Preparation method and intermediate of tris(hydroxyalkyl)methylamine

Abstract

The present invention discloses a method for preparing tris(hydroxyalkyl)methylamine and an intermediate thereof, belonging to the field of organic synthesis. The present invention provides a new intermediate, compound 4, for the synthesis of tris(hydroxyalkyl)methylamine. Compound 4 is sequentially reacted with ozone and a reducing agent to obtain a new intermediate, compound 5. The amino group is then deprotected to obtain the target compound, tris(hydroxyalkyl)methylamine, represented by formula 6. The present method is simpler and more suitable for industrialization, and a range of tris(hydroxyalkyl)methylamines can be obtained by simply varying the carbon chain length of the raw materials.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a preparation method and intermediate of tris(hydroxyalkyl)methylamine. Background Art

[0002] Tris(hydroxyalkyl)methylamine refers to a series of compounds including tris(hydroxymethyl)methylamine, tris(2-hydroxyethyl)methylamine, and tris(3-hydroxypropyl)methylamine. Most of these compounds have similar chemical properties and have broad application prospects.

[0003] According to literature reports, tris(hydroxyalkyl)methylamine can be used to prepare buffer solutions with acidic reagents such as hydrochloric acid (for example, journal literature Li D, Chen R, Zhu X, et al. Light fueled mixing in open surface droplet microfluidics for rapid probe preparation. [J]. Physical chemistry chemical physics, 2021, 23(46): 26356-26365.), and can also be used to form salts with active substances with carboxylic acid groups to obtain new crystal forms of some drugs (for example, patent literature US20110230524).

[0004] In the prior art, George R. Newkome et al. (George R. Newkome, Charles N. Moorefield, et A Convenient Synthesis of "Bis-homotris": 4-Amino-4-[1-(3-hydroxypropyl)]-1,7-heptanediol and 1-Azoniapropellane. [J]. J. Org. Chem. 1988, 53, 5552-5554.) reported a method for preparing tris(3-hydroxypropyl)methylamine. The specific reaction formula is as follows:

[0005]

[0006] As can be seen from the above formula, since its starting material is acrylonitrile, it cannot be used to prepare tris(hydroxymethyl)methylamine or tris(2-hydroxyethyl)methylamine, and is not universally applicable. In addition, it is also recorded that its first step reaction is highly exothermic, so it is not suitable for industrial production.

[0007] D.W. Moore et al. (CN 104254516A) reported a method for preparing tris(hydroxymethyl)methylamine. The method uses formaldehyde and nitromethane as starting materials to react to produce tris(hydroxymethyl)nitromethane, which is then reduced to produce tris(hydroxymethyl)methylamine. However, this method is limited to the preparation of tris(hydroxymethyl)methylamine. If an aldehyde with a longer carbon chain (such as acetaldehyde) is used instead of formaldehyde, the resulting product has a hydroxyl group located at the beta position of the nitro group, rather than a product with a hydroxyl group at the alkyl end. Summary of the Invention

[0008] The present invention is made to solve the above problems, and aims to provide a preparation method of tris(hydroxyalkyl)methylamine with milder reaction conditions and capable of being used to prepare more types of tris(hydroxyalkyl)methylamine, and an intermediate formed by synthesizing tris(hydroxyalkyl)methylamine using the method.

[0009] The present invention provides a method for preparing tris(hydroxyalkyl)methylamine, which has the following characteristics and comprises the following reaction steps:

[0010]

[0011] In the above formula, PG is an amino protecting group, and x and y are independently selected from any integer between 0 and 5.

[0012] Step 1, compound 4 reacts with ozone and a reducing agent in sequence to obtain compound 5;

[0013] Step 2: Compound 5 reacts with an amino protecting group removal reagent to obtain compound 6.

[0014] In one embodiment of the present invention, x=y=0 or 1.

[0015] In one embodiment of the present invention, the reducing agent is a metal complex hydride compound, which is selected from any one or more of sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, and sodium thioborohydride.

[0016] In one embodiment of the present invention, the amino protecting group is selected from benzyloxycarbonyl, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, p-methoxybenzyl, benzyl, trityl, p-toluenesulfonyl, phthaloyl, and allyloxycarbonyl.

[0017] In one embodiment of the present invention, in step 1, compound 4 is mixed with an organic solvent 1 and an alkaline reagent, and the temperature is controlled at -50°C to -80°C (specifically, -78°C), and ozone is introduced to react; after the reaction is completed, the temperature is returned to 0°C to 10°C (specifically, 0°C), and an organic solvent 2 and a reducing agent are added, and then the temperature is raised to room temperature to react to obtain compound 5.

[0018] In one embodiment of the present invention, the concentration of compound 4 relative to organic solvent 1 is 0.2-0.5 mol / L; specifically, 0.35 mol / L.

