WO2020020370A1 - 三甲铵基乙硫磷酰二乙酯碘化物的制备方法 - Google Patents

三甲铵基乙硫磷酰二乙酯碘化物的制备方法 Download PDF

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WO2020020370A1
WO2020020370A1 PCT/CN2019/098001 CN2019098001W WO2020020370A1 WO 2020020370 A1 WO2020020370 A1 WO 2020020370A1 CN 2019098001 W CN2019098001 W CN 2019098001W WO 2020020370 A1 WO2020020370 A1 WO 2020020370A1
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diethyl
dimethylaminoethylthiophosphoryl
dimethylaminochloroethane
reaction
diethyl ester
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PCT/CN2019/098001
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English (en)
French (fr)
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刘日魁
张报进
刘筱
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上饶市康可得生物科技有限公司
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Priority to CN201980049986.2A priority Critical patent/CN112513056A/zh
Publication of WO2020020370A1 publication Critical patent/WO2020020370A1/zh

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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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
    • C07F9/165—Esters of thiophosphoric acids

Definitions

  • the field belongs to the field of medical technology and organic synthesis, and particularly relates to a method for preparing a cholinesterase inhibitor, namely, trimethylammonium ethylthiophosphoryl diethyl iodide.
  • Trimethylammonium ethylthiophosphoryl diethyl iodide also known as Echothiopate Iodide, also known as iodophos, CAS number: 513-10-0.
  • iocoride and trimethylammonium ethylthiophosphoryl diethyl iodide may be used interchangeably instead.
  • Trimethylammonium ethylthiophosphoryl diethyl iodide is a potent inhibitor of cholinesterase. It is mainly used in open-angle glaucoma, iris adhesion caused by anterior chamber fluid obstruction, after iris resection, and co-transverse esotropia. It can treat myasthenia gravis and is widely used.
  • the intermediate dimethylaminoethyl mercaptan is very odorous and highly toxic.
  • the solvent benzene is a carcinogen. It is also necessary to treat the dimethylaminoethylthiophosphoryl diethyl ester by distillation under reduced pressure. Yield and purity of the compound.
  • the 2-dimethylaminoethoxythiophosphoryl diethyl ester is converted by heating
  • the dimethylaminoethylthiophosphoryl diethyl ester is obtained by a situ reaction, and the yield of the translocation reaction is about 50%, and then methyl iodide is added to perform the reaction to obtain iocoate iodide.
  • this route does not use the toxic intermediate dimethylaminoethyl mercaptan
  • the first two steps of the reaction also use carcinogen benzene as a solvent.
  • the first three steps of the reaction require vacuum distillation, and the total yield of the four steps of the reaction is very low. , About 17.3%.
  • Iocoate can be used to treat glaucoma.
  • a variety of drugs for glaucoma have been approved in China.
  • these drugs have many problems such as short-term effects, many adverse reactions, and high prices.
  • the efficacy and safety of these drugs still need to be further improved.
  • the glaucoma treatment market is still an area where demand is far from being met and has great potential for development.
  • Iocoate can be used to prepare eye drops, which can be used to treat a series of eye diseases, including glaucoma, ocular hypertension, age-related macular degeneration, macular cysts, macular holes, presbyopia, myopia, solar retinopathy, diabetic retinopathy , Retinal branch vein occlusion, Leiber's congenital darkening, strabismus, visual aberration of dilated pupils, etc.
  • eye diseases including glaucoma, ocular hypertension, age-related macular degeneration, macular cysts, macular holes, presbyopia, myopia, solar retinopathy, diabetic retinopathy , Retinal branch vein occlusion, Leiber's congenital darkening, strabismus, visual aberration of dilated pupils, etc.
  • a method for preparing trimethylammonium ethylthiophosphoryl diethyl iodide comprising the following steps: i. The sodium salt of O, O-diethyl thiophosphate and 2-dimethylaminohaloethane Reaction to obtain dimethylaminoethylthiophosphoryl diethyl ester; ii. Reacting dimethylaminoethylthiophosphoryl diethyl ester with methyl iodide to obtain trimethylammonium ethylthiophosphoryl diethyl halide salt.
  • step i the reaction molar ratio of the sodium salt of O, O-diethyl thiophosphate to 2-dimethylaminohaloethane is (0.5-3): 1.
  • step ii the reaction molar ratio of methyl iodide to dimethylaminoethylthiophosphoryl diethyl ester is (1-3): 1.
  • the O, O-diethyl thiophosphate sodium salt in step i can be obtained by sequentially reacting diethyl phosphite with metal sodium and sulfur powder. Diethyl phosphite reacts with metal sodium and sulfur powder in sequence under the protection of nitrogen. The reaction is preferably performed at low temperature, such as room temperature or 0 ° and below.
  • the 2-dimethylaminohaloethane in step i can be obtained by reacting N, N-dimethylaminoethanolamine and a sulfoxide halide. Specifically, N, N-dimethylaminoethanolamine and sulfoxide halide are reacted to obtain 2-dimethylaminohaloethane salt first, and then desalting to obtain 2-dimethylaminohaloethane, where recrystallization is performed as required. .
  • the above reaction is carried out in an organic solvent including ethyl acetate, methanol, ethanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, petroleum ether, ether, dimethylsulfoxide, dioxane or Its mixture.
  • an organic solvent including ethyl acetate, methanol, ethanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, petroleum ether, ether, dimethylsulfoxide, dioxane or Its mixture.
  • a mixture of organic solvents such as a mixture of two organic solvents
  • the organic solvent is an anhydrous organic solvent.
  • the volume ratio between any two of the organic solvent mixtures is about 1: 1 to 1: 3.
  • These organic solvents can also be used as recrystallization solvents or extractants. In recrystallization and extraction, the organic solvent can be used in combination with other solvents, such as inorganic solvents,
  • dimethylaminoethylthiophosphoryl diethyl ester can be prepared as follows:
  • THF stands for anhydrous tetrahydrofuran
  • the O, O-diethyl thiophosphate sodium salt was reacted with 2-dimethylaminochloroethane in anhydrous tetrahydrofuran to obtain dimethylaminoethylthiophosphoryl diethyl ester.
  • dimethylaminoethylthiophosphoryl diethyl ester is reacted with methyl iodide to form trimethylammonium ethylthiophosphoryl diethyl iodide:
  • the dimethylaminoethylthiophosphoryl diethyl ester obtained in the reaction formula (1) is reacted with methyl iodide to obtain trimethylammonium ethylthiophosphoryl diethyl iodide, where N is positively charged and I is Negative charge.
  • step i The reactants O, O-diethyl thiophosphate sodium salt and 2-dimethylaminochloroethane in step i can be prepared by the following reaction:
  • diethyl phosphite is sequentially reacted with metal sodium and sulfur powder to obtain O, O-diethyl thiophosphate sodium salt, which is stable in nature and can exist stably;
  • DCM dichloromethane
  • N, N-dimethylaminoethanolamine is reacted with sulfoxide in dichloromethane to give 2-dimethylaminochloroethane.
  • a method for preparing trimethylammonium ethylthiophosphoryl diethyl halide salt is provided herein.
  • the method is simple in process and (1) avoids the use of the odorous and toxic intermediate dimethylaminoethylthiol; 2 )
  • the starting material is diethyl phosphite, which is obtained by one-pot addition of sodium metal and sulfur powder in order to avoid the use of trichloride, a precursor chemical.
  • Phosphorus or Phosphorus trichloride while avoiding quenching and distillation of wastes of Phosphorus or Phosphorus Trichloride, it is easier to control the reaction; 3) Avoid the use of benzene, a carcinogenic solvent, and reduce the formation of by-products.
  • each intermediate and product is mainly extraction and recrystallization, compared with conