CN113121596A - Preparation method of diethyl p-toluenesulfonyloxymethylphosphonate - Google Patents
Preparation method of diethyl p-toluenesulfonyloxymethylphosphonate Download PDFInfo
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- UOEFFQWLRUBDME-UHFFFAOYSA-N diethoxyphosphorylmethyl 4-methylbenzenesulfonate Chemical compound CCOP(=O)(OCC)COS(=O)(=O)C1=CC=C(C)C=C1 UOEFFQWLRUBDME-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 213
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 117
- 238000006243 chemical reaction Methods 0.000 claims abstract description 83
- 239000000243 solution Substances 0.000 claims abstract description 67
- 239000003513 alkali Substances 0.000 claims abstract description 60
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims abstract description 57
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 55
- 239000007864 aqueous solution Substances 0.000 claims abstract description 53
- 238000003756 stirring Methods 0.000 claims abstract description 47
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 46
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000011780 sodium chloride Substances 0.000 claims abstract description 23
- 239000012074 organic phase Substances 0.000 claims abstract description 20
- 239000007788 liquid Substances 0.000 claims abstract description 17
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 17
- 238000005406 washing Methods 0.000 claims abstract description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
- 239000012263 liquid product Substances 0.000 claims abstract description 11
- 239000008346 aqueous phase Substances 0.000 claims abstract description 10
- 239000012044 organic layer Substances 0.000 claims abstract description 10
- 239000000463 material Substances 0.000 claims description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- 238000005070 sampling Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000008098 formaldehyde solution Substances 0.000 claims description 9
- MGJURKDLIJVDEO-UHFFFAOYSA-N formaldehyde;hydrate Chemical compound O.O=C MGJURKDLIJVDEO-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 4
- 239000000047 product Substances 0.000 abstract description 12
- 238000005265 energy consumption Methods 0.000 abstract description 6
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 239000012267 brine Substances 0.000 abstract description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000007031 hydroxymethylation reaction Methods 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 5
- 239000002351 wastewater Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 229960004556 tenofovir Drugs 0.000 description 3
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 239000010842 industrial wastewater Substances 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QRBPRPXDUFXPGR-UHFFFAOYSA-N 2-methoxypropyl dihydrogen phosphate Chemical compound COC(C)COP(O)(O)=O QRBPRPXDUFXPGR-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The invention relates to a preparation method of diethyl p-toluenesulfonyloxymethylphosphonate. The method comprises the following steps: under the protection of nitrogen, adding diethyl phosphite into a reaction vessel, then sequentially adding carbonate and tetrabutylammonium bromide, and stirring and dropwise adding a formaldehyde aqueous solution; then continuously adding carbonate and formaldehyde aqueous solution in batches; after the reaction end point is reached, adding toluene, adding p-toluenesulfonyl chloride under stirring, and reacting; dropwise adding an alkali solution; after dropwise adding, preserving heat until the reaction end point, and standing; separating the liquid, placing the upper organic phase for later use, and extracting the lower aqueous phase with toluene; and combining the two organic phases, adding a sodium chloride aqueous solution for washing, and concentrating the organic layer under reduced pressure to obtain a liquid product. Because extra energy consumption is not needed in the reaction, the temperature reduction of the frozen brine required by the traditional process is abandoned, and the energy consumption is greatly reduced; compared with the traditional process, the yield of about 85 percent in the step is improved by 10 to 15 percent, the economic value of the product is greatly improved, and the method is beneficial to environmental protection.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of diethyl p-toluenesulfonyloxymethylphosphonate.
Background
Tenofovir, also known as Tenofovir, has the chemical name of (R) -9- (2-methoxypropyl phosphate) -adenine, and has a strong inhibitory effect on retrovirus (HIV) and Hepatitis B Virus (HBV) as a novel ring-opening nucleotide antiviral drug. Can be used for patients with drug resistance to lamivudine (HBV), and has good tolerance to HIV-infected patients.
In the preparation process of the tenofovir bulk drug, a key medical intermediate, namely diethyl p-toluenesulfonyloxymethylphosphonate (desmp), is required. The intermediate is required to be used in the existing production route for synthesizing the API, and the diethyl p-toluenesulfonyloxymethylphosphonate is not replaceable.
The prior traditional process route of diethyl p-toluenesulfonyloxymethylphosphonate is to perform low-temperature hydroxymethylation reaction on diethyl phosphite and formaldehyde under the catalysis of organic base, and then to continue esterification and butt joint with p-toluenesulfonyl chloride under the condition of liquid alkali. For example, Wangshijai et al, in the research on preparation and separation of diethyl p-toluenesulfonyloxymethylphosphonate, disclose that diethyl phosphite is condensed with paraformaldehyde, and subjected to acylation reaction with p-toluenesulfonyl chloride to obtain diethyl p-toluenesulfonyloxymethylphosphonate, which is then separated and purified by column chromatography. The paper also examined the effect of triethylamine usage and reaction time on yield, which was 79.2% by IR and HNMR characterization.
