Preparation method of urea type HATU

Abstract

The invention provides a preparation method of urea type HATU, which comprises the following steps: step S1, carrying out reaction on N-hydroxy-7-aza-benzotriazole and inorganic alkali to obtain N-hydroxy-7-aza-benzotriazole salt; and step S2, enabling the N-hydroxy-7-aza-benzotriazole salt to react with tetramethyl chlorourea hexafluorophosphate, so as to generate the urea type HATU. The preparation method disclosed by the embodiment of the invention is simple in process, easy to operate, low in synthesis cost, high in experimental safety, easy in condition control and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and more specifically, relates to a method for preparing urea-type HATU. Background Art

[0002] Condensation reaction is a type of reaction widely used in organic synthesis and medicine, especially in the synthesis of peptides, amides, and esters, which often require the help of condensation reagents.

[0003] 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) is a commonly used condensation reagent. HATU promotes the formation of amide bonds by activating carboxyl groups, so it is widely used in the synthesis of amide bonds. The amidation reaction using HATU has mild conditions and high yields. Many sterically hindered condensation agents can also react, and it is widely used in the synthesis of various pharmaceutical intermediates. In addition, compared with other similar condensation agents, it has a faster reaction speed and is not easy to racemize.

[0004] In 2002, Louis A. Carpino et al. conducted a systematic study on the structure and reactivity of HATU. The study showed that HATU has two configurations, namely urea type and guanidine type. For the convenience of description, urea type HATU is denoted as O-HATU and guanidine type HATU is denoted as N-HATU in this article. Their respective structural formulas are shown in the following formula (1):

[0005] Based on the research results of Louis A. Carpino et al., it can be seen that, in comparison, the reactivity of O-HATU is significantly stronger than that of N-HATU, and N-HATU is the stable structure of HATU. In the presence of organic tertiary amines, O-HATU will gradually transform into N-HATU, so the HATU currently sold on the market is N-HATU.

[0006] At present, there is no report on an industrial method that can achieve large-scale preparation.

[0007] Therefore, it is urgent to provide a method for preparing O-HATU suitable for large-scale industrial production. Summary of the invention

[0008] In view of this, the object of the present invention is to provide a method for preparing urea-type HATU which is simple to operate, has mild reaction conditions and can be scaled up.

[0009] In order to solve the above technical problems, the present invention adopts the following technical solutions: The method for preparing urea-type HATU according to an embodiment of the present invention comprises the following steps: Step S1, N-hydroxy-7-azabenzotriazole (hereinafter, sometimes referred to as HOAT) reacts with an inorganic base to obtain an N-hydroxy-7-azabenzotriazole salt (hereinafter, sometimes referred to as HOAT-salt); In step S2, the N-hydroxy-7-azabenzotriazole salt is reacted with tetramethylchlorouronium hexafluorophosphate (hereinafter, sometimes referred to as TCFH) to generate urea-type HATU (hereinafter, sometimes referred to as O-HATU).

[0010] In some embodiments of the present invention, the inorganic base includes any one or more of hydroxides, carbonates, bicarbonates, acetates, and phosphates of alkali metals or alkaline earth metals.

[0011] In some embodiments of the present invention, the inorganic base includes any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium phosphate, and potassium phosphate.

[0012] In some embodiments of the present invention, the reaction in step S1 is carried out in a first solvent, and the first solvent is methanol, ethanol, or a mixed solvent thereof.

[0013] In some embodiments of the present invention, in step S1, the molar ratio of N-hydroxy-7-azabenzotriazole to the metal ion in the inorganic base is 1:(1-2), the reaction temperature is 0-50° C., and the reaction time is 1-10 hours.

[0014] In some embodiments of the present invention, in step S1, after the reaction is completed, the N-hydroxy-7-azabenzotriazole salt is separated to obtain a light yellow solid, and the separation includes desolventizing in a high-temperature water bath to dryness, or filtering and eluting and finally drying.

[0015] In some embodiments of the present invention, in step S2, the reaction is carried out in a second solvent, and the second solvent is any one or more of toluene, benzene, ethanol, isopropanol, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, and dichloromethane.