[0019] In one embodiment of the present invention, the organic solvent 1 and the organic solvent 2 are independently selected from one or a combination of methanol and dichloromethane. In particular, the organic solvent 1 and the organic solvent 2 are preferably a combination of methanol and dichloromethane, and the volume ratio of the two is 1:1.

[0020] In one embodiment of the present invention, the volume ratio of the organic solvent 1 to the organic solvent 2 is 2:1.

[0021] In one embodiment of the present invention, the alkaline agent is selected from any one or more of sodium bicarbonate, sodium carbonate or sodium hydroxide. The molar ratio of the alkaline agent to compound 4 is (2-4):1.

[0022] In one embodiment of the present invention, the molar ratio of the reducing agent to compound 4 is (8-15):1, and can be specifically 10:1.

[0023] In one embodiment of the present invention, when the amino protecting group is benzyloxycarbonyl or benzyl, in step 2, compound 5 is dissolved in organic solvent 3, and then Pd / C / hydrogen is used as an amino deprotection reagent and heated to react.

[0024] In one embodiment of the present invention, the organic solvent 3 is an alcohol solvent, preferably methanol and / or ethanol.

[0025] The present invention provides an intermediate for synthesizing tris(hydroxyalkyl)methylamine, the structure of which is shown in Formula 4:

[0026]

[0027] In the above formula, PG is an amino protecting group, and x and y are independently selected from any integer between 0 and 5.

[0028] In one embodiment of the present invention, PG is benzyloxycarbonyl or tert-butyloxycarbonyl.

[0029] In one embodiment of the present invention, x=y=1.

[0030] In one embodiment of the present invention, the preparation process of the above intermediate comprises:

[0031]

[0032] Wherein, X is a halogen (Br, Cl, I), and x and y are independently selected from any integer between 0 and 5;

[0033] A. First, compound 1 reacts with compound 2 to obtain compound 3;

[0034] B. Compound 3 then reacts with an amino protecting agent to obtain compound 4.

[0035] In one embodiment of the present invention, in step A, compound 2 is dispersed in a tetrahydrofuran solution, cooled to -10-5°C, and then a diethyl ether solution of compound 1 is added dropwise, and then the temperature is raised to 40-60°C and reacted for a period of time to obtain compound 3.

[0036] In one embodiment of the present invention, after the reaction is completed, the reaction solution is mixed with a saturated aqueous ammonium chloride solution, and then the pH is adjusted to 3-4, extracted, and the organic phase is collected and then concentrated to obtain compound 3.

[0037] In one embodiment of the present invention, the molar ratio of compound 1 to compound 2 in step A is 1:(2-3).

[0038] In one embodiment of the present invention, the concentration of the ether solution of Compound 1 in Step A is 0.3-1.0 g / mL, and specifically 0.5 g / mL.

[0039] In one embodiment of the present invention, the concentration of compound 2 dispersed in tetrahydrofuran solution in step A is 0.8-1.5 mol / L; specifically, 1.0 mol / L is optional.

[0040] In one embodiment of the present invention, in step B, compound 3 is dispersed in a solvent, and an alkali reagent and an amino protecting reagent are added, followed by mixing and reacting.

[0041] In one embodiment of the present invention, the molar ratio of the alkaline reagent, the amino protecting reagent and the compound 3 is (2-4): (1-2):1.

[0042] In one embodiment of the present invention, the alkaline reagent is diisopropylethylamine or triethylamine. The amino protecting reagent is selected from any one of benzyl chloroformate, tert-butyl chloroformate, and di-tert-butyl dicarbonate.

[0043] The present invention provides an intermediate for synthesizing tris(hydroxyalkyl)methylamine, the structure of which is shown in Formula 5:

[0044]

[0045] In the above formula, PG is an amino protecting group, and x and y are independently selected from any integer between 1 and 5.

[0046] In one embodiment of the present invention, PG is benzyloxycarbonyl or tert-butyloxycarbonyl.

[0047] In one embodiment of the present invention, x=y=1.

[0048] Functions and effects of the invention

[0049] According to the method for preparing tris(hydroxyalkyl)methylamine involved in the present invention, because a terminal olefinic compound is treated with ozone / reducing agent, the terminal olefinic group can be converted into a hydroxyl group having one less carbon atom. Therefore, the preparation method provided by the present invention is simpler and more suitable for industrialization. Moreover, a series of tris(hydroxyalkyl)methylamines can be obtained by simply changing the carbon chain length of the raw material, which is more universally applicable than the existing technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 is a high performance liquid chromatogram of compound 6a prepared in Example 4;

[0051] Figure 2 is the H NMR spectrum of compound 6a prepared in Example 4. DETAILED DESCRIPTION

[0052] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is described in detail below with reference to embodiments and drawings.

