Synthesis method of (1-oxo-1, 2, 3, 4-tetrahydronaphthalene-2-yl) phosphonate

Abstract

The invention discloses a synthesis method of (1-oxo-1, 2, 3, 4-tetrahydronaphthalene-2-yl) phosphonate, which comprises the following steps: mixing a raw material compound with bis (trimethylsilyl) potassium amide and dimethyl chlorophosphate, and reacting in a solvent to obtain a target compound. According to the method, the bis (trimethylsilyl) potassium amide is adopted to replace traditional lithium diisopropylamide to serve as a deprotonation reagent, the synthesis process of the target phosphinate is successfully optimized, the system does not need an extremely low temperature condition, the rearrangement side reaction participated by LDA is avoided, meanwhile, the requirement for multi-equivalent strong base is reduced, and the method is suitable for industrial production. Therefore, the synthetic method is more efficient and controllable and has industrial application potential.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate. Background Art

[0002] β-ketophosphonates are a class of compounds that can be synthesized from a variety of precursors. They can be used in a variety of chemical reactions and serve as important intermediates in the synthesis of prostaglandins and other molecules. In addition, they exhibit a wide range of biological activities and have excellent metal complexing abilities. However, there are relatively few reports on the synthesis methods of phosphonate compounds on benzocycloketones.

[0003] Currently, the synthesis methods of such phosphonates are mainly divided into three categories:

[0004] (1) Keto α-deprotonation strategy: Starting from benzocyclohexanone, it is deprotonated under the action of a strong base LDA (lithium diisopropylamide) and then attacks phosphoryl chloride. However, this reaction has the following problems: more by-products are generated, resulting in a low yield of the target product; in addition, the reaction needs to be carried out at extremely low temperature conditions and consumes more than two equivalents of LDA, making the process cost high and the environmental friendliness poor.

[0005] (2) Reaction of α-halobenzylacetone with trialkoxyphosphine: This method uses α-halobenzylacetone to carry out a substitution reaction with trialkoxyphosphine, but α-halobenzylacetone is expensive and has a higher cost compared to ordinary benzylacetone. In addition, the reaction requires the use of an excessive amount of highly toxic trialkoxyphosphine, which not only has a low yield but also increases the safety and environmental protection risks.

[0006] (3) Olefin-phosphite addition reaction: An addition reaction is carried out between an olefin and a phosphite under the action of catalysts such as copper and iron. However, the main limitation of this method is that the required olefins are difficult to obtain, and at the same time, the catalytic system is complex and the yield of the target product is low, which limits its practical application.

[0007] In summary, the existing methods all have problems such as economy, environmental protection or low yield, and there is an urgent need to develop a more efficient, cost-controlled and green phosphonate synthesis strategy. Summary of the Invention

[0008] The purpose of this part is to outline some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this part, as well as in the abstract and title of the specification of this application, to avoid obscuring the purpose of this part, the abstract and the title of the invention. However, such simplifications or omissions shall not be used to limit the scope of the present invention.

[0009] In view of the above and / or problems existing in the prior art, the present invention is proposed.

[0010] One object of the present invention is to provide a method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate. This system does not require extremely low temperature conditions and reduces the demand for multiple equivalents of strong base, making the synthesis method more efficient.

[0011] To solve the above technical problems, the present invention provides the following technical solutions: A method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate, comprising,

[0012] Mixing the compound shown in Formula I with potassium bis(trimethylsilyl)amide and dimethyl chlorophosphate, and reacting in a solvent to obtain the target compound shown in Formula II;

[0013]

[0014] wherein, X is selected from CH2 or O; R is selected from one of hydrogen, methyl, halogen, and methoxy.

[0015] As a preferred embodiment of the method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate of the present invention, wherein: the molar ratio of the compound shown in Formula I to potassium bis(trimethylsilyl)amide is 1:1 to 2.

[0016] As a preferred embodiment of the method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate of the present invention, wherein: the molar ratio of the compound shown in Formula I to dimethyl chlorophosphate is 1:1 to 2.

[0017] As a preferred embodiment of the method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate of the present invention, wherein: the solvent includes one of tetrahydrofuran, diethyl ether, 1,4-dioxane, and ethylene glycol dimethyl ether.

[0018] As a preferred embodiment of the method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate of the present invention, wherein: for the reaction, the reaction temperature is -60 to 0 °C.