[0016] In some embodiments of the present invention, in step S2, the molar ratio of the N-hydroxy-7-azabenzotriazole salt to the tetramethyl chlorouronium hexafluorophosphate is 1:(1-2), and the mass ratio of the N-hydroxy-7-azabenzotriazole salt to the second solvent is 1:(5-30).

[0017] In some embodiments of the present invention, in step S2, the reaction temperature is 0-50° C., and the reaction time is 10 minutes-10 hours.

[0018] In some embodiments of the present invention, in step S2, after the reaction is completed, the step further comprises: The reaction system is filtered and dried to obtain a crude product; The crude product was dissolved in acetonitrile, dried over anhydrous sodium sulfate, filtered, and dried to obtain refined urea-type HATU.

[0019] The above technical solution of the present invention has at least one of the following beneficial effects: The preparation method according to the embodiment of the present invention has simple process steps, low synthesis cost, high experimental safety, simple operation, easy controllable conditions, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the NMR identification spectrum of the product obtained in Example 1. DETAILED DESCRIPTION

[0021] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0022] First, the preparation method of urea-type HATU according to an embodiment of the present invention is described in detail below.

[0023] The method for preparing urea-type HATU according to an embodiment of the present invention comprises the following steps: Step S1, HOAT reacts with an inorganic base to obtain a HOAT-salt; Step S2, reacting HOAT-salt with TCFH to generate urea-type HATU.

[0024] Specifically, the preparation method of the present application has a synthetic route as shown in the following formula (2):

[0025] That is, according to the preparation method of O-HATU in the embodiment of the present invention, HOAT-salt is obtained by reacting HOAT and an inorganic base; then, HOAT-salt is reacted with TCFH to obtain the target product urea-type HATU (O-HATU). According to the preparation method of the present application, the route is short, the synthesis cost is low, the process steps are simple, the experimental safety is high, the operation is simple, and it is suitable for industrial large-scale production.

[0026] Below, each step is explained in detail.

[0027] Step S1: HOAT reacts with an inorganic base to obtain a HOAT-salt.

[0028] In some embodiments of the present invention, the inorganic base may include any one or more of hydroxides, carbonates, bicarbonates, acetates, and phosphates of alkali metals or alkaline earth metals.

[0029] That is to say, it can be any one or more of the hydroxides, carbonates, bicarbonates, acetates, and phosphates of alkali metals (such as lithium, sodium, potassium, etc.); it can also be any one or more of the hydroxides, carbonates, bicarbonates, acetates, and phosphates of alkaline earth metals (such as calcium, magnesium, barium, etc.); it can also be a mixture of any one or more of the above-mentioned alkali metal compounds and any one or more of the above-mentioned alkaline earth metal compounds.

[0030] In some embodiments of the present invention, the inorganic base includes any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium phosphate, and potassium phosphate. That is, these inorganic bases react with HOAT to generate a potassium salt of HOAT or a sodium salt of HOAT. These inorganic bases are low in price and easy to obtain from the market, and the intermediate product potassium salt of HOAT or sodium salt of HOAT obtained by the reaction can be simply precipitated by removing the solvent.

[0031] According to some embodiments of the present invention, the reaction in step S1 is carried out in a first solvent, and the first solvent is methanol, ethanol, or a mixed solvent thereof. For example, before the reaction, the reactants HOAT and the inorganic base are dissolved in the first solvent respectively, and the reaction is carried out in the form of a solution, which can promote the reaction. In addition, the reaction time can be appropriately extended to ensure a more complete reaction.

[0032] According to some embodiments of the present invention, in step S1, the molar ratio of N-hydroxy-7-azabenzotriazole to the alkali metal ion in the inorganic base is 1:(1-2), such a ratio can ensure that the reaction is sufficient to obtain KOAT and avoid the waste of excess reactants. The reaction temperature is 0-50° C. and the reaction time is 1-10 hours.

