A process for the preparation of 3-iodooxetanes

Abstract

The application discloses a preparation method of 3-iodooxetane. The 3-iodooxetane is prepared by adding a copper ion catalyst to make halogen exchange reaction of 3-substituted oxetane, an iodination reagent and a solvent. In the application, the introduction of the catalyst greatly reduces the activation energy of the reaction, thereby improving the selectivity of the reaction and the yield of the reaction. The application has the advantages of low raw material cost, short reaction time, high product purity and yield and the like, is very friendly to the environment and meets the requirements of green chemical process.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, specifically to a method for preparing 3-iodooxetine. Background Technology

[0002] 3-Iodooxetane, with CAS number [26272-85-5], has a boiling point of 159℃ and its chemical structural formula is as follows:

[0003]

[0004] Due to the unique properties of oxetyl groups, such as their ability to act as a metabolically stable tert-butyl bioisostere, oxetanes can also alter the ester-water partition coefficient of drug molecules to improve drug bioavailability. Oxetyl groups are widely present in drug molecules and are among the most frequently introduced substituents in new drug development. In existing technologies, aryloxetanes can be synthesized via the Suzuki reaction, or through SN alkylation or the Buchwald–Hartwig coupling reaction.

[0005] CN115960121A discloses a method for synthesizing 1-(3-oxacyclobutane)-1H-pyrazole-4-boronic acid pinacol ester. The technical solution involves using 3-iodooxacyclobutane and 4-bromo-1H-pyrazole as raw materials, and undergoing an N-alkylation reaction in the presence of a weak base to generate the intermediate 4-bromo-1-(oxacyclobutane-3-yl)-1H-pyrazole. The reaction equation is as follows:

[0006]

[0007] CN108822060A discloses a method for preparing 3-aryl-substituted oxetanes, which involves exchanging a haloaryl compound with an isopropyl Grignard reagent to obtain an aryl Grignard reagent, and then reacting the aryl Grignard reagent with 3-iodooxetane under copper catalyst catalysis. The reaction equation is as follows:

[0008]

[0009] WO2020 / 257143A1 discloses a method for preparing N-(3-(2-(difluoromethoxy)-5-((1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)phenyl)-1-(oxacyclobutane-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which is obtained by reacting N-[3-[5-bromo-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and 3-iodooxane under alkaline conditions. The reaction equation is as follows:

[0010]

[0011] US2016 / 52930A1 and CN111072645A also disclose the preparation of 1-(oxetane-3-yl)-1H-pyrazole-4-amine from 4-nitro-1H-pyrazole and 3-iodooxetane as starting materials via N-alkylation and nitro reduction. This is a key intermediate for a class of TGF-βR1 inhibitors. The reaction equation is as follows:

[0012]

[0013] The existing synthetic routes for 3-iodooxetane include the following:

[0014] One method uses inexpensive 3-oxetanebutanol as a starting material, reacting it with p-toluenesulfonyl chloride to prepare a sulfonate ester, followed by an iodine substitution reaction in triethylene glycol solvent at elevated temperature to obtain 3-halogenated oxetane. This is a conventional synthetic process for iodinated products; the preparation requires high temperatures (up to 180°C, with a product boiling point of 159°C), and the reaction equation is as follows:

[0015]

[0016] The residue from distillation using this method contains a large amount of potassium p-toluenesulfonate, resulting in a large volume of waste.

[0017] Another method is to prepare 3-iodooxetane by reacting 3-oxetanol with triphenylphosphine / iodine / imidazol in dichloromethane solvent. The reaction equation is as follows:

[0018]

[0019] This synthetic method generates a large amount of triphenylphosphine oxide, resulting in significant waste; furthermore, iodine is expensive, making this route uneconomical. However, the reaction is relatively mild and does not require high temperatures.

[0020] In summary, current synthetic processes all suffer from large amounts of waste, severe pollution, low yields, and lack the technological requirements for large-scale production. Therefore, developing a low-cost, industrially viable process route for 3-iodooxetine is of great significance in significantly reducing the production cost of the new drug and improving public accessibility to it. Summary of the Invention

[0021] The purpose of this invention is to provide a method for preparing 3-iodooxetane, which has the advantages of low raw material cost, short reaction time, high product purity and yield, and is very environmentally friendly, meeting the requirements of green chemical processes.

[0022] Therefore, the technical solution of the present invention is as follows:

[0023] A method for preparing 3-iodooxetane, the reaction formula of which is as follows:

[0024]

[0025] Wherein, R is a sulfonate, chlorine, or bromine with leaving ability, preferably chlorine or bromine; the iodide reagent is lithium iodide, sodium iodide, or potassium iodide; preferably sodium iodide or potassium iodide; more preferably sodium iodide.

[0026] In view of the shortcomings of existing synthesis methods, the origin and theoretical basis of the innovative technical method of the present invention will be explained in detail below.