The process has the defects that the auxiliary alkali used in the first step of hydroxymethylation is organic alkali (triethylamine) with high alkalinity, so that the side reaction (hydrolysis of diethyl phosphite) is high, in the prior art, the side reaction is controlled at a low temperature of below 0 ℃, the energy consumption and the control difficulty are high, the characteristic ethyl ester impurity of a final product is often high (> 0.3%), and the impurity level in the API is influenced. In addition, the solvent toluene adopted in the second step of the prior art needs to be recycled and reused in industrial production, and due to the use of the liquid organic alkali in the first step, acid washing, alkali washing and brine washing are needed in the process of recycling toluene, and finally, the solvent toluene can be recycled and reused continuously, so that a large amount of industrial wastewater is generated, the toluene recovery rate is lower than 80%, and the environmental protection is not facilitated on the premise of improving the production cost.
In addition, a method for synthesizing diethyl tosyloxymethylphosphonate is also provided, namely, diethyl phosphite is subjected to hydroxymethylation reaction with formaldehyde under the catalysis of inorganic base (sodium carbonate and potassium carbonate), and then is subjected to esterification and butt joint with p-toluenesulfonyl chloride under the condition of liquid alkali to obtain the product. The method has the disadvantages that inorganic base replaces organic base, and is certainly superior to the first existing production scheme in terms of reducing the intensity of the first step reaction, but because inorganic base solid is easily wrapped by milky foam generated in the reaction stirring process, the reaction is terminated early, a large amount of raw materials are remained in the first step hydroxymethylation reaction, the yield of products is unstable, the second step side reaction is increased, impurities are increased, and the purity is reduced.
Therefore, there is a need to improve the above-mentioned process and to develop a process for preparing diethyl tosyloxymethylphosphonate with high conversion rate and high purity and reduced wastewater discharge.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of diethyl tosyloxymethyl phosphonate, which can react under mild conditions of room temperature, has the conversion rate of more than 98 percent and less process wastewater.
The preparation method of the diethyl tosyloxymethyl phosphonate provided by the invention mainly comprises the following steps:
firstly, inorganic base solid is used for dispersing and feeding in batches in the hydroxymethylation reaction to promote the reaction continuity, and meanwhile, a proper amount of phase transfer catalyst is added in the reaction to reduce milky foam in reaction stirring and ensure that the reaction is completed mildly and completely;
in addition, in the aspect of toluene recycling, because inorganic base is used for carrying out hydroxymethylation reaction, the toluene solvent needs to be recycled in the next step of reaction, so that the toluene solvent does not contain organic base components, various water washing links can be removed, and the toluene solvent is directly concentrated and collected for recycling to the next batch of production. On the premise of greatly improving the recovery rate of the toluene, the wastewater generated in the step of recovering and washing the toluene is completely improved to zero discharge.
The preparation method of the diethyl tosyloxymethyl phosphonate provided by the invention specifically comprises the following steps:
(1) adding diethyl phosphite into a reaction container under the protection of nitrogen, and controlling the temperature to 10-18 ℃; sequentially adding carbonate and tetrabutylammonium bromide, stirring and dropwise adding a formaldehyde water solution, heating the system, and controlling the temperature to be 20-25 ℃;
(2) after the feeding is finished, controlling the reaction temperature within 20-25 ℃, and continuously adding carbonate and formaldehyde aqueous solution in batches; after the feeding is finished again, stirring, sampling and detecting the content of diethyl phosphite in the mixture until the content is less than 0.1 percent, and taking the reaction end point as the reaction end point;
(3) reducing the temperature of the materials in the bottle to 0-5 ℃; adding toluene, adding p-toluenesulfonyl chloride while stirring, and continuing stirring; dropwise adding an alkali solution, wherein the temperature of materials in the reaction container is controlled to be 0-10 ℃ in the dropwise adding process;
(4) dropwise adding, keeping the temperature, sampling, detecting HPLC (high performance liquid chromatography), taking the p-toluenesulfonyl chloride content in the reaction liquid less than 0.1 percent as a reaction end point, and standing; separating the liquid, placing the upper organic phase for later use, and extracting the lower aqueous phase with toluene;
(5) and combining the two organic phases, adding a sodium chloride aqueous solution for washing, and concentrating the organic layer under reduced pressure to obtain a liquid product while recovering the toluene.
Preferably, in the step (1), the weight ratio of diethyl phosphite, carbonate and tetrabutylammonium bromide is 30-35: 0.8-1.2: 0.8 to 1.2;
preferably, the weight ratio of diethyl phosphite, carbonate and tetrabutylammonium bromide is 32: 1: 1;
preferably, (1) adding diethyl phosphite into a reaction vessel under the protection of nitrogen, and controlling the temperature to 15 ℃;
preferably, in (2), the carbonate is potassium carbonate or sodium carbonate.