[0033] In addition, according to some embodiments of the present invention, in the step S1, after the reaction is completed, a light yellow solid N-hydroxy-7-azabenzotriazole salt is obtained by separation, and the separation includes desolventizing to dryness in a high-temperature water bath (e.g., a 50-80°C water bath), or filtering, rinsing and finally drying.

[0034] That is to say, after the reaction is completed, the light yellow solid obtained by simple separation can be directly used for the next reaction. For example, the light yellow intermediate HOAT-salt can be obtained by removing the solvent in a high-temperature water bath and drying; or after the reaction is completed, the light yellow intermediate HOAT-salt can be filtered, rinsed with ethanol and dried to obtain the light yellow intermediate HOAT-salt. The light yellow intermediate HOAT-salt can be precipitated from the reaction solvent and separated by desolventizing or filtering. The process is simple and easy to operate.

[0035] By separating and drying, it can be ensured that in the subsequent reaction process, the agglomeration will not be affected by the influence of moisture, thereby affecting further reaction, which is beneficial to improving reaction efficiency and yield.

[0036] Step S2: HOAT-salt is reacted with TCFH to generate urea-type HATU.

[0037] That is, after obtaining the intermediate HOAT-salt, it is further reacted with TCFH to obtain the target product O-HATU.

[0038] In some embodiments of the present invention, in step S2, the reaction is carried out in a second solvent, and the second solvent is any one or more of toluene, benzene, ethanol, isopropanol, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, and dichloromethane. The second solvent is a non-polar solvent with poor solubility for the substrate KOAT or the product O-HATU. By selecting these solvents, the product can be kept in a solid form during the reaction, reducing dissolution, thereby reducing the conversion of O-HATU to N-HATU. Among them, toluene and methyl tert-butyl ether are particularly preferred.

[0039] In some embodiments of the present invention, in step S2, the molar ratio of the N-hydroxy-7-azabenzotriazole salt to the tetramethyl chlorouronium hexafluorophosphate is 1: (1-2), and the mass ratio of the N-hydroxy-7-azabenzotriazole salt to the second solvent is 1: (5-30). According to the actual reaction conditions in different solvents, the appropriate amount of solvent is determined to ensure that no lumps are formed during the reaction process to achieve the effect of uniform stirring and sufficient reaction.

[0040] In some embodiments of the present invention, in step S2, the reaction temperature is 0-50° C., and the reaction time is 10 minutes-10 hours. The process conditions are mild and easy to operate.

[0041] In some embodiments of the present invention, in step S2, after the reaction is completed, the step further comprises: The reaction system is filtered and dried to obtain a crude product; The crude product is dissolved in acetonitrile, dried over anhydrous sodium sulfate, filtered, and dried to obtain the refined urea-type HATU.

[0042] That is to say, refined O-HATU can be obtained by simple filtration, drying, etc. The reaction conditions are mild, the cost is low, and it is easy to implement.

[0043] It should be noted that the refined O-HATU after the above treatment is sufficient to meet the requirements of the reaction for the condensation agent. If necessary, further purification methods such as recrystallization and beating can be selected.

[0044] The preparation method of the urea-type HATU of the present invention is further described in detail below through specific examples.

[0045] Example 1 (1) Preparation of intermediate KOAT (i.e. potassium salt of HOAT) HOAT (500 g, 1.0 eq) was added to EtOH (10 L) and stirred until it was evenly dissolved and became a uniform suspension; KOH (208 g, 1.01 eq) was added portionwise to EtOH (5 L) to obtain a KOH solution; Add KOH solution dropwise into the HOAT suspension and stir. A large amount of yellow solid will precipitate quickly. Add appropriate amount of ethanol until the suspension can be stirred well and stir overnight.

[0046] Finally, the product was desolventized in a 60°C water bath to dryness to obtain 640 g of light yellow solid KOAT with a yield of 100%.

[0047] The purity of the intermediate was 99.7% as determined by HPLC.

[0048] (2) Preparation of urea-type HATU (O-HATU) The KOAT (300 g, 1.0 eq) obtained in the above (1) was added to toluene (3 L), stirred evenly, and TCFH (483 g, 1.0 eq) was added in batches, stirred for 2 h, filtered, and dried to obtain a pale pink crude product O-HATU (702 g). The yield of the crude product exceeded 100%.