[0027] Oxybutane is a four-membered heterocyclic compound containing one oxygen atom, with a ring strain of 106 kJ / mol. The strained COC bond angle results in full exposure of the lone pair electrons of the oxygen atom in oxybutane, making it a good hydrogen bond acceptor and Lewis base. Acidic catalysts can facilitate the breaking of the bond between the oxygen atom and the adjacent carbon atom in the oxybutane molecule, thereby promoting the ring-opening reaction. Furthermore, under heating conditions, the bond between the oxygen atom in the four-membered ring of the oxybutane molecule and the adjacent carbon atom is broken, forming a ring-opening alcohol.

[0028] From the perspective of organic synthesis theory, the electron-withdrawing inductive effect of oxygen atoms makes it difficult for halogen atoms to leave. Furthermore, the field effect created by oxygen as an electronegative atom in oxobutanes also hinders the attack of iodide ions. Therefore, this reaction requires a high temperature; a reaction temperature below 100℃ may result in an extremely slow reaction rate or even prevent the reaction from occurring.

[0029] The Finkelstein reaction is an SN2 reaction in which a primary alkyl halide or primary sulfonic acid ester reacts with a metal halide to yield another halide. This is an important method for preparing iodoalkanes. Typically, an excess of the metal halide salt is added to the reaction. Iodide salts are readily soluble in acetone, while chloride or bromide salts produced through halogen exchange reactions are almost insoluble in acetone; therefore, the reaction shifts towards the formation of iodoalkanes.

[0030] Through extensive experimental research, the inventors creatively discovered that adding copper ion catalysts can promote the reaction, and the reaction temperature can be reduced to 50-100℃ to allow the reaction to proceed smoothly, thus forming the current preparation process.

[0031] Preferably, the preparation method includes the following steps:

[0032] (1) Add 3-substituted oxetane, copper catalyst and iodide reagent to the solvent while stirring. After the addition is complete, slowly raise the temperature to 50-150℃ and keep the reaction until the content of residual 3-substituted oxetane in the product is less than 5%, then stop the reaction.

[0033] (2) The reaction product obtained in step 1 is filtered to remove solid salt or water and solvent are added to separate the layers. The organic layer is then distilled under reduced pressure, and the fraction at 80-85℃ / 40-50mmHg is collected to obtain a pale yellow liquid, which is 3-iodooxetane.

[0034] Furthermore, the reaction temperature is 60-100℃.

[0035] Furthermore, the copper catalyst is a cuprous ion catalyst, including cuprous chloride, cuprous bromide, cuprous iodide, copper acetylacetone, and 8-hydroxyquinoline copper, preferably 8-hydroxyquinoline copper.

[0036] Further, the solvent is DMSO, N,N-dimethylformamide, N,N-dimethylacetamide, diethylene glycol, triethylene glycol, acetone, butanone, or methyl isobutyl ketone; preferably acetone.

[0037] The beneficial effects of this invention are:

[0038] 1. In this invention, 3-iodooxetane 2, iodide reagent 3, and solvent are used to produce 3-iodooxetane 1 by halogen exchange reaction with the addition of a copper ion catalyst. The introduction of the catalyst greatly reduces the activation energy of the reaction, thereby improving the selectivity and yield of the reaction.

[0039] 2. This invention has the advantages of low raw material cost, short reaction time, high product purity and yield, and is very environmentally friendly, meeting the requirements of green chemical processes. Attached Figure Description

[0040] Figure 1 This is the GC spectrum for purity detection of 3-iodooxoheterobutane in Example 1. Detailed Implementation

[0041] The following examples will help researchers understand the key points of the preparation technology of this invention, but they cannot limit the scope of this invention.

[0042] Example 1

[0043] In a clean reaction vessel, 120.0 g of anhydrous sodium iodide and 300 g of acetone were added. Stirring was started, and the mixture was purged with nitrogen three times. Then, 136.9 g of 3-bromooxybutane and 2.0 g of cuprous chloride were added. After the addition was complete, the temperature was slowly raised to 80-90 °C, with an internal pressure of approximately 0.20 MPa, and the reaction was maintained for 5 hours. The mixture was then cooled and filtered. The filter cake was washed with 50 g of acetone, and the filtrates were combined. The acetone solvent was removed under normal pressure to obtain the crude product. The crude product was then subjected to vacuum distillation using a water pump, and the fraction collected at 80-85 °C / 40-50 mmHg was used to obtain 147.20 g of product 1, with a GC purity of 99.58% and a yield of 80.0%.

[0044] Example 2

[0045] In a clean reaction vessel, 140.0 g of potassium iodide and 300 g of DMF were added, and stirring was started. The mixture was purged with nitrogen three times. Then, 92.5 g of 3-chlorooxyhexacyclobutane and 0.5 g of 8-hydroxyquinoline copper were added. After the addition was completed, the temperature was slowly raised to 70-80 °C and the reaction was maintained for 5 hours. The mixture was cooled and filtered, and 600 mL of water and 300 mL of dichloromethane were added. The mixture was stirred for 1 hour. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with 200 mL of dichloromethane. The dichloromethane layers were combined. The solvent dichloromethane was first recovered by atmospheric distillation, and then the fraction at 80-85 °C / 40-50 mmHg was collected by vacuum distillation using a water pump to obtain 137.9 g of product 1 with a GC purity of 99.78% and a yield of 75.0%.