Preferably, in the step (1), the mass concentration of the aqueous formaldehyde solution is 35-39%, and the volume mass ratio of the aqueous formaldehyde solution to diethyl phosphite is 1 ml: (7-9) g;
preferably, the mass concentration of the aqueous formaldehyde solution is 37%, and the volume mass ratio of the aqueous formaldehyde solution to the diethyl phosphite is 1 ml: 8 g.
Preferably, in the step (2), the carbonate and the formaldehyde aqueous solution are added in four times; the mass ratio of the total addition of carbonate to diethyl phosphite is 1: 7-9;
preferably, in the step (2), the carbonate and the formaldehyde aqueous solution are added in four times; the mass ratio of the addition amount of the carbonate to the diethyl phosphite is 1: 8;
the mass concentration of the formaldehyde aqueous solution is 35-39%, and the volume mass ratio of the formaldehyde aqueous solution to the carbonate added in the step is (3-5) ml: 1g of a compound;
the mass concentration of the formaldehyde aqueous solution is 35-39%, and the volume mass ratio of the formaldehyde aqueous solution to the carbonate added in the step is 4 ml: 1g of a compound;
preferably, in (2), the carbonate is potassium carbonate or sodium carbonate.
Preferably, in the step (2), after the re-feeding is finished, stirring is carried out for 25-35 minutes;
preferably, in (2), after the re-feeding is completed, stirring is carried out for 30 minutes.
Preferably, in the step (3), the volume-to-mass ratio of the added toluene to the diethyl phosphite is (23-27) ml: (15-17) g;
preferably, in (3), the volume mass ratio of the added toluene to the diethyl phosphite is 25 ml: 16g of a mixture;
preferably, in (3), the mass-to-volume ratio of the added p-toluenesulfonyl chloride to the toluene is: (20-23) g: (24-26) ml;
preferably, in (3), the mass-to-volume ratio of the added p-toluenesulfonyl chloride to the toluene is: 21 g: 25 ml;
preferably, in the step (3), stirring is continuously carried out for 8-12 minutes;
preferably, in (3), stirring is continued for 10 minutes;
preferably, in the step (3), the mass concentration of the alkali solution is 30-33%;
preferably, in the step (3), the volume ratio of the alkali solution to the toluene is 16-18: 23-27;
preferably, in (3), the volume ratio of the alkali solution to the toluene is 17: 25;
preferably, in the step (3), the time for dripping the alkali solution is 50-70 min;
preferably, in (3), the time for dropping the alkali solution is 1 hour.
Preferably, in the step (4), the material in the step (3) is dropwise added with an alkali solution and then is subjected to heat preservation at 0-10 ℃;
preferably, the materials in the step (4) and the step (3) are dropwise added with an alkali solution and then are subjected to heat preservation for 50-70 min;
preferably, in the step (4), the material in the step (3) is dropwise added with an alkali solution and then is kept warm for 1 hour;
preferably, in the step (4), the standing time is 20-40 min;
preferably, in (4), the standing time is 30 min;
preferably, in the step (4), the volume ratio of the toluene used for extraction to the alkali solution in the step (3) is 33-37: 15-19;
preferably, in (4), the volume ratio of the toluene used for extraction to the alkali solution in (3) is 35: 17.
preferably, in the step (5), the mass concentration of the sodium chloride aqueous solution is 3-7%;
preferably, in the step (5), the mass concentration of the sodium chloride aqueous solution is 5%;
preferably, in the step (5), the volume ratio of the sodium chloride aqueous solution to the alkali solution in the step (3) is 5-7: 15-19;
preferably, the volume ratio of the sodium chloride aqueous solution in (5) to the alkali solution in (3) is 6: 17.