[0019] As a preferred embodiment of the method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate of the present invention, wherein: the reaction is carried out under a protective atmosphere.

[0020] As a preferred embodiment of the method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate of the present invention, wherein: for the reaction in the solvent, the compound shown in Formula I is dissolved in the solvent, cooled to the reaction temperature, and a solution of potassium bis(trimethylsilyl)amide dissolved in the solvent is added dropwise. After stirring and mixing, dimethyl chlorophosphate is added, and the temperature is gradually raised to 0 °C and then the reaction is continued.

[0021] As a preferred embodiment of the synthesis method of the (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate of the present invention, it further includes the step of purifying the target compound.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] By using potassium bis(trimethylsilyl)amide (KHMDS) to replace traditional lithium diisopropylamide (LDA) as the deprotonating agent, the present invention successfully optimizes the synthesis process of the target phosphonate. This system does not require extremely low temperature conditions, avoids the rearrangement side reaction involving LDA, and at the same time reduces the demand for multiple equivalents of strong base, making the synthesis method more efficient, controllable and potentially applicable to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts. Among them:

[0025] Figure 1 1H NMR spectrum of the product of Example 1 of the present invention;

[0026] Figure 2 1H NMR spectrum of the product of Example 4 of the present invention;

[0027] Figure 3 1H NMR spectrum of the product of Example 5 of the present invention;

[0028] Figure 4 1H NMR spectrum of the product of Example 6 of the present invention;

[0029] Figure 5 1H NMR spectrum of the product of Example 7 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0030] To make the above objects, features and advantages of the present invention more obvious and understandable, the following will describe the specific embodiments of the present invention in detail in conjunction with the embodiments of the specification.

[0031] In the following description, many specific details are set forth in order to fully understand the present invention. However, the present invention can also be implemented in other ways different from those described herein. Those skilled in the art can make similar extensions without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0032] Second, as used herein, "an embodiment" or "embodiments" refer to specific features, structures, or characteristics that may be included in at least one implementation of the present invention. The appearances of "in one embodiment" in different places in this specification do not all refer to the same embodiment, nor are they separate or alternative embodiments that are mutually exclusive of other embodiments.

[0033] Unless otherwise specified, the raw materials used in the examples are all commercially purchased.

[0034] Example 1

[0035] (1) Under nitrogen protection, benzocyclohexanone (2.0 mmol, 1.0 equiv.) was dissolved in 10 mL of anhydrous THF solution, cooled to -40 °C, and potassium bis(trimethylsilyl)amide solution (1 M in THF, 2.4 ml) was added dropwise. After stirring for 30 minutes, dimethyl chlorophosphate (2.6 mmol, 1.3 equiv.) was added, and the temperature was gradually raised to 0 °C within 1 hour, and the reaction was continued for another 1 hour. Then, the reaction was terminated using saturated NH4Cl solution (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure. Finally, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 2) to obtain the target product 2a.

[0036] The reaction equation is as follows:

[0037]

[0038] The above target product was characterized, and the 1H NMR spectrum is as Figure 1 shown below:

[0039] 1 H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 7.9, 1.5 Hz, 1H), 7.45 (td, J = 7.5, 1.5 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 3.76 (dd, J = 18.9, 11.0 Hz, 6H), 3.26–3.16 (m, 2H), 2.90 (dt, J = 16.8, 6.0 Hz, 1H), 2.49–2.39 (m, 2H).

[0040] According to the characterization data, the prepared reaction product was dimethyl (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)phosphonate (purity > 98%); the product yield was calculated, and the result was 90%.

[0041] Example 2

[0042] On the basis of Example 1, in Example 2, the reaction conditions such as temperature, solvent, the equivalent of potassium bis(trimethylsilyl)amide, and the equivalent of dimethyl chlorophosphate were optimized. The specific optimization results are shown in Table 1 below:

[0043] Table 1

[0044]

[0045]

[0046] It can be seen from Table 1 that within the range of -40 to -60 for the reaction temperature, the yield is the highest, and the yield shows a decreasing trend when the reaction temperature continues to decrease. Under the same reaction conditions, the target products can be obtained by selecting solvents THF, Et2O, Dioxane, DME, and HMPA. The yields are relatively high in THF and Et2O solvents, followed by the reactions in Dioxane and DME solvents, while the yield is very low in HMPA solvent. Under the same reaction conditions, when gradually increasing the equivalent of KHMDS, the yield gradually increases and reaches the maximum value at 1.2 equiv. Under the same reaction conditions, when gradually increasing the equivalent of dimethyl chlorophosphate, the yield also gradually increases and reaches the maximum value at 1.3 equiv.