[0046] Example 3

[0047] In a clean reactor, 125.0 g of sodium iodide and 300 g of triethylene glycol were added, and stirring was started. The mixture was purged with nitrogen three times, and then 228.5 g of 3-p-toluenesulfonyloxyoxetane and 1.2 g of cuprous bromide were added. After the addition was completed, the temperature was slowly raised to 70-80 °C and the reaction was maintained for 5 hours. The mixture was then cooled and filtered. The filtrate was then distilled under reduced pressure using a water pump, and the fraction at 80-85 °C / 40-50 mmHg was collected to obtain 115.9 g of product 1 with a GC purity of 99.28% and a yield of 63%.

[0048] Example 4

[0049] In a clean reactor, 133.0 g of anhydrous lithium iodide and 500 g of butanone were added. Stirring was started, and nitrogen was used to purge the mixture three times. Then, 92.5 g of 3-chlorooxyhexacyclobutane and 1.5 g of copper acetylacetonate were added. After the addition was completed, the temperature was slowly raised to 70-80 °C and the reaction was maintained for 5 hours. The mixture was then cooled and filtered. The filtrate was then distilled under reduced pressure using a water pump. The fraction collected at 80-85 °C / 40-50 mmHg was obtained, yielding 125.7 g of product 1 with a GC purity of 99.78% and a yield of 68.1%.

[0050] Example 5

[0051] In a clean reaction vessel, 140.0 g of sodium iodide and 200 g of dimethyl sulfoxide were added, and stirring was started. The mixture was purged with nitrogen three times. Then, 152.0 g of 3-p-methanesulfonic acid oxycyclobutane and 0.5 g of 8-hydroxyquinoline copper were added. After the addition was completed, the temperature was slowly raised to 70-80 °C and maintained for 5 hours. The temperature was then lowered to 20-30 °C, 400 mL of water was added, followed by 200 mL of dichloromethane. The mixture was stirred for 1 hour. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with 100 mL of dichloromethane twice. The dichloromethane layers were combined. The solvent dichloromethane was first recovered by atmospheric distillation, and then the fraction at 80-85 °C / 40-50 mmHg was collected by vacuum distillation using a water pump to obtain 120.2 g of product 1 with a GC purity of 99.78% and a yield of 65.0%.

[0052] Comparative Example 1

[0053] The technical solution described in the literature Wojtowicz; Polak [Journal of Organic Chemistry, 1973, vol. 38, p. 2061] is repeated:

[0054] In a reaction vessel, 45.6 g of 3-p-toluenesulfonic acid oxycyclobutane, 50 mL of triethylene glycol, and 25.0 g of dry potassium iodide were added. The mixture was stirred and heated in an oil bath, slowly increasing the temperature to 120 °C. The system was operated with a water pump under negative pressure, and the product was distilled off while the reaction was underway. The temperature was then slowly increased to 150 °C until no more distillate was distilled off. The mixture was then cooled to obtain 29.0 g of crude product with a purity of 79.57% and a yield of 65.2%.

[0055] Experimental data confirm that the yield and content of existing synthesis techniques are very low, which is consistent with the theoretical explanation of oxobutane rings.

[0056] This invention is not limited to the above embodiments. Based on the technical solutions disclosed in this invention, those skilled in the art can make some substitutions and modifications to some of the technical features without creative effort, and all such substitutions and modifications are within the protection scope of this invention.

Claims

1. A method for preparing 3-iodooxetane, characterized in that, 3-Iodooxetane was prepared according to the following reaction formula: Wherein, R is chlorine or bromine; the iodide reagent is lithium iodide, sodium iodide or potassium iodide; Specifically, the steps include the following: (1) Add 3-substituted oxetane, copper catalyst and iodide reagent to the solvent while stirring. After the addition is complete, slowly raise the temperature to 60-100℃ and keep the reaction until the content of residual 3-substituted oxetane in the product is less than 5%, then stop the reaction. (2) The reaction product obtained in step 1 is filtered to remove solid salt or water and solvent are added to separate the layers. The organic layer is then distilled under reduced pressure, and the fraction at 80-85℃ / 40-50mmHg is collected to obtain a pale yellow liquid, which is 3-iodooxacyclobutane. The copper catalyst is cuprous chloride, cuprous bromide, cuprous iodide, copper acetylacetone, or 8-hydroxyquinoline copper.

2. The method for preparing 3-iodooxetane according to claim 1, characterized in that, The iodide reagent is sodium iodide or potassium iodide.

3. The method for preparing 3-iodooxetane according to claim 2, characterized in that, The iodide reagent is sodium iodide.

4. The method for preparing 3-iodooxetane according to claim 1, characterized in that, The copper catalyst is 8-hydroxyquinoline copper.

5. The method for preparing 3-iodooxetane according to claim 1, characterized in that, The solvent is DMSO, N,N-dimethylformamide, N,N-dimethylacetamide, diethylene glycol, triethylene glycol, acetone, butanone, or methyl isobutyl ketone.

6. The method for preparing 3-iodooxetane according to claim 5, characterized in that, The solvent is acetone.

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