the preparation method of the diethyl p-toluenesulfonyloxymethylphosphonate comprises the following steps:
(1) adding diethyl phosphite into a reaction container under the protection of nitrogen, and controlling the temperature to 10-18 ℃; sequentially adding carbonate and tetrabutylammonium bromide, stirring and dropwise adding 35-39% by mass of formaldehyde water solution, and controlling the temperature to be 20-25 ℃;
wherein the weight ratio of diethyl phosphite, carbonate and tetrabutylammonium bromide is 30-35: 0.8-1.2: 0.8 to 1.2;
the volume mass ratio of the formaldehyde aqueous solution to the diethyl phosphite is 1 ml: (7-9) g;
(2) after the feeding is finished, controlling the reaction temperature within 20-25 ℃, and continuously adding carbonate and formaldehyde aqueous solution in batches; after the feeding is finished again, stirring, sampling and detecting the content of diethyl phosphite in the mixture until the content is less than 0.1 percent, and taking the reaction end point as the reaction end point;
the mass ratio of the total addition of carbonate to diethyl phosphite is 1: 7-9;
the mass concentration of the formaldehyde aqueous solution is 35-39%, and the volume mass ratio of the formaldehyde aqueous solution to the carbonate added in the step is (3-5) ml: 1g of a compound;
(3) reducing the temperature of the materials in the bottle to 0-5 ℃; adding toluene, adding paratoluensulfonyl chloride while stirring, and continuously stirring for 8-12 minutes; dropwise adding an alkali solution, wherein the temperature of materials in the reaction container is controlled to be 0-10 ℃ in the dropwise adding process;
the volume mass ratio of the added toluene to the diethyl phosphite is (23-27) ml: (15-17) g;
the mass-volume ratio of the added p-toluenesulfonyl chloride to the toluene is as follows: (20-23) g: (24-26) ml;
the mass concentration of the alkali solution is 30-33%, and the volume ratio of the alkali solution to the toluene is 17: 25, dropwise adding the aqueous alkali for 50-70 min;
(4) dropwise adding liquid caustic soda, keeping the temperature for 50-70 min, sampling, detecting HPLC (high performance liquid chromatography), taking the p-toluenesulfonyl chloride content in the reaction liquid less than 0.1% as a reaction end point, and standing for 20-40 min; separating the liquid, placing the upper organic phase for later use, and extracting the lower aqueous phase with toluene; the volume ratio of the toluene used for extraction to the alkali solution in the step (3) is 33-37: 15-19;
(5) combining the two organic phases, adding a sodium chloride aqueous solution with the mass concentration of 3-7% for washing, decompressing and concentrating the organic layer to obtain a liquid product, and recovering toluene;
wherein the volume ratio of the sodium chloride aqueous solution to the alkali solution in the step (3) is 5-7: 15 to 19.
Preferably, the preparation method of the diethyl p-toluenesulfonyloxymethylphosphonate comprises the following steps:
(1) adding diethyl phosphite into a reaction container under the protection of nitrogen, and controlling the temperature to 10-18 ℃; sequentially adding carbonate and tetrabutylammonium bromide, stirring and dropwise adding a formaldehyde water solution with the mass concentration of 37%, and simultaneously controlling the temperature to be 20-25 ℃;
wherein, the weight ratio of the diethyl phosphite, the carbonate and the tetrabutylammonium bromide is 32: 1: 1;
the volume mass ratio of the formaldehyde aqueous solution to the diethyl phosphite is 1 ml: 8g of the total weight of the mixture;
(2) after the feeding is finished, controlling the reaction temperature within 20-25 ℃, and continuously adding carbonate and formaldehyde aqueous solution in batches; after the feeding is finished again, stirring, sampling and detecting the content of diethyl phosphite in the mixture until the content is less than 0.1 percent, and taking the reaction end point as the reaction end point;
the mass ratio of the total addition of carbonate to diethyl phosphite is 1: 8;
the mass concentration of the formaldehyde aqueous solution is 37 percent, and the volume mass ratio of the formaldehyde aqueous solution to the carbonate added in the step is 4 ml: 1g of a compound;
(3) reducing the temperature of the materials in the bottle to 0-5 ℃; adding toluene, adding p-toluenesulfonyl chloride while stirring, and continuing stirring for 10 minutes; dropwise adding an alkali solution, wherein the temperature of materials in the reaction container is controlled to be 0-10 ℃ in the dropwise adding process;
the volume mass ratio of the added toluene to the diethyl phosphite is 25 ml: 16g of a mixture;
the mass-volume ratio of the added p-toluenesulfonyl chloride to the toluene is as follows: 21 g: 25 ml;
the mass concentration of the alkali solution is 20%, and the volume ratio of the alkali solution to the toluene is 17: 25, dropwise adding the alkali solution for 60 min;
(4) dropwise adding liquid caustic soda, keeping the temperature for 60min, sampling, detecting HPLC, taking the reaction solution with the content of the tosyl chloride less than 0.1% as a reaction end point, and standing for 30 min; separating the liquid, placing the upper organic phase for later use, and extracting the lower aqueous phase with toluene; the volume ratio of the toluene used for extraction to the alkali solution in (3) was 35: 17;
(5) combining the two organic phases, adding a sodium chloride aqueous solution with the mass concentration of 5% for washing, decompressing and concentrating the organic layer to obtain a liquid product, and simultaneously recovering toluene;
wherein, the volume ratio of the sodium chloride aqueous solution to the alkali solution in the step (3) is 6: 17.
the invention has the beneficial effects that:
(1) greatly reduces the production cost
In the preparation process of the product, as the reaction is carried out at a mild room temperature, no extra energy consumption is needed, and the cooling of the frozen brine required by the traditional process is abandoned, so that the energy consumption is greatly reduced;
(2) product yield improvement
As the reaction conversion rate of the first step is more than 98 percent, the yield of the first step is improved by 10 to 15 percent compared with that of the traditional process in which the yield is about 85 percent, and the economic value of the product is greatly improved;
(3) reduce the discharge amount of waste water
The process of the invention can obtain products with the same yield, and the generated industrial wastewater is reduced by one third of the wastewater generation amount before improvement, which is beneficial to environmental protection.