[0047] Example 3

[0048] On the basis of Example 1, in Example 3, the raw materials were adjusted, and the obtained target products are shown in Table 2.

[0049] Table 2

[0050]

[0051]

[0052] Example 4

[0053] (1) Under nitrogen protection, 6-bromo-4-chromenone (2.0 mmol, 1.0 equiv.) was dissolved in 10 mL of anhydrous THF solution, cooled to -40 °C, and 2.4 ml of potassium bis(trimethylsilyl)amide solution (1 M in THF) was added dropwise. After stirring for 30 minutes, dimethyl chlorophosphate (2.6 mmol, 1.3 equiv.) was added, and the temperature was gradually raised to 0 °C within 1 hour and then reacted for another 1 hour. Then, the reaction was terminated using saturated NH4Cl solution (20 mL). The obtained mixture was extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure. Finally, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 2) to obtain the target product 2b.

[0054] The reaction equation is as follows:

[0055]

[0056] The above target product was characterized, and the 1H NMR spectrum is as follows Figure 2 shown below:

[0057] 1 1H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 7.9, 1.5 Hz, 1H), 7.45 (td, J = 7.5, 1.5 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 3.76 (dd, J = 18.9, 11.0 Hz, 6H), 3.26–3.16 (m, 2H), 2.90 (dt, J = 16.8, 6.0 Hz, 1H), 2.49–2.39 (m, 2H).

[0058] According to the characterization data, the prepared reaction product was dimethyl (6-bromo-4-oxodihydrobenzopyran-3-yl)phosphonate (purity > 98%); the product yield was calculated, and the result was 70%.

[0059] Example 5

[0060] (1) Under nitrogen protection, 6-fluoro-4-chromanol (2.0 mmol, 1.0 equiv.) was dissolved in 10 mL of anhydrous THF solution, cooled to -40 °C, and potassium bis(trimethylsilyl)amide solution (1 M in THF, 2.4 mL) was added dropwise. After stirring for 30 minutes, dimethyl chlorophosphate (2.6 mmol, 1.3 equiv.) was added, and the temperature was gradually raised to 0 °C within 1 hour and then reacted for another 1 hour. Then, the reaction was terminated with saturated NH4Cl solution (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure. Finally, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 2) to obtain the target product 2c.

[0061] The reaction equation is as follows:

[0062]

[0063] The above target product was characterized, and the 1H NMR spectrum is as follows Figure 3 shown below:

[0064] 11H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 8.2, 3.2 Hz, 1H), 7.21 (ddd, J = 9.1, 7.6, 3.2 Hz, 1H), 6.97 (dd, J = 9.1, 4.2 Hz, 1H), 4.83 (ddd, J = 11.8, 9.4, 5.3 Hz, 1H), 4.63 (ddd, J = 28.6, 11.8, 4.3 Hz, 1H), 3.79 (d, J = 11.2 Hz, 3H), 3.72 (d, J = 11.2 Hz, 3H), 3.29 (ddd, J = 25.3, 5.3, 4.3 Hz, 1H).

[0065] According to the characterization data, the obtained reaction product is dimethyl (6-fluoro-4-oxodihydrobenzopyran-3-yl)phosphonate (purity > 98%); the product yield was calculated, and the result was 75%.

[0066] Example 6

[0067] (1) Under nitrogen protection, dissolve 6,7-dimethoxy-1-tetralone (2.0 mmol, 1.0 equiv.) in 10 mL of anhydrous THF solution, cool it to -40 °C, and add 2.4 ml of potassium bis(trimethylsilyl)amide solution (1 M in THF) dropwise. After stirring for 30 minutes, add dimethyl chlorophosphate (2.6 mmol, 1.3 equiv.), gradually warm it to 0 °C within 1 hour, and continue to react for 1 hour. Then, terminate the reaction with saturated NH₄Cl solution (20 mL). The obtained mixture was extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, and then concentrated under reduced pressure. Finally, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 - 1 / 2) to obtain the target product 2d.

