Preparation of 1,8-diamino-3,6-dioxaoctane bifunctional derivatives

Abstract

The application discloses a preparation method of 1,8-diamino-3,6-dioxaoctane bifunctional derivative. Specifically provided is a preparation method of a compound of formula I, which comprises the following steps: performing condensation reaction on a compound of formula II and a compound of formula IV in an organic solvent in the presence of a condensing agent, and obtaining the compound of formula I, wherein the R group in the compound of formula IV is trifluoromethylsulfonyloxy, p-nitrobenzenesulfonyloxy or halogen. The preparation method has high yield and purity, and raw materials are cheap, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of 1,8-diamino-3,6-dioxaoctane bifunctional derivative preparation. BACKGROUND

[0002] 1,8-diamino-3,6-dioxaoctane is an organic compound, chemical formula C6H 12 N2O2. It is composed of 6 carbon atoms and 2 nitrogen atoms, with 2 oxygen atoms connected in the middle. It is a colorless transparent liquid at room temperature and normal pressure, and is soluble in water and common organic solvents. 1,8-diamino-3,6-dioxaoctane molecule contains two amino groups and two glycol ether groups, and these functional groups are polar functional groups, so this compound is a polar molecule, has polar interaction, and can interact with polar molecules and ions. Because the molecule has high polarity, the interaction between molecules is strong, so the boiling point of the compound is relatively high.

[0003] 1,8-diamino-3,6-dioxaoctane is an important raw material for the synthesis of macrocyclic coordination compounds, and has wide application in supramolecular chemistry, especially in crown ether chemistry. In addition, due to its structure with two amino groups at 1,8 position, it can also be used as a linker for protease, for modification and coupling of bioactive molecules. 1,8-diamino-3,6-dioxaoctane can be used as an intermediate in pharmaceutical chemistry, such as the drug tinaparano for treating adult constipation type irritable bowel syndrome, which can also be used to treat hyperphosphatemia in patients with heart and kidney disease undergoing dialysis. In summary, 1,8-diamino-3,6-dioxaoctane is an important organic compound with wide application. It has important application and development prospect in the fields of organic synthesis, semiconductor materials, drugs, coatings, etc.

[0004] However, in the application of 1,8-diamino-3,6-dioxaoctane, one amino group is often derivatized and protected, and after the derivatization of the unprotected amino group, the protecting group is removed and the derivatization of the other amino group is carried out. In the process of amino protection, a large excess of 1,8-diamino-3,6-dioxaoctane (about 10 equivalents, Chemical Communications, 2006, 11,1182-1184; CN115612090A) is needed to control the proportion of single protection product. Although the preparation method of double derivative is disclosed in the prior art, the raw materials are expensive, which is not suitable for industrial production. SUMMARY

[0005] In view of the defects of existing preparation methods with high reaction temperature and expensive raw materials, the present application provides a new preparation method of 1,8-diamino-3,6-dioxaoctane bifunctional derivative, which has high yield and purity, and the raw materials are cheap, suitable for industrial production.

[0006] Specifically, the present application provides a preparation method of a compound of formula I, which comprises the following steps: performing a condensation reaction of a compound of formula II with a compound of formula IV in an organic solvent in the presence of a condensing agent to prepare the compound of formula I, wherein the R group in the compound of formula IV is trifluoromethylsulfonyloxy, p-nitrobenzenesulfonyloxy or halogen.

[0007] .

[0008] In some embodiments, in the condensation reaction, the organic solvent is anhydrous tetrahydrofuran or N, N-dimethylacetamide.

[0009] In some embodiments, in the condensation reaction, the molar volume ratio of the compound of formula II to the organic solvent is 0.6 mol / L-2 mol / L.

[0010] In some embodiments, in the condensation reaction, the condensing agent is sodium hydride or a mixture of sodium hydride and tetrabutylammonium halide, such as tetrabutylammonium iodide or tetrabutylammonium bromide.

[0011] In some embodiments, in the condensation reaction, the halogen is chlorine or bromine.

[0012] In some embodiments, in the condensation reaction, when the R group is trifluoromethylsulfonyloxy or p-nitrobenzenesulfonyloxy, the condensing agent is sodium hydride (e.g., 60% sodium hydride); the molar ratio of sodium hydride to the compound of formula II is preferably 2.1:1.

[0013] In some embodiments, in the condensation reaction, when the R group is halogen, the condensing agent is a mixture of sodium hydride (e.g., 60% sodium hydride) and tetrabutylammonium halide; the molar ratio of sodium hydride to the compound of formula II is preferably 2.3:1; the molar ratio of tetrabutylammonium halide to the compound of formula II is preferably 0.1:1.

[0014] In some embodiments, in the condensation reaction, the molar ratio of the compound of formula IV to the compound of formula II is 1:1.

[0015] In some embodiments, the reaction temperature of the condensation reaction is an ice water bath (e.g., below 5°C) or room temperature.

[0016] In some embodiments, the preparation method of the compound of formula I further comprises preparing the compound of formula II by performing an amino protection reaction of ethanolamine with di-tert-butyl dicarbonate in an organic solvent to prepare the compound of formula II, as shown below.

[0017] .

[0018] In some embodiments, in the amino protection reaction, the organic solvent is toluene.

[0019] In some embodiments, in the amino protection reaction, the mass volume ratio of the ethanolamine to the organic solvent is 1 g:3.1 mL.

[0020] In some embodiments, in the amino protection reaction, the mass ratio of the ethanolamine to di-tert-butyl dicarbonate is 1:3.4.

[0021] In some embodiments, the reaction temperature of the amino protection reaction is room temperature.

[0022] In some embodiments, when the R group is trifluoromethylsulfonyloxy or p-nitrobenzenesulfonyloxy, the method for preparing the compound of formula I further comprises preparing a compound of formula IV by subjecting a compound of formula III to a condensation reaction with a sulfonyl chloride or an anhydride in an organic solvent in the presence of a base to form a compound of formula IV; the sulfonyl chloride or anhydride is trifluoromethylsulfonyl chloride, p-nitrobenzenesulfonyl chloride, trifluoromethylsulfonic anhydride or p-nitrobenzenesulfonic anhydride;

[0023] .

[0024] In some embodiments, in the condensation reaction, the organic solvent is dichloromethane.

[0025] In some embodiments, in the condensation reaction, the molar volume ratio of the compound of formula III to the organic solvent is 0.4 mol / L.

[0026] In some embodiments, in the condensation reaction, the base is triethylamine.

[0027] In some embodiments, in the condensation reaction, the molar ratio of the base to the compound of formula III is 1.2:1.

[0028] In some embodiments, in the condensation reaction, the molar ratio of the sulfonyl chloride or anhydride to the compound of formula III is 1.1:1.

[0029] In some embodiments, the reaction temperature of the condensation reaction is room temperature.

[0030] In some embodiments, when the R group is bromine or chlorine, the method for preparing the compound of formula I further comprises preparing a compound of formula IV by subjecting a compound of formula III to a substitution reaction with carbon tetrabromide or dichlorosulfoxide to form a compound of formula IV, and

[0031] .

[0032] In some embodiments, when R is bromine, the reaction system of the substitution reaction further comprises an organic solvent and triphenylphosphine;

[0033] The organic solvent is preferably tetrahydrofuran; and the molar volume ratio of the compound of formula III to the organic solvent is preferably 0.8 mol / L.

[0034] The molar ratio of the triphenylphosphine to the compound of formula III is preferably 1.5:1.

[0035] In some embodiments, in the substitution reaction, the molar ratio of the carbon tetrabromide to the compound of formula III is 1.2:1.

[0036] In some embodiments, when R is bromine, the method further comprises the following operation: mixing the product obtained after the substitution reaction with toluene and anhydrous calcium chloride.

[0037] In some embodiments, when R is bromine, the reaction temperature of the substitution reaction is room temperature.