Drawings
FIG. 1 is a table showing the results of liquid chromatography detection in example 1;
FIG. 2 is a table showing the results of liquid chromatography detection in example 2;
FIG. 3 is a table showing the results of liquid chromatography detection in example 3.
Detailed Description
The present invention will now be further described with reference to specific embodiments in order to enable those skilled in the art to better understand the present invention.
Example 1
The preparation method of diethyl p-toluenesulfonyloxymethylphosphonate adopts the following reaction principle:
(1) under the protection of nitrogen, 160g of diethyl phosphite is added into a 1000ml glass reaction bottle, and the temperature is reduced to about 15 ℃; sequentially adding 5g of sodium carbonate and 5g of tetrabutylammonium bromide, stirring and dropwise adding 20.0ml of 37% formaldehyde water solution, reacting, slightly heating, and controlling the temperature to be about 23 ℃;
(2) after the addition, controlling the reaction in the temperature range, and continuously adding 20g of sodium carbonate and 80.0ml of 37% formaldehyde aqueous solution (mass concentration, the same below) in four times (adding in four times in average); after the feeding is finished again, stirring for 30 minutes, sampling and detecting the content of diethyl phosphite in the mixture until the content is less than 0.1 percent, and taking the reaction end point;
(3) reducing the temperature of the materials in the bottle to about 2 ℃; adding 250ml of toluene, adding 210g of paratoluensulfonyl chloride while stirring, and stirring for 10 minutes; dropping 170.0ml of 30% alkali solution, controlling the temperature of the materials in the reaction bottle to be 5 ℃ in the dropping process, and the dropping time to be 1.0 hour;
(4) preserving the heat of the material in the step (3) for 1 hour at about 3 ℃, sampling and detecting HPLC, and taking the reaction end point as the reaction end point when the content of the tosyl chloride in the reaction liquid is less than 0.1 percent; standing for 30 minutes, separating liquid, standing an upper organic phase for later use, and extracting a lower aqueous phase with 350.0ml of toluene;
(5) the organic phases are combined for 2 times, 60.0ml of 5% sodium chloride aqueous solution is added for washing, the organic layer is decompressed and concentrated to obtain 340g of liquid product (purity 99%), 580.0ml of toluene is recovered, and the liquid product can be directly used for the next batch of reaction.
As can be seen from the reaction steps, when the method is used for preparing the diethyl p-toluenesulfonyloxymethylphosphonate, firstly, the reaction can be carried out at a mild room temperature, so that the energy consumption increase caused by the temperature reduction of the frozen saline water used in the traditional process is avoided; and the recovered toluene can be directly used for the next batch of reaction, so that the utilization rate of the toluene is improved.
In addition, the purity of the product obtained by the method is up to 99%, and the conversion rate is up to more than 98%, so that the yield and the purity of the product are greatly improved compared with the existing production method of diethyl p-toluenesulfonyloxymethylphosphonate.
The following table is a table of chromatographic results in the present invention:
table 1 table of product analysis results in example 1
Analytical results table
Example 2
The preparation method of diethyl p-toluenesulfonyloxymethylphosphonate comprises the following steps:
(1) under the protection of nitrogen, 160g of diethyl phosphite is added into a 1000ml glass reaction bottle, and the temperature is reduced to about 15 ℃; sequentially adding 5.0g of potassium carbonate and 5.0g of tetrabutylammonium bromide, stirring and dropwise adding 20.0ml of 37% formaldehyde water solution, and slightly heating to about 22 ℃ for reaction;
(2) after the addition is finished, controlling the reaction to be carried out at the temperature of about 22 ℃, and continuously adding 20.0g of potassium carbonate and 80.0ml of 37 percent formaldehyde aqueous solution for four times; after the feeding is finished again, stirring for 30 minutes, sampling and detecting the content of diethyl phosphite in the mixture until the content is less than 0.1 percent, and taking the reaction end point;
(3) reducing the temperature of the contents to about 1 ℃; adding 250.0ml of toluene, adding 210.0g of paratoluensulfonyl chloride while stirring, and stirring for 10 minutes; dropping 170.0ml of 30% alkali solution, wherein the temperature of the materials in the reaction bottle is controlled to be about 4 ℃ in the dropping process, and the dropping time is 1.0 hour;
(4) preserving the heat of the material in the step (3) at 6 ℃ for 1 hour, sampling and detecting HPLC, and taking the reaction end point as the reaction end point when the content of the tosyl chloride in the reaction liquid is less than 0.1 percent; standing for 30 minutes, separating liquid, standing an upper organic phase for later use, and extracting a lower aqueous phase with 350ml of toluene;
(5) the organic phases were combined 2 times, washed with 60ml of 5% aqueous sodium chloride solution and the organic layer was concentrated under reduced pressure to give 335.0g of a liquid product (purity 99%) which was recovered in 600ml of toluene and used directly in the next batch.
Table 2 table of product analysis results in example 2
Example 3
The preparation method of diethyl p-toluenesulfonyloxymethylphosphonate comprises the following steps:
(1) under the protection of nitrogen, 160g of diethyl phosphite is added into a 1000ml glass reaction bottle, and the temperature is reduced to 15 ℃; sequentially adding 5.0g of potassium carbonate and 5.0g of tetrabutylammonium hydrogen sulfate, stirring and dropwise adding 20.0ml of 37% formaldehyde water solution, and slightly heating the reaction to about 23 ℃;
(2) after the feeding is finished, controlling the reaction at about 23 ℃, continuously adding 20.0g of potassium carbonate and 80.0ml of 37% formaldehyde aqueous solution for four times, stirring for 30 minutes after the feeding is finished again, sampling and detecting the content of diethyl phosphite in the solution until the content is less than 0.1%, and taking the reaction as a reaction end point;
(3) reducing the temperature of the materials in the bottle to about 2 ℃; adding 250.0ml of toluene, adding 210.0g of paratoluensulfonyl chloride while stirring, and stirring for 10 minutes; dropping 170.0ml of 30% alkali solution, wherein the temperature of the materials in the reaction bottle is controlled to be about 5 ℃ in the dropping process, and the dropping time is 1.0 hour;
(4) preserving the heat of the material in the step (3) at 4 ℃ for 1 hour, sampling and detecting HPLC, and taking the reaction end point as the reaction end point when the content of the tosyl chloride in the reaction liquid is less than 0.1 percent; standing for 30 minutes, separating liquid, standing an upper organic phase for later use, and extracting a lower aqueous phase with 350.0ml of toluene;
(5) the organic phases were combined 2 times, washed with 60.0ml of 5% aqueous sodium chloride solution and the organic layer was concentrated under reduced pressure. 337.0g of liquid product (purity 99%) was obtained, and 585.0ml of toluene was recovered and used in the next batch reaction.
Table 3 table of product analysis results in example 3
Analytical results table
The results of the analyses in tables 1 to 3 above were performed under the following instrumental and environmental conditions: the instrument model in the liquid chromatography detection is as follows: LC-10A, the column temperature is 25 ℃, the column model is C18, and the gradient mode is as follows: a high pressure gradient; a detector: and an ultraviolet detector with the wavelength of 260 nm.
Claims (10)
1. The preparation method of diethyl p-toluenesulfonyloxymethylphosphonate comprises the following steps:
(1) adding diethyl phosphite into a reaction container under the protection of nitrogen, and controlling the temperature to 10-18 ℃; sequentially adding carbonate and tetrabutylammonium bromide, stirring and dropwise adding a formaldehyde water solution, heating the system, and controlling the temperature to be 20-25 ℃;
(2) after the feeding is finished, controlling the reaction temperature within 20-25 ℃, and continuously adding carbonate and formaldehyde aqueous solution in batches; after the feeding is finished again, stirring, sampling and detecting the content of diethyl phosphite in the mixture until the content is less than 0.1 percent, and taking the reaction end point as the reaction end point;
(3) reducing the temperature of the materials in the bottle to 0-5 ℃; adding toluene, adding p-toluenesulfonyl chloride while stirring, and continuing stirring; dropwise adding an alkali solution, wherein the temperature of materials in the reaction container is controlled to be 0-10 ℃ in the dropwise adding process;
(4) dropwise adding, keeping the temperature, sampling, detecting HPLC (high performance liquid chromatography), taking the p-toluenesulfonyl chloride content in the reaction liquid less than 0.1 percent as a reaction end point, and standing; separating the liquid, placing the upper organic phase for later use, and extracting the lower aqueous phase with toluene;
(5) and combining the two organic phases, adding a sodium chloride aqueous solution for washing, and concentrating the organic layer under reduced pressure to obtain a liquid product while recovering the toluene.
2. The method for preparing diethyl p-toluenesulfonyloxymethylphosphonate according to claim 1, wherein the weight ratio of diethyl phosphite, carbonate and tetrabutylammonium bromide in (1) is 30 to 35: 0.8-1.2: 0.8 to 1.2;
preferably, the weight ratio of diethyl phosphite, carbonate and tetrabutylammonium bromide is 32: 1: 1;
preferably, (1) adding diethyl phosphite into a reaction vessel under the protection of nitrogen, and controlling the temperature to 15 ℃;
preferably, in (2), the carbonate is potassium carbonate or sodium carbonate.