[0053] In the following examples, unless otherwise specified, all raw materials are commercially available products.

[0054] <Example 1>

[0055] Preparation method of compound 3a

[0056] This example provides a method for preparing compound 3a, and the reaction formula is as follows:

[0057]

[0058] The steps include:

[0059] Under nitrogen, 3.36 L of a tetrahydrofuran solution (1.0 mol / L) of compound 2a was added to a reaction vessel, and the temperature was lowered to 0°C. 200 mL of a diethyl ether solution (500 g / L, 1.49 mol) of compound 1a was added dropwise to the reaction vessel. After the addition was complete, the temperature was raised to 45°C and stirred for 4 h. The reaction was complete by TLC. The reaction solution was poured into 5 L of a saturated aqueous ammonium chloride solution, and the pH was adjusted to 3 with a 2 mol / L aqueous hydrochloric acid solution. The organic phase was extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 158.5 g of compound 3a (a yield of 70.3%) as a light yellow oil, which could be used directly in the next step without further purification.

[0060] 1H NMR (400MHz, Chloroform-d) δ5.79 (ddt, J=17.5, 10.2, 7.5Hz, 3H), 5.14–4.96 (m, 6H), 2.06 (d, J=7.5Hz, 6H).

[0061] <Example 2>

[0062] Preparation method of compound 4a

[0063] This example provides a method for preparing compound 4a, and the reaction formula is as follows:

[0064]

[0065] The steps include:

[0066] 150 g of compound 3a (0.99 mol, 1.0 eq) was dissolved in 2 L of dichloromethane, followed by the addition of 385 g of diisopropylethylamine (2.98 mol, 3.0 eq) and 280 g of benzyl chloroformate (1.64 mol, 1.66 eq). The mixture was stirred at 25°C for 3 h. TLC indicated completion of the reaction. The mixture was extracted with 750 mL of 2 mol / L aqueous hydrochloric acid. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under pressure, and purified by column chromatography to afford 180.0 g of compound 4a (63.7% yield) as a yellow liquid.

[0067] LCMS: m / z(ESI),[M+H] + =286.

[0068] 1 H NMR (400MHz, DMSO-d6) δ7.39–7.28(m,5H),6.90(s,1H),5.81–5.67(m,3H),5.11–4.97(m,8H),2.32(d,J=7.2Hz,6H).

[0069] <Example 3-1>

[0070] Preparation method of compound 5a

[0071] This example provides a method for preparing compound 5a, and the reaction formula is as follows:

[0072]

[0073] The steps include:

[0074] 200 g of compound 4a (0.70 mol, 1.0 eq) and 1 L of methanol were added to 1 L of dichloromethane, and 176.4 g of sodium bicarbonate (2.10 mol, 3.0 eq) was added. The temperature was lowered to -78°C, and ozone was introduced (at a rate of 1 L / min for 10 h). The reaction solution turned blue, and the reaction was stirred for 10 h (the timer started from the time of ozone introduction).

[0075] The resulting reaction solution was returned to 0°C, and 0.5 L of methanol and 0.5 L of dichloromethane were added, followed by 266 g of sodium borohydride (7.0 mol, 10.0 eq). The temperature was raised to 25°C, and the mixture was stirred for reaction for 2 h.

[0076] The reaction was complete after LCMS detection. The mixture was cooled to 0°C in an ice-water bath and the pH value was adjusted to 5 with 4 mol / L aqueous hydrochloric acid. The mixture was filtered through celite and the filtrate was concentrated and purified by column chromatography to obtain 172 g of compound 5a (yield 82.6%) as a colorless liquid.

[0077] LCMS: m / z(ESI),[M+H] + =298.

[0078] 1H NMR (400MHz, Methanol-d4) δ7.36–7.29(m,5H),5.01(s,2H),3.65(t,J=7.1Hz,6H),1.98(t,J=7.2Hz,6H).

[0079] <Example 3-2>

[0080] Preparation method of compound 5a

[0081] This example provides a method for preparing compound 5a, and the reaction formula is as follows:

[0082]

[0083] The steps include:

[0084] 200 g of compound 4a (0.70 mol, 1.0 eq) was added to 2 L of dichloromethane, and 176.4 g of sodium bicarbonate (2.10 mol, 3.0 eq) was added. The temperature was lowered to -78°C, and ozone was introduced (at a rate of 1 L / min for 10 h). The reaction solution turned blue, and the reaction was stirred for 10 h (the timer started from the time of ozone introduction).

[0085] The resulting reaction solution was returned to 0°C, 1 L of methanol was added, 266 g of sodium borohydride (7.0 mol, 10.0 eq) was added, and the temperature was raised to 25°C and stirred for reaction for 2 h.

[0086] The reaction was complete after LCMS detection. The mixture was cooled to 0°C in an ice-water bath and the pH value was adjusted to 5 with 4 mol / L aqueous hydrochloric acid. The mixture was filtered through celite and the filtrate was concentrated and purified by column chromatography to obtain 144.7 g of compound 5a (yield 69.5%) as a colorless liquid.

[0087] <Example 4>

[0088] Preparation method of compound 6a

[0089] This example provides a method for preparing compound 6a, and the reaction formula is as follows:

[0090]

[0091] The steps include:

[0092] Dissolve 70 g of compound 5a in 700 mL of methanol, add 7 g of 10 wt% palladium-on-carbon catalyst, replace the hydrogen atmosphere, and heat to 40°C with stirring for 5 h. TLC monitoring indicated the reaction was complete. The mixture was filtered through celite and concentrated under reduced pressure to remove the solvent, yielding 31.5 g of compound 6a (82% yield, 99.9% purity) as a white solid.

[0093] The HPLC chromatogram and H-spectrum of compound 6a are shown in Figure 2. Figure 1-2 shown.

[0094] HPLC (ELSD): Rt=1.844 min, HPLC purity: 99.9%.

[0095] 1 H NMR (400MHz, DMSO-d6) δ3.87 (s, 5H), 3.52 (t, J = 6.9 Hz, 6H), 1.51 (t, J = 6.9 Hz, 6H).

[0096] Functions and Effects of the Embodiments

[0097] According to the method for preparing tris(hydroxyalkyl)methylamine involved in the above embodiment, since the terminal olefinic compound is treated with ozone / reducing agent, the terminal olefinic group can be converted into a hydroxyl group having one less carbon atom. Therefore, the preparation method provided by the present invention is simpler and more suitable for industrialization. Moreover, a series of tris(hydroxyalkyl)methylamines can be obtained by simply changing the carbon chain length of the raw material, which is more universally applicable than the existing technology.

[0098] Furthermore, in the above embodiment, after the ozonolysis reaction, conventional reducing agents such as zinc powder / acid and trimethyl phosphite are not used to treat the peroxides formed by the reaction. Instead, sodium borohydride is creatively selected. As a result, the peroxides formed after the ozonolysis reaction are directly converted into hydroxyl groups rather than aldehyde groups, which greatly saves reaction steps.

[0099] Furthermore, in the above embodiment, methanol and dichloromethane were selected as a mixed solvent in the steps of ozone decomposition and the subsequent reduction reaction, a higher yield was achieved compared with using a single solvent.

[0100] The embodiments provided above are preferred examples of the present invention and are not intended to limit the scope of the present invention. The steps described are not intended to limit the order in which they are performed. Any obvious improvements to the present invention made by those skilled in the art in combination with existing common knowledge will fall within the scope of protection defined by the claims of the present invention.

Claims

1. A method for preparing tris(hydroxyalkyl)methylamine, characterized in that: The process comprises the following reaction steps: In the above formula, PG is an amino protecting group, and x and y are independently selected from any integer between 0 and 5. Step 1, compound 4 reacts with ozone and a reducing agent in sequence to obtain compound 5; the reducing agent is a metal complex hydrogen compound; Step 2: Compound 5 reacts with an amino protecting group removal reagent to obtain compound 6.

2. The method for preparing tris(hydroxyalkyl)methylamine according to claim 1, wherein: in, The preparation method of compound 4 comprises the following steps: In the above formula, X is selected from any one of chlorine, bromine or iodine, Reacting compound 1 with compound 2 to obtain compound 3; Compound 3 reacts with an amino protecting reagent to obtain compound 4.

3. The method for preparing tris(hydroxyalkyl)methylamine according to claim 1, wherein: in, x=y=0 or 1.

4. The method for preparing tris(hydroxyalkyl)methylamine according to claim 1, wherein: in, The metal complex hydride compound is selected from any one or more of sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, and sodium thioborohydride.

5. The method for preparing tris(hydroxyalkyl)methylamine according to claim 1, wherein in, The amino protecting group is selected from benzyloxycarbonyl, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, p-methoxybenzyl, benzyl, trityl, p-toluenesulfonyl, phthaloyl, and allyloxycarbonyl.

6. An intermediate for synthesizing tris(hydroxyalkyl)methylamine, characterized in that: The structural formula is as follows: ， In the above formula, PG is an amino protecting group, and x and y are independently selected from any integer between 0 and 5.

7. The intermediate for synthesizing tris(hydroxyalkyl)methylamine according to claim 6, characterized in that: in, PG is benzyloxycarbonyl or tert-butyloxycarbonyl.

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