[0038] In some embodiments, when R is chlorine, the reaction system of the substitution reaction does not need to add an organic solvent, and the molar volume ratio of the compound of formula III to the thionyl chloride is 2.1 mol / L.

[0039] In some embodiments, when R is chlorine, the reaction temperature of the substitution reaction is heated to reflux.

[0040] In some embodiments, the method for preparing the compound of formula I further comprises preparing the compound of formula III by the following steps: condensing 2-(2-aminoethoxy)ethanol with phthalic anhydride in an organic solvent to obtain the compound of formula III as shown below:

[0041] .

[0042] In some embodiments, in the condensation reaction, the organic solvent is toluene.

[0043] In some embodiments, in the condensation reaction, the molar volume ratio of the 2-(2-aminoethoxy)ethanol to the organic solvent is 1.0 mol / L.

[0044] In some embodiments, in the condensation reaction, the molar ratio of the 2-(2-aminoethoxy)ethanol to the phthalic anhydride is 1:1.

[0045] In some embodiments, the reaction temperature of the condensation reaction is heated to reflux.

[0046] The above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present application.

[0047] The reagents and raw materials used in the present application are commercially available.

[0048] The positive progress effect of the present application is that the present application provides a new preparation method of 1,8-diamino-3,6-dioxaoctane bifunctional derivative, which has high yield and purity, and the reaction raw materials are cheap and suitable for industrial production. DETAILED DESCRIPTION

[0049] The present application will be further described by way of examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples are not specified, and the methods are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0050] Example 1 Preparation of compound II:

[0051]

[0052] Under nitrogen protection, 100 mL of toluene and 64 g of ethanolamine were added to a reaction bottle. A solution of 218 g of di-tert-butyl dicarbonate in 100 mL of toluene was added dropwise to the resulting solution at room temperature, and reacted at room temperature for 4-5 hours. The reaction solution was washed with 5% sodium chloride solution (100 mL x 3), and the organic phase was concentrated to obtain an oily liquid 161 g with a yield of 100%. MS (M+H): 162, 1 H NMR (400 MHz, CDCl3): δ (ppm) 1.43 (s, 9H), 3.2-3.1 (bs, 1H), 3.25 (bd, 2H), 3.65 (t, 2H, J = 5.04 Hz), 1H 5.13 (bs, 1H)

[0053] Example 2 Preparation of compound III:

[0054]

[0055] Into a reaction bottle, 11.0 g of 2-(2-aminoethoxy)ethanol (100 mmol), 14.8 g of phthalic anhydride (100 mmol), and 105 mL of toluene were added, heated to reflux, and water was removed while refluxing for 8 hours. After cooling to room temperature, the reaction solution was washed with water (30 mL x 2 times), and the organic phase was concentrated to dryness under reduced pressure. 50 mL of n-heptane was added, stirred for 30 minutes, filtered, and dried under vacuum to obtain a white solid 22.7 g with a yield of 96.6%. MS (M+H + ): 236, 1H NMR (400MHz, CDCl3): δ(ppm) 3.61 (m, 2H),3.69 (m, 2H), 3.75 (t, 2H), 3.91 (t, 2H), 5.21(bs, 1H), 7.73 (m, 2H), 7.85(m, 2H).

[0056] Example 3 Preparation of compound IV:

[0057]

[0058] Method one, R is sulfonyloxy derivative

[0059] Into a reaction flask was placed 23.5 g of compound III (100 mmol), 12.1 g of triethylamine (120 mmol), and 118 mL of dichloromethane and cooled to below 5°C with an ice water bath. With stirring, a solution of 105 mmol of sulfonyl chloride (or anhydride) in 118 mL of dichloromethane was added dropwise to the solution at a temperature not to exceed 10°C. After the addition was complete, the ice water bath was removed and stirring was continued until TLC indicated that the reaction of compound III was complete. To the reaction was added 100 mL of water and stirring was continued at room temperature for 2-3 hours. The phases were separated. The organic phase was washed successively with 1 M hydrochloric acid (50 mL*2), 5% sodium bicarbonate solution (50 mL*2), and 50 mL of water. The organic phase was concentrated to dryness under reduced pressure. 118 mL of n-heptane was added, the mixture was stirred at room temperature for 10-20 minutes, filtered, and dried under vacuum.