3. The method for preparing diethyl p-toluenesulfonyloxymethylphosphonate according to claim 1, wherein in (1), the mass concentration of the aqueous formaldehyde solution is 35 to 39%, and the volume to mass ratio of the aqueous formaldehyde solution to diethyl phosphite is 1 ml: (7-9) g;
preferably, the mass concentration of the aqueous formaldehyde solution is 37%, and the volume mass ratio of the aqueous formaldehyde solution to the diethyl phosphite is 1 ml: 8 g.
4. The process for producing diethyl p-toluenesulfonyloxymethylphosphonate according to claim 1, wherein in (2), the carbonate and the aqueous formaldehyde solution are added in four divided portions; the mass ratio of the total addition of carbonate to diethyl phosphite is 1: 7-9;
preferably, in the step (2), the carbonate and the formaldehyde aqueous solution are added in four times; the mass ratio of the addition amount of the carbonate to the diethyl phosphite is 1: 8;
the mass concentration of the formaldehyde aqueous solution is 35-39%, and the volume mass ratio of the formaldehyde aqueous solution to the carbonate added in the step is (3-5) ml: 1g of a compound;
the mass concentration of the formaldehyde aqueous solution is 35-39%, and the volume mass ratio of the formaldehyde aqueous solution to the carbonate added in the step is 4 ml: 1g of a compound;
preferably, in (2), the carbonate is potassium carbonate or sodium carbonate.
5. The method for preparing diethyl p-toluenesulfonyloxymethylphosphonate according to claim 1, wherein in (2), after the completion of the re-addition, the mixture is stirred for 25 to 35 minutes;
preferably, in (2), after the re-feeding is completed, stirring is carried out for 30 minutes.
6. The method for preparing diethyl p-toluenesulfonyloxymethylphosphonate according to claim 1, wherein in (3), the volume to mass ratio of the added toluene to diethyl phosphite is (23 to 27) ml: (15-17) g;
preferably, in (3), the volume mass ratio of the added toluene to the diethyl phosphite is 25 ml: 16g of a mixture;
preferably, in (3), the mass-to-volume ratio of the added p-toluenesulfonyl chloride to the toluene is: (20-23) g: (24-26) ml;
preferably, in (3), the mass-to-volume ratio of the added p-toluenesulfonyl chloride to the toluene is: 21 g: 25 ml;
preferably, in the step (3), stirring is continuously carried out for 8-12 minutes;
preferably, in (3), stirring is continued for 10 minutes;
preferably, in the step (3), the mass concentration of the alkali solution is 30-33%;
preferably, in the step (3), the volume ratio of the alkali solution to the toluene is 16-18: 23-27;
preferably, in (3), the volume ratio of the alkali solution to the toluene is 17: 25;
preferably, in the step (3), the time for dripping the alkali solution is 50-70 min;
preferably, in (3), the time for dropping the alkali solution is 1 hour.
7. The method for preparing diethyl p-toluenesulfonyloxymethylphosphonate according to claim 1, wherein in (4), the material in (3) is added with an alkali solution dropwise and then is subjected to heat preservation at 0-10 ℃;
preferably, the materials in the step (4) and the step (3) are dropwise added with an alkali solution and then are subjected to heat preservation for 50-70 min;
preferably, in the step (4), the material in the step (3) is dropwise added with an alkali solution and then is kept warm for 1 hour;
preferably, in the step (4), the standing time is 20-40 min;
preferably, in (4), the standing time is 30 min;
preferably, in the step (4), the volume ratio of the toluene used for extraction to the alkali solution in the step (3) is 33-37: 15-19;
preferably, in (4), the volume ratio of the toluene used for extraction to the alkali solution in (3) is 35: 17.
8. the method for preparing diethyl p-toluenesulfonyloxymethylphosphonate according to claim 1, wherein in (5), the mass concentration of the aqueous sodium chloride solution is 3 to 7%;
preferably, in the step (5), the mass concentration of the sodium chloride aqueous solution is 5%;
preferably, in the step (5), the volume ratio of the sodium chloride aqueous solution to the alkali solution in the step (3) is 5-7: 15-19;
preferably, the volume ratio of the sodium chloride aqueous solution in (5) to the alkali solution in (3) is 6: 17.
