2.85;
in the step 2), the mol ratio of the compound 1, the n-butyllithium and the compound 2 is 1.0: 2.25: 1.20;
in the step 3), the molar ratio of the compound 3, the compound 4, the 1-hydroxybenzotriazole, the benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate to the N, N-diisopropylethylamine is 1.21: 1: 1.51: 1.51: 2.96;
in the step 4), the molar ratio of the compound 6, the compound 7, the 1-hydroxybenzotriazole, the benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate to the N, N-diisopropylethylamine is 1.19: 1: 1.51: 1.51: 1.98 of;
in the step 5), the molar ratio of the compound 8 to the trifluoroacetic acid is 1: 2.51;
in the step 6), the molar ratio of the compound 5 to the compound 9 to the potassium carbonate is 1: 1.13: 2.52.
the invention has the following technical effects: the invention firstly uses the low-price deuterated tetrahydrofuran as the raw material to synthesize the deuterated 1, 4-dibromobutane-D8, uses the deuterated tetrahydrofuran as a deuterated intermediate for synthesizing the deuterated lomitapide-D8, successfully synthesizes the deuterated lomitapide-D8, changes the conventional synthetic route, and enables the difficultly obtained deuterated atoms to achieve the maximum atom economic benefit.
Drawings
FIG. 1 is a HNMR map of lometaside-D8 prepared in example 1.
Detailed Description
Deuterated tetrahydrofuran was purchased from Cambridge Isotope Laboratories, inc.
Example 1
The synthesis method of the lomitapide-D8 comprises the following steps:
step 1)
The synthetic route is as follows:
Figure 889320DEST_PATH_IMAGE003
under the ice bath condition, 22 ml of concentrated sulfuric acid is slowly added into 60 g of 48% wt hydrobromic acid aqueous solution, then compound 2a (10.0 g, 124.8 mmol) is slowly added, after the reaction is completed, the temperature is raised to 110 ℃ for reaction for 6 hours, the reaction is monitored, after the reaction is completed, the reaction is cooled to room temperature, the lower layer is separated, the lower layer is dissolved by 150 ml of n-hexane, washed by water for 2 times, washed by saturated sodium bicarbonate aqueous solution for 1 time, dried by anhydrous sodium sulfate, and distilled under reduced pressure to obtain 26.2 g of colorless liquid, compound 2, and the yield is 94%.
Step 2)
The synthetic route is as follows:
Figure 711782DEST_PATH_IMAGE004
compound 1 (4.2 g, 20.0 mmol) was dissolved in 100 ml of anhydrous tetrahydroIn furan under nitrogen protection at 0oSlowly adding n-butyllithium (2.5M, 18mL) at the temperature of C, keeping the temperature for reaction for 1 hour, then adding the compound 2 (5.4 g, 24.1 mmol), heating to room temperature after the reaction is finished, reacting for 24 hours, monitoring the reaction, adding 100 mL of ice water in an ice bath after the reaction is completed, extracting the reaction liquid by using ethyl acetate (80 mL x 3), combining organic phases, washing the organic phases once by using saturated salt solution, drying by using anhydrous sodium sulfate, spin-drying, and carrying out column chromatography on a crude product to obtain 4.8g of the compound 3 with the yield of 68 percent.
Step 3)
The synthetic route is as follows:
Figure 916499DEST_PATH_IMAGE005
compound 3 (2.0 g, 5.7 mmol), compound 4 (0.64 g, 4.7 mmol), 1-hydroxybenzotriazole (HOBT, 0.96g, 7.1 mmol), benzotriazole-N, N' -tetramethyluronium hexafluorophosphate (HBTU, 2.7g, 7.1 mmol), N-diisopropylethylamine (DIPEA, 1.8g, 13.9 mmol) were added to 20 ml of N, N-dimethylformamide in this order to react at room temperature for 24 hours, the reaction was monitored, after completion of the reaction, 100 ml of water was added, the reaction solution was extracted with ethyl acetate (60 ml × 3), the organic layers were combined and washed with water once, brine once, dried over anhydrous sodium sulfate, spin-dried, and crude product column chromatography gave 1.4g of compound 5 in 68% yield.
Step 4)
The synthetic route is as follows:
Figure 115399DEST_PATH_IMAGE006
compound 6 (1.5 g, 5.6 mmol), compound 7 (0.94 g, 4.7 mmol), 1-Hydroxybenzotriazole (HOBT) (0.96 g, 7.1 mmol), benzotriazole-N, N' -tetramethyluronium hexafluorophosphate (HBTU, 2.7g, 7.1 mmol), N-diisopropylethylamine (DIPEA, 1.2g, 9.3 mmol) were added to 15 ml of N, N-dimethylformamide in this order, after completion, the reaction was stirred at room temperature for 24 hours, the reaction was monitored, after completion, 60ml of water was added, the reaction solution was extracted with ethyl acetate (50 ml × 3), the organic layers were combined and washed with water once, saturated salt once, dried over anhydrous sodium sulfate, spin-dried, and the crude product of column chromatography gave 1.7g of compound 8, yield 81%.
Step 5)
The synthetic route is as follows:
Figure 784278DEST_PATH_IMAGE007
dissolving a compound 8 (1.5 g and 3.3 mmol) in 15 ml of dichloromethane, slowly dropwise adding trifluoroacetic acid (0.95 g and 8.3 mmol) under stirring at room temperature, reacting at room temperature for 1 hour, monitoring the reaction, removing the trifluoroacetic acid after the reaction is completed, adjusting a crude product to be alkalescent by using a saturated sodium bicarbonate aqueous solution, extracting the dichloromethane (50 ml x 4), combining organic layers, washing once by using saturated salt solution, drying by using anhydrous sodium sulfate, and spin-drying to obtain 1.1g of a compound 9 which is directly used for the next reaction.
Step 6)
The synthetic route is as follows:
Figure 964592DEST_PATH_IMAGE008
adding compound 5 (1.0 g, 2.3 mmol), compound 9 (0.9 g, 2.6 mmol) and potassium carbonate (0.8 g, 5.8 mmol) into 20 ml of N, N-methylformamide in sequence, heating the reaction solution to 50 ℃ after the reaction is finished, reacting for 24 hours, monitoring the reaction, adding 60ml of water after the reaction is finished, extracting with ethyl acetate (30 ml x 3), combining organic layers and washing with water once, washing with saturated common salt water once, drying with anhydrous sodium sulfate, spin-drying, performing column chromatography on a crude product to obtain 1.1g of a final product with the yield of 68%, M/z, M +1=702.4
The detection result of the obtained product is shown in FIG. 1, which shows that the product is Lomitapide-D8.

Claims (3)

1. A method for synthesizing lometasai-D8, the structure of lometasai-D8 is shown as formula I,
Figure 980810DEST_PATH_IMAGE001
the method is characterized in that the synthetic route is as follows:
Figure 376019DEST_PATH_IMAGE002
the method comprises the following steps:
1) under the acidic condition, carrying out halogenation reaction on the compound 2a and hydrobromic acid to obtain a compound 2;
2) under the protection of nitrogen, firstly, carrying out hydrogen abstraction reaction on the compound 1 and n-butyllithium, and then adding the compound 2 for substitution reaction to prepare a compound 3;
3) carrying out condensation reaction on the compound 3 and the compound 4 in the presence of 1-hydroxybenzotriazole, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine to prepare a compound 5;
4) carrying out condensation reaction on a compound 6 and a compound 7 in the presence of 1-hydroxybenzotriazole, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine to prepare a compound 8;
5) removing tert-butyloxycarbonyl protection from the compound 8 and trifluoroacetic acid to obtain a compound 9;
6) carrying out substitution reaction on the compound 5 and the compound 9 in the presence of potassium carbonate to obtain lomitapide-D8;
in the step 1), the acid is concentrated sulfuric acid, the reaction temperature is 110 ℃, and the reaction time is 6 hours;
in the step 2), the reaction solvent is anhydrous tetrahydrofuran, the reaction condition of the compound 1 and n-butyllithium is 0 ℃ for 1 hour, and the reaction condition of adding the compound 2 is room temperature reaction for 24 hours;
in the step 3), the reaction solvent is N, N-dimethylformamide, the reaction temperature is room temperature, and the reaction time is 24 hours;
in the step 4), the reaction solvent is N, N-dimethylformamide, the reaction temperature is room temperature, and the reaction time is 24 hours;
in the step 5), the reaction solvent is dichloromethane, the reaction temperature is room temperature, and the reaction time is 1 hour;
in the step 6), the reaction solvent is N, N-methylformamide, the reaction temperature is 50 ℃, and the reaction time is 24 hours.
2. The method of claim 1, wherein the method comprises the steps of:
1) under the ice bath condition, slowly adding concentrated sulfuric acid into an aqueous solution of hydrobromic acid, then slowly adding a compound 2a, and after completion, heating to 110 ℃ for reacting for 6 hours to obtain a compound 2;
2) dissolving compound 1 in anhydrous tetrahydrofuran under nitrogen protection at 0oSlowly adding n-butyllithium under the condition of C, preserving heat, reacting for 1 hour, then adding the compound 2, heating to room temperature, and reacting for 24 hours to obtain a compound 3;
3) adding the compound 3, the compound 4, the 1-hydroxybenzotriazole, the benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate and the N, N-diisopropylethylamine into the N, N-dimethylformamide in sequence, and reacting at room temperature for 24 hours to obtain a compound 5;
4) adding the compound 6, the compound 7, the 1-hydroxybenzotriazole, the benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate and the N, N-diisopropylethylamine into the N, N-dimethylformamide in sequence, and stirring at room temperature for reacting for 24 hours to obtain a compound 8;
5) dissolving the compound 8 in dichloromethane, slowly dropwise adding trifluoroacetic acid while stirring at room temperature, and reacting at room temperature for 1 hour to obtain a compound 9;
6) and sequentially adding the compound 5, the compound 9 and potassium carbonate into N, N-methylformamide, heating to 50 ℃ and reacting for 24 hours to obtain the lomitapide-D8.
3. The method according to claim 1 or 2,
in the step 1), the molar ratio of the compound 2a to the hydrobromic acid is 1.0: 2.85;
in the step 2), the mol ratio of the compound 1, the n-butyllithium and the compound 2 is 1.0: 2.25: 1.20;
in the step 3), the molar ratio of the compound 3, the compound 4, the 1-hydroxybenzotriazole, the benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate to the N, N-diisopropylethylamine is 1.21: 1: 1.51: 1.51: 2.96;
in the step 4), the molar ratio of the compound 6, the compound 7, the 1-hydroxybenzotriazole, the benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate to the N, N-diisopropylethylamine is 1.19: 1: 1.51: 1.51: 1.98 of;
in the step 5), the molar ratio of the compound 8 to the trifluoroacetic acid is 1: 2.51;
in the step 6), the molar ratio of the compound 5 to the compound 9 to the potassium carbonate is 1: 1.13: 2.52.
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