[0049] This is because the reaction by-product is potassium hexafluorophosphate, which is also insoluble in the solution, so some potassium hexafluorophosphate is still present in the obtained crude product.

[0050] (3) Refined urea-type HATU The crude O-HATU obtained above is dissolved in acetonitrile (the potassium hexafluorophosphate impurity is insoluble in acetonitrile), filtered, and the filtrate is dried with anhydrous sodium sulfate, and filtered and dried to obtain refined O-HATU.

[0051] The total yield of the two-step reaction is 78.5%.

[0052] The NMR spectrum of the product is as follows Figure 1 As shown in the figure, it is consistent with the structure of the target product O-HATU.

[0053] Example 2 (1) Preparation of intermediate KOAT (i.e. potassium salt of HOAT) HOAT (500 g, 1.0 eq) was added to EtOH (10 L) and stirred until it was evenly dissolved and became a uniform suspension; KOH (208 g, 1.01 eq) was added portionwise to EtOH (5 L) to obtain a KOH solution; KOH solution was added dropwise to the HOAT suspension and stirred. A large amount of yellow solid was precipitated quickly. An appropriate amount of ethanol was added until good stirring was possible and the mixture was stirred overnight.

[0054] Finally, the solid was filtered, washed with ethanol, and dried under vacuum at 60°C to obtain 523 g of a light yellow solid with a yield of 81.7%. This is because the intermediate KOAT has a certain solubility in ethanol, and part of the KOAT is lost with the solvent ethanol when separated by filtration, resulting in a partial loss of yield.

[0055] (2) Preparation of urea-type HATU (O-HATU) KOAT (300 g, 1.0 eq) obtained in (1) was added to methyl tert-butyl ether (3 L), stirred evenly, and TCFH (483 g, 1.0 eq) was added in batches, stirred for 2 h, filtered, and dried to obtain a pale pink crude product O-HATU (720 g). The yield of the crude product exceeded 100%, because some potassium hexafluorophosphate was contained in the crude product.

[0056] (3) Refined urea-type HATU The crude O-HATU obtained above is dissolved in acetonitrile (the potassium hexafluorophosphate impurity is insoluble in acetonitrile), filtered, and the filtrate is dried with anhydrous sodium sulfate, and filtered and dried to obtain refined O-HATU.

[0057] The total yield of the two-step reaction is 78.5%.

[0058] Example 3 (1) Preparation of intermediate KOAT (i.e. potassium salt of HOAT) Add pure water (15 mL) to methanol (80 mL), add potassium carbonate (406 g, 0.8 eq) in batches while stirring, and a uniform white suspension is formed. Add HOAT (500 g, 1.0 eq) in batches, release the gas, and stir overnight; Filter and wash the filter cake with methanol until the filtrate is colorless. Add the filtrate dropwise into methyl tert-butyl ether (500 mL) to precipitate a light yellow solid. Filter and dry to obtain 550 g of a light yellow solid with a yield of 86%.

[0059] (2) Preparation of urea-type HATU (O-HATU) KOAT (300 g, 1.0 eq) obtained in (1) was added to methyl tert-butyl ether (3 L), stirred evenly, and TCFH (483 g, 1.0 eq) was added in batches, stirred for 2 h, filtered, and dried to obtain a pale pink crude product O-HATU (720 g). The yield of the crude product exceeded 100%, because some potassium hexafluorophosphate was contained in the crude product.

[0060] (3) Refined urea-type HATU The crude O-HATU obtained above is dissolved in acetonitrile (the potassium hexafluorophosphate impurity is insoluble in acetonitrile), filtered, and the filtrate is dried with anhydrous sodium sulfate, and filtered and dried to obtain refined O-HATU.

[0061] The total yield of the two-step reaction is 78.5%.