9. the process for preparing diethyl p-toluenesulfonyloxymethylphosphonate according to claim 1, comprising the steps of:
(1) adding diethyl phosphite into a reaction container under the protection of nitrogen, and controlling the temperature to 10-18 ℃; sequentially adding carbonate and tetrabutylammonium bromide, stirring and dropwise adding 35-39% by mass of formaldehyde water solution, and controlling the temperature to be 20-25 ℃;
wherein the weight ratio of diethyl phosphite, carbonate and tetrabutylammonium bromide is 30-35: 0.8-1.2: 0.8 to 1.2;
the volume mass ratio of the formaldehyde aqueous solution to the diethyl phosphite is 1 ml: (7-9) g;
(2) after the feeding is finished, controlling the reaction temperature within 20-25 ℃, and continuously adding carbonate and formaldehyde aqueous solution in batches; after the feeding is finished again, stirring, sampling and detecting the content of diethyl phosphite in the mixture until the content is less than 0.1 percent, and taking the reaction end point as the reaction end point;
the mass ratio of the total addition of carbonate to diethyl phosphite is 1: 7-9;
the mass concentration of the formaldehyde aqueous solution is 35-39%, and the volume mass ratio of the formaldehyde aqueous solution to the carbonate added in the step is (3-5) ml: 1g of a compound;
(3) reducing the temperature of the materials in the bottle to 0-5 ℃; adding toluene, adding paratoluensulfonyl chloride while stirring, and continuously stirring for 8-12 minutes; dropwise adding an alkali solution, wherein the temperature of materials in the reaction container is controlled to be 0-10 ℃ in the dropwise adding process;
the volume mass ratio of the added toluene to the diethyl phosphite is (23-27) ml: (15-17) g;
the mass-volume ratio of the added p-toluenesulfonyl chloride to the toluene is as follows: (20-23) g: (24-26) ml;
the mass concentration of the alkali solution is 30-33%, and the volume ratio of the alkali solution to the toluene is 17: 25, dropwise adding the aqueous alkali for 50-70 min;
(4) dropwise adding liquid caustic soda, keeping the temperature for 50-70 min, sampling, detecting HPLC (high performance liquid chromatography), taking the p-toluenesulfonyl chloride content in the reaction liquid less than 0.1% as a reaction end point, and standing for 20-40 min; separating the liquid, placing the upper organic phase for later use, and extracting the lower aqueous phase with toluene; the volume ratio of the toluene used for extraction to the alkali solution in the step (3) is 33-37: 15-19;
(5) combining the two organic phases, adding a sodium chloride aqueous solution with the mass concentration of 3-7% for washing, decompressing and concentrating the organic layer to obtain a liquid product, and recovering toluene;
wherein the volume ratio of the sodium chloride aqueous solution to the alkali solution in the step (3) is 5-7: 15 to 19.
10. The process for preparing diethyl p-toluenesulfonyloxymethylphosphonate according to claim 1, comprising the steps of:
(1) adding diethyl phosphite into a reaction container under the protection of nitrogen, and controlling the temperature to 10-18 ℃; sequentially adding carbonate and tetrabutylammonium bromide, stirring and dropwise adding a formaldehyde water solution with the mass concentration of 37%, and simultaneously controlling the temperature to be 20-25 ℃;
wherein, the weight ratio of the diethyl phosphite, the carbonate and the tetrabutylammonium bromide is 32: 1: 1;
the volume mass ratio of the formaldehyde aqueous solution to the diethyl phosphite is 1 ml: 8g of the total weight of the mixture;
(2) after the feeding is finished, controlling the reaction temperature within 20-25 ℃, and continuously adding carbonate and formaldehyde aqueous solution in batches; after the feeding is finished again, stirring, sampling and detecting the content of diethyl phosphite in the mixture until the content is less than 0.1 percent, and taking the reaction end point as the reaction end point;
the mass ratio of the total addition of carbonate to diethyl phosphite is 1: 8;
the mass concentration of the formaldehyde aqueous solution is 37 percent, and the volume mass ratio of the formaldehyde aqueous solution to the carbonate added in the step is 4 ml: 1g of a compound;
(3) reducing the temperature of the materials in the bottle to 0-5 ℃; adding toluene, adding p-toluenesulfonyl chloride while stirring, and continuing stirring for 10 minutes; dropwise adding an alkali solution, wherein the temperature of materials in the reaction container is controlled to be 0-10 ℃ in the dropwise adding process;
the volume mass ratio of the added toluene to the diethyl phosphite is 25 ml: 16g of a mixture;
the mass-volume ratio of the added p-toluenesulfonyl chloride to the toluene is as follows: 21 g: 25 ml;
the mass concentration of the alkali solution is 20%, and the volume ratio of the alkali solution to the toluene is 17: 25, dropwise adding the alkali solution for 60 min;
(4) dropwise adding liquid caustic soda, keeping the temperature for 60min, sampling, detecting HPLC, taking the reaction solution with the content of the tosyl chloride less than 0.1% as a reaction end point, and standing for 30 min; separating the liquid, placing the upper organic phase for later use, and extracting the lower aqueous phase with toluene; the volume ratio of the toluene used for extraction to the alkali solution in (3) was 35: 17;
(5) combining the two organic phases, adding a sodium chloride aqueous solution with the mass concentration of 5% for washing, decompressing and concentrating the organic layer to obtain a liquid product, and simultaneously recovering toluene;
wherein, the volume ratio of the sodium chloride aqueous solution to the alkali solution in the step (3) is 6: 17.
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