[0060] R is trifluoromethylsulfonyloxy

[0061] A yellow solid, 30.1 g, was obtained in a yield of 96.2%. MS (M+H + ): 368. 1 H NMR (400 MHz, CDCl3) δppm: 3.55 (m, 4H), 3.60 (t, 2H), 3.80 (t, 2H), 3.85 (t, 2H), 4.29 (t, 2H),7.65 (m, 2H), 7.81 (m, 2H).

[0062] R is 4-nitrobenzenesulfonyloxy

[0063] A yellow solid, 30.1 g, was obtained in a yield of 96.2%. MS (M+H + ): 314. 1H NMR (400 MHz, CDCl3) δppm: 3.71-3.75 (m, 4H), 3.91 (t, 2H), 4.31-4.33 (d, 2H), 7.71-7.75(m, 2H),7.81-7.85 (m, 2H) 8.41 (d, 2H), 8.14 (dd, 2H).

[0064] Method two: R is bromo

[0065] To a reaction flask was added 23.5 g of compound III (100 mmol), 393 g of triphenylphosphine (150 mmol) and 39.8 g of carbon tetrabromide (120 mmol) was added portionwise with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature until TLC showed that compound III was consumed. The reaction was concentrated to dryness under reduced pressure. To the residue was added 470 mL of toluene and 80 g of anhydrous calcium chloride. The mixture was stirred at room temperature for 16 hours and filtered. The filtrate was concentrated to about 50 mL under reduced pressure. The mixture was cooled to 0 °C and stirred for 2 hours. The mixture was filtered and the filter cake was rinsed with n-heptane and dried under vacuum to give a yellowish solid 24.3 g in 81.5% yield. MS (M+H + ): 298, 3.41 (t, 2H), 3.76-3.81 (m, 4H), 3.92 (t, 2H), 7.70-7.74 (m, 2H), 7.79-7.85 (m, 2H)

[0066] Method three: R is chloro

[0067] To a reaction flask was added 23.5 g of compound III (100 mmol) and 47 mL of dichloro sulfoxide. The mixture was heated to reflux and allowed to react until TLC showed that compound III was consumed. The reaction was concentrated to dryness under reduced pressure. To the residue was added 50 mL of n-heptane. The mixture was stirred for 20-30 minutes and concentrated to dryness under reduced pressure. To the residue was added 100 mL of n-heptane. The mixture was cooled to 0 °C and stirred for 2 hours. The mixture was filtered and the filter cake was rinsed with n-heptane and dried under vacuum to give a yellowish solid 19.8 g in 78.0% yield. MS (M+H + ): 254, 3.44 (t, 2H), 3.77-3.82 (m, 4H), 3.91 (t, 2H), 7.71-7.75 (m, 2H), 7.78-7.83 (m, 2H)

[0068] Example 4 Preparation of compound I:

[0069] Method one: R is sulfonyloxy derivative

[0070]

[0071] Dissolve 16.1 g of compound II (100 mmol) in 80 mL of dry tetrahydrofuran and cool to below 5°C with an ice-water bath. Add 4.2 g of NaH (60%, 210 mmol) while maintaining the temperature below 5°C and stir for 0.5-1 hour with the ice-water bath. Then add a solution of 100 mmol of compound IV in 80 mL of dry tetrahydrofuran while maintaining the temperature below 5°C. After the addition, remove the ice-water bath and stir at room temperature until TLC shows that the reaction of compound IV is complete, or heat if necessary. Cool to 0°C with an ice-water bath and add 5 mL of ethanol, then 200 mL of saturated sodium bicarbonate solution, while maintaining the temperature below 5°C. Concentrate under reduced pressure to about 150 mL, add 80 mL of ethyl acetate, separate, and wash the organic phase with water (80 mL x 2). Concentrate the organic phase under reduced pressure to dryness to give an oily liquid. 1 H NMR (400 MHz, CDCl3): δ(ppm) 1.36 (s, 9 H), 3.18-3.61 (m, 12 H), 7.58 (bs, 1 H), 7.74 (dd, 2 H),7.80 (dd, 2 H).

[0072] R is trifluoromethylsulfonyloxy: react at room temperature until the sulfonate disappears, and then process to give 33.2 g, yield: 87.8%

[0073] R is p-nitrobenzenesulfonyloxy: react at about 35°C until the sulfonate disappears, and then process to give 25.3 g, yield: 66.9%.

[0074] Method two, R is halogen

[0075] Dissolve 100 mmol of compound IV, 10 mmol of tetrabutylammonium halide, and 16.9 g of compound II (105 mmol) in 50 mL of N,N-dimethylacetamide and cool to below 5°C with an ice-water bath. Slowly add 5.76 g of NaH (60%, 240 mmol) while maintaining the temperature below 5°C. After the addition, continue stirring for 2 hours with the ice-water bath. Remove the ice-water bath and stir at room temperature until TLC shows that compound IV is gone. Slowly add 9.2 g of ethanol, 100 mL of water, and 200 mL of toluene while maintaining the temperature below 30°C. Adjust the pH to 6-7 while stirring, separate, wash the organic phase with 5% sodium bicarbonate solution (50 mL x 2), and concentrate the organic phase under pressure to give compound I.

[0076] R is chloro: tetrabutylammonium halide is tetrabutylammonium iodide, and process to give 27.2 g, yield: 72.0%

[0077] R is bromo: tetrabutylammonium halide is tetrabutylammonium bromide, and process to give 29.8 g, yield: 78.8%

[0078] Example 5 Preparation of compound VI:

[0079]

[0080] 3.78 g of compound I was dissolved in ethyl acetate, and a 2 M HCl solution in ethyl acetate was added at room temperature. After the addition was complete, the mixture was stirred at room temperature until TLC showed that compound I had disappeared. The solution was filtered and dried under reduced pressure to give 3.10 g of a white solid, yield: 98.4%. MS (M+H) + ):279.

[0081] Example 6 Preparation of compound VI:

[0082]

[0083] Add 3.78 g of compound I, 20 mL of ethanol, and 2 g of hydrazine hydrate (80%) to a reaction flask. Heat to reflux and maintain the reaction temperature until TLC shows the disappearance of compound I. Cool to room temperature, concentrate to dryness under reduced pressure, add 50 mL of tetrahydrofuran and 2 g of citric acid, stir for 3-4 hours, filter, and wash the filter cake with 20 mL of tetrahydrofuran. Add the filter cake to water, adjust the pH to 9-10 with sodium carbonate, and extract with toluene (10 mL * 3 times). Combine the organic phases, wash with 10 mL of saturated sodium chloride, dry to anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to give 2.1 g of an oily liquid, yield: 84.7%. MS (M+H) + ): 249.

[0084] Comparative Example

[0085] 1. Referring to Method 1 of Example 3, when R is methylsulfonyloxy or R is p-toluenesulfonyloxy, compound IV was prepared, and the results are as follows:

[0086] R is p-toluenesulfonyloxy

[0087] 37.1 g of white solid was obtained, yield: 95.4%. MS (M+H) + ): 390. 1 H NMR (400 MHz, CDCl3) δppm: 2.41 (s, 3H), 3.51 (m, 4H), 3.58 (t, 2H), 3.66 (t, 2H), 3.84 (t, 2H), 4.06 (t, 2H), 7.30 (d, 2H), 7.68 (m, 2H), 7.74 (d, 2H), 7.80 (m, 2H).

[0088] R is methylsulfonyloxy

[0089] 30.1 g of white solid was obtained, yield: 96.2%. MS (M+H) +): 314. 1 H NMR (400 MHz, CDCl3) δppm: 2.98 (s, 3H), 3.71-3.76 (m, 4H), 3.88 (t, 2H), 4.27-4.31 (m, 2H), 7.70-7.75 (m, 2H), 7.82-7.84 (m, 2H).