[0062] Example 4 (1) Preparation of intermediate NaOAT (sodium salt of HOAT) HOAT (500 g, 1.0 eq) was added to EtOH (10 L) and stirred until it was evenly dissolved and became a uniform suspension; NaOH (148.4 g, 1.01 eq) was added to EtOH (10 L) in batches, and stirred with slight heating until completely dissolved to obtain a NaOH solution; Add NaOH solution dropwise into the HOAT suspension and stir. A large amount of light yellow solid will precipitate quickly. Add appropriate amount of ethanol until the suspension can be stirred well and stir overnight.

[0063] Finally, the product was desolventized in a 60°C water bath to dryness to obtain 579.2 g of yellow-white solid NaOAT with a yield of 100%.

[0064] The purity of the intermediate was 99.7% as determined by HPLC.

[0065] (2) Preparation of urea-type HATU (O-HATU) The NaOAT (300 g, 1.0 eq) obtained in the above (1) was added to toluene (6 L) and stirred evenly. TCFH (532 g, 1.0 eq) was added in batches and stirred for 2 h. The mixture was filtered and dried to obtain 842 g of pale pink crude O-HATU.

[0066] The recovery rate of the crude product exceeds 100%, and the crude product also contains some potassium hexafluorophosphate.

[0067] (3) Refined urea-type HATU The crude O-HATU obtained above is dissolved in acetonitrile (the potassium hexafluorophosphate impurity is insoluble in acetonitrile), filtered, and the filtrate is dried with anhydrous sodium sulfate, and filtered and dried to obtain refined O-HATU.

[0068] The total yield of the two-step reaction is 84%.

[0069] It can be seen from the above examples that the method for preparing urea-type HATU (O-HATU) of the present invention has the advantages of simple operation, short route, low cost and high yield.

[0070] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing urea-type HATU, It is characterized in that The steps include: Step S1, N-hydroxy-7-azabenzotriazole reacts with an inorganic base to obtain an N-hydroxy-7-azabenzotriazole salt; Step S2, reacting the N-hydroxy-7-azabenzotriazole salt with tetramethyl chlorouronium hexafluorophosphate to generate urea-type HATU.

2. The preparation method according to claim 1, It is characterized in that The inorganic base includes any one or more of hydroxides, carbonates, bicarbonates, acetates, and phosphates of alkali metals or alkaline earth metals.

3. The preparation method according to claim 2, It is characterized in that The inorganic base includes any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium phosphate, and potassium phosphate.

4. The preparation method according to claim 2, It is characterized in that The reaction in step S1 is carried out in a first solvent, and the first solvent is methanol, ethanol, or a mixed solvent thereof.

5. The preparation method according to claim 4, It is characterized in that In the step S1, the molar ratio of N-hydroxy-7-azabenzotriazole to the metal ion in the inorganic base is 1:(1-2), the reaction temperature is 0-50° C., and the reaction time is 1-10 hours.

6. The preparation method according to claim 5, It is characterized in that In the step S1, after the reaction is completed, the N-hydroxy-7-azabenzotriazole salt is separated to obtain a light yellow solid. The separation includes desolventizing in a high-temperature water bath to dryness, or filtering, eluting and finally drying.

7. The preparation method according to claim 1, It is characterized in that In the step S2, the reaction is carried out in a second solvent, and the second solvent is any one or more of toluene, benzene, ethanol, isopropanol, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, and dichloromethane.

8. The preparation method according to claim 7, It is characterized in that In the step S2, the molar ratio of the N-hydroxy-7-azabenzotriazole salt to the tetramethyl chlorouronium hexafluorophosphate is 1:(1-2), and the mass ratio of the N-hydroxy-7-azabenzotriazole salt to the second solvent is 1:(5-30).

9. The preparation method according to claim 7, It is characterized in that In the step S2, the reaction temperature is 0-50° C., and the reaction time is 10 minutes-10 hours.

10. The preparation method according to claim 7, It is characterized in that In the step S2, after the reaction is completed, the step further comprises: The reaction system is filtered and dried to obtain a crude product; The crude product is dissolved in acetonitrile, dried over anhydrous sodium sulfate, filtered, and dried to obtain the refined urea-type HATU.

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