A process for the preparation of methylene bisphosphorodichloride
By using tetraethylmethylene diphosphate to undergo pyrolysis and chlorination reactions with trimethylhalosilane under mild conditions, the problems of difficult-to-obtain raw materials and high reaction risks in existing technologies have been solved, achieving high-yield preparation of methylene dichloride phosphorus, which is suitable for industrial production.
Patent Information
- Application Number
- CN202211356787.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-11-01
- Publication Date
- 2025-11-07
- Estimated Expiration
- 2042-11-01
AI Technical Summary
Existing methods for preparing methylene phosphorus dichloride suffer from problems such as difficulty in obtaining raw materials, harsh reaction conditions, high risk, and low yield, making it difficult to achieve large-scale industrial production.
Tetraethylmethylene diphosphate was used as a substrate and underwent a cleavage reaction in the presence of trimethylhalosilane. Then, it was chlorinated under mild conditions with a chlorination reagent to produce methylene phosphorus dichloride.
This invention provides a preparation method that uses readily available raw materials, has low cost, high safety, and high yield, making it suitable for large-scale industrial production.
Smart Images
Figure CN115651015B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of biopharmaceutical synthesis, in particular to a preparation method of methylene phosphorus dichloride. BACKGROUND
[0002] Methylene phosphorus dichloride is an important chemical intermediate and is widely used in various pharmaceutical synthesis. The structure of methylene phosphorus dichloride is as follows:
[0003]
[0004] At present, there are mainly three methods for preparing methylene phosphorus dichloride in the prior art:
[0005] (1) Chlorination of isopropyl phosphate. This method is difficult to obtain raw materials, and the reaction conditions are harsh. Usually, PCl5, a high-activity chlorinating agent, is used for reaction at high temperature, and the reaction has high risk. There is danger in industrial amplification.
[0006] (2) Chlorination of ethyl or butyl phosphate in the presence of methylenediphosphonic acid to obtain the product methylene phosphorus dichloride. However, the starting raw material of this reaction is complex and not easy to obtain, and the reaction is sensitive to temperature. The yield is generally low.
[0007] (3) Oxidation of bis(dichlorophosphino) methane to obtain the product methylene phosphorus dichloride. However, the starting raw material of this method is also complex and not easy to obtain. Based on economic considerations, it is difficult to realize large-scale industrial production.
[0008] Therefore, there is a need for a preparation method of methylene phosphorus dichloride in the art, which is easy to obtain raw materials, low in cost and high in yield, and has mild reaction conditions and low risk, which is beneficial to large-scale industrial production. SUMMARY
[0009] To solve the above technical problems, the present application provides the following technical solutions:
[0010] A preparation method of methylene phosphorus dichloride, in the presence of an organic solvent, compound 1 is used as a substrate. The compound 1 is subjected to a cleavage reaction under the action of trimethyl halosilane to generate an intermediate product. The intermediate product is subjected to a chlorination reaction with a chlorinating agent to finally generate the product methylene phosphorus dichloride. The compound 1 is tetraethyl methylenediphosphonate, and the structure of the compound 1 is as follows:
[0011]
[0012] Specifically, the steps of the preparation method are as follows:
[0013] S1, tetraethyl methylenediphosphonate is added to an organic solvent to prepare a solution;
[0014] S2, adding trimethyl halosilane to the solution obtained in S1, stirring at 20-25 °C for 12-15 h, and concentrating under reduced pressure to obtain an intermediate compound 2, the structure of which is:
[0015]
[0016] S3, adding the compound 2 obtained in S2 to an organic solvent, adding a chlorinating agent and N,N-dimethylformamide DMF, mixing, and stirring at 15-25 °C for 12-20 h, filtering, and concentrating under reduced pressure to obtain a crude product;
[0017] S4, mixing the crude product with a small polar solvent, beating, filtering, and drying at 15-25 °C to obtain a pure product methylene bisphosphorochloridite.
[0018] Specifically, the organic solvent is selected from any one or a combination of at least two of chloroform, dichloromethane, 1,2-dichloroethane, chlorobenzene, toluene, xylene, and mesitylene.
[0019] Preferably, the organic solvent is selected from dichloromethane.
[0020] Specifically, the trimethyl halosilane is trimethylchlorosilane, trimethylbromosilane, or trimethyliodosilane.
[0021] Preferably, the trimethyl halosilane is trimethylbromosilane.
[0022] Specifically, the chlorinating agent is SOCl2, (COCl)2, or POCl3.
[0023] Preferably, the chlorinating agent is (COCl)2.
[0024] Specifically, the molar ratio of the compound 1 to the trimethyl halosilane is 1:(4.5-5).
[0025] Preferably, the molar ratio of the compound 1 to the trimethyl halosilane is 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, or 1:5.
[0026] Specifically, the molar ratio of the intermediate to the chlorinating agent is 1:(5-6).
[0027] Preferably, the molar ratio of the intermediate to the chlorinating agent is 1:5.0, 1:5.2, 1:5.4, 1:5.6, 1:5.8, or 1:6.0.
[0028] Specifically, in S1, the mass concentration of the tetraethyl methylenediphosphonate in the solution is 0.14-0.15 kg / L, preferably 0.14 kg / L.
[0029] Specifically, in the S4, the small polar solvent is selected from any one of ethyl ether, isopropyl ether, methyl tert-butyl ether, n-heptane, petroleum ether, n-pentane, n-hexane and cyclohexane.
[0030] Preferably, in the S4, the small polar solvent is methyl tert-butyl ether.