[0090] 2. Referring to Method 1 of Example 4, when R is methylsulfonyloxy or R is p-toluenesulfonyloxy, compound I was prepared, and the results are as follows:

[0091] R is methylsulfonyloxy: reflux until the sulfonate ester disappears, and 5.5 g is obtained by column purification, yield 14.6%.

[0092] R is p-toluenesulfonyloxy: reflux until the sulfonate ester disappears: 13.8 g, yield: 36.5%.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: performing a condensation reaction of a compound of formula II with a compound of formula IV in an organic solvent in the presence of a condensing agent to prepare the compound of formula I, wherein R is trifluoromethylsulfonyloxy or p-nitrobenzenesulfonyloxy; and the condensing agent is sodium hydride. ； The method for preparing the compound of formula I satisfies one or more of the following conditions:

2. The production method according to claim 1, wherein (1) In the condensation reaction, the organic solvent is anhydrous tetrahydrofuran or N, N-dimethylacetamide; (2) In the condensation reaction, the molar volume ratio of the compound of formula II to the organic solvent is 0.6 mol / L-2 mol / L; (3) In the condensation reaction, the molar ratio of sodium hydride to the compound of formula II is 2.1:1; (4) In the condensation reaction, the molar ratio of the compound of formula IV to the compound of formula II is 1:

1. The method for preparing the compound of formula I further comprises preparing the compound of formula II by performing an amino protection reaction of ethanolamine with di-tert-butyl dicarbonate in an organic solvent to prepare the compound of formula II, wherein 3. The production method according to claim 1, wherein The method for preparing the compound of formula II satisfies one or more of the following conditions: 。 4. The production method according to claim 3, wherein (1) In the amino protection reaction, the organic solvent is toluene; (2) In the amino protection reaction, the mass-volume ratio of ethanolamine to the organic solvent is 1 g:3.1 mL; (3) In the amino protection reaction, the mass ratio of ethanolamine to di-tert-butyl dicarbonate is 1:3.

4. The method for preparing the compound of formula I further comprises preparing the compound of formula IV by performing a condensation reaction of a compound of formula III with sulfonyl chloride or anhydride in an organic solvent in the presence of a base to prepare the compound of formula IV, wherein the sulfonyl chloride or anhydride is trifluoromethylsulfonyl chloride, p-nitrobenzenesulfonyl chloride, trifluoromethylsulfonic anhydride, or p-nitrobenzenesulfonic anhydride.

5. The production method according to claim 1, wherein The method for preparing the compound of formula IV satisfies one or more of the following conditions: 。 6. The production method according to claim 5, wherein (1) In the condensation reaction, the organic solvent is dichloromethane; (2) In the condensation reaction, the molar volume ratio of the compound of formula III to the organic solvent is 0.4 mol / L; (3) In the condensation reaction, the base is triethylamine; (4) In the condensation reaction, the molar ratio of the base to the compound of formula III is 1.2:1; (5) In the condensation reaction, the molar ratio of the sulfonyl chloride or anhydride to the compound of formula III is 1.1:

1. The method for preparing the compound of formula I further comprises preparing the compound of formula III by performing a condensation reaction of 2-(2-aminoethoxy)ethanol with phthalic anhydride in an organic solvent to prepare the compound of formula III, wherein 7. The production method according to claim 5, wherein The method for preparing the compound of formula III satisfies one or more of the following conditions: 。 8. The production method according to claim 7, wherein (1) In the condensation reaction, the organic solvent is toluene; (2) In the condensation reaction, the molar volume ratio of 2-(2-aminoethoxy)ethanol to the organic solvent is 1.0 mol / L; ​ (3) In the condensation reaction, the molar ratio of 2-(2-aminoethoxy)ethanol to phthalic anhydride is 1:

1. (3) In the condensation reaction, the molar ratio of 2-(2-aminoethoxy)ethanol to phthalic anhydride is 1:1.

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