[0068] The reaction equation is as follows:

[0069]

[0070] Characterize the above target product, and the nuclear magnetic resonance hydrogen spectrum is as Figure 4 shown below:

[0071] 1 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 6.62 (s, 1H), 3.88 (d, J = 14.6 Hz, 6H), 3.76 (dd, J = 15.1, 11.0 Hz, 6H), 3.21–3.11 (m, 2H), 2.82 (dt, J = 16.8, 5.7 Hz, 1H), 2.47–2.36 (m, 2H).

[0072] According to the characterization data, the obtained reaction product is (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate (purity > 98%); the product yield is calculated, and the result is 80%.

[0073] Example 7

[0074] (1) Under nitrogen protection, dissolve 7-methoxy-1-tetralone (2.0 mmol, 1.0 equiv.) in 10 mL of anhydrous THF solution, cool it to -40 °C, and add 2.4 ml of potassium bis(trimethylsilyl)amide solution (1 M in THF) dropwise. After stirring for 30 minutes, add dimethyl chlorophosphate (2.6 mmol, 1.3 equiv.), gradually warm up to 0 °C within 1 hour, and then continue to react for 1 hour. Then, use saturated NH4Cl solution (20 mL) to terminate the reaction. The obtained mixture is extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL), dried with anhydrous Na2SO4, and then concentrated under reduced pressure. Finally, the residue is purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 - 1 / 2) to obtain the target product 2e.

[0075] The reaction formula is:

[0076]

[0077] Characterize the above target product, and the 1H NMR spectrum is as Figure 5 shown:

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.31 (q, J = 3.0 Hz, 1H), 6.98 (dd, J = 8.4, 3.0 Hz, 1H), 6.88 (dt, J = 8.5, 2.9 Hz, 1H), 3.67–3.59 (m, 9H), 3.11–2.93 (m, 2H), 2.74–2.64 (m, 1H), 2.33–2.20 (m, 2H).

[0079] According to the characterization data, the obtained reaction product is dimethyl (7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate (purity > 98%); the product yield is calculated, and the result is 80%.

[0080] In summary, in the present invention, potassium bis(trimethylsilyl)amide (KHMDS) is used to replace traditional lithium diisopropylamide (LDA) as a deprotonating agent, and the synthesis process of the target phosphonate is successfully optimized.

[0081] Compared with LDA, due to its larger bis(trimethylsilyl)amide group, KHMDS can form weak interactions with the carbonyl oxygen, thus effectively inhibiting the formation of by-products caused by the direct binding of phosphine to oxygen. In addition, this system does not require extremely low temperature conditions, avoiding the rearrangement side reactions involved in LDA and reducing the need for multiple equivalents of strong base. Thanks to these optimization measures, the yield of the target product has been significantly improved (90%), making this synthesis method more efficient, controllable and potentially applicable to industrialization.

[0082] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate, characterized in that: including, mixing the compound shown in Formula I with potassium bis(trimethylsilyl)amide and dimethyl chlorophosphate, and reacting in a solvent to obtain the target compound shown in Formula II; wherein, X is selected from CH2 or O; R is selected from one of hydrogen, methyl, halogen, and methoxy.

2. The synthesis method of (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate according to claim 1, characterized in that: The molar ratio of the compound shown in Formula I to potassium bis(trimethylsilyl)amide is 1:1 to 2.

3. The synthesis method of (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate according to claim 1, characterized in that: The molar ratio of the compound shown in Formula I to dimethyl chlorophosphate is 1:1 to 2.

4. The synthesis method of (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate according to any one of claims 1 to 3, characterized in that: The solvent includes one of tetrahydrofuran, diethyl ether, 1,4-dioxane, and ethylene glycol dimethyl ether.

5. The synthesis method of the (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate according to claim 4, characterized in that: For the said reaction, the reaction temperature is -60 to 0 °C.

6. The synthesis method of the (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate according to claim 5, characterized in that: The said reaction is carried out under a protective atmosphere.

7. The synthetic method of (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate according to claim 5 or 6, characterized in that: For the reaction in the solvent, dissolve the compound shown in Formula I in the solvent, cool it to the reaction temperature, add dropwise the solution of potassium bis(trimethylsilyl)amide dissolved in the solvent, stir and mix, then add dimethyl chlorophosphate to react, gradually heat up to 0 °C and then continue the reaction.

8. The method for synthesizing (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) phosphonate according to claim 1, characterized in that: It also includes the step of purifying the target compound.

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