[0031] Specifically, in the S4, the time for beating is 10-18h, preferably 12h.
[0032] The beneficial effects of the present application include:
[0033] (1) The reaction process of the present application is reasonable in design, tetraethyl methylene diphosphonate is used as a reaction substrate, which is cheap and easy to obtain, thereby reducing the production cost.
[0034] (2) The reaction method provided by the present application first uses trimethyl halosilane to crack tetraethyl methylene diphosphonate, and the reaction condition is mild, without the need for high temperature, thereby improving the safety of production.
[0035] (3) The reaction method provided by the present application does not need high-temperature reaction conditions when the intermediate product is subjected to chlorination reaction with a chlorinating agent, but only needs to be carried out at 15-25℃, the risk coefficient of the reaction is low, and the safety of production is significantly improved.
[0036] (4) The reaction method provided by the present application prepares methylene bisphosphorus chloride under relatively mild reaction conditions through one-step cracking reaction and one-step chlorination reaction, and the yield is higher, reaching more than 70%, which is conducive to industrial scale production. BRIEF DESCRIPTION OF DRAWINGS
[0037] Figure 1 It is a synthesis route map of methylene bisphosphorus chloride of Example 1;
[0038] In the figure, DCM is dichloromethane, TMSBr is trimethylsilyl bromide, (COCl)2 is oxalyl chloride, DMF is N,N-dimethylformamide, and MTBE is methyl tert-butyl ether. DETAILED DESCRIPTION
[0039] The technical solutions of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor belong to the scope of protection of the present application.
[0040] Example 1
[0041] As Figure 1The synthetic route map is shown below:
[0042] S1, add tetraethyl methylene diphosphonic acid ester 4.60 kg into 32.2 L dichloromethane (DCM) to prepare a solution;
[0043] S2, add trimethyl silyl bromide (11.7 kg, 9.94 L) into the solution obtained in S1, stir the reaction at 25°C for 12 h, and concentrate under reduced pressure to obtain the crude product of intermediate compound 2, which is a yellow oil;
[0044] S3, take 6 kg of compound 2 obtained in S2, add 24 L of dichloromethane, and then add (COCl)2 (8.19 kg, 5.65 L) and N,N-dimethylformamide (DMF) (28.3 g, 29.8 mL), mix, stir the reaction at 20°C for 12 h, filter, and concentrate under reduced pressure to obtain the crude product;
[0045] S4, mix the crude product with methyl tert-butyl ether (MTBE), perform slurry at 20°C, grind for 12 h, filter, and dry to obtain white solid compound 3, i.e., the product methylene bisphosphorus dichloride (3.40 kg), with a yield of 74%.
[0046] In specific implementation, the staff can add DMF or increase the reaction temperature according to the remaining raw materials in the reaction system to shorten the total length of the reaction and improve the reaction efficiency.
[0047] In summary, the above examples are only preferred embodiments of the present application and are not intended to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.
Claims
1. A process for the preparation of methylene bisphosphorochloridite, characterized in that, In the presence of an organic solvent, compound 1 is used as a substrate, which is cleaved by trimethylhalosilane to generate an intermediate product, and the intermediate product is chlorinated by a chlorinating agent to generate the product methylene phosphorus dichloride finally, wherein the compound 1 is tetraethyl methylenediphosphonate, and the structure of the compound 1 is as follows: The chlorinating agent is SOCl2, (COCl)2 or POCl3.
2. The method for preparing methylene dichloride as described in claim 1, characterized in that, The preparation method comprises the following steps: S1, adding tetraethyl methylenediphosphonate into an organic solvent to prepare a solution; S2, adding trimethylhalosilane into the solution obtained in S1, stirring and reacting at 20-25 ℃ for 12-15 h, and concentrating under reduced pressure to obtain an intermediate product compound 2, wherein the structure of the compound 2 is as follows: S3, adding the compound 2 obtained in S2 into an organic solvent, adding a chlorinating agent and N,N-dimethylformamide DMF, mixing, stirring and reacting at 15-25 ℃ for 12-20 h, filtering and concentrating under reduced pressure to obtain a crude product; S4, mixing the crude product with a small-polarity solvent, beating, filtering and drying at 15-25 ℃ to obtain a pure product methylene phosphorus dichloride.
3. The method for preparing methylene dichloride as described in claim 1, characterized in that, The organic solvent is any one or a combination of at least two of chloroform, dichloromethane, 1,2-dichloroethane, chlorobenzene, toluene, xylene and trimethylbenzene.
4. The method for preparing methylene dichloride as described in claim 1, characterized in that, The trimethylhalosilane is trimethylchlorosilane, trimethylbromosilane or trimethyliodosilane.
5. The method for preparing methylene dichloride as described in claim 1, characterized in that, The molar ratio of the compound 1 to the trimethylhalosilane is 1:(4.5-5).
6. The method for preparing methylene phosphorus dichloride as described in claim 1, characterized in that, The molar ratio of the intermediate product to the chlorinating agent is 1:(5-6).
7. The method for preparing methylene dichloride as described in claim 2, characterized in that, In S1, the mass concentration of the tetraethyl methylenediphosphonate in the solution is 0.14-0.15 kg / L.
8. The method for preparing methylene dichloride as described in claim 2, characterized in that, In S4, the small-polarity solvent is any one of diethyl ether, isopropyl ether, methyl tert-butyl ether, n-heptane, petroleum ether, n-pentane, n-hexane and cyclohexane.
9. The method for preparing methylene phosphorus dichloride as described in claim 2, characterized in that, In S4, the beating time is 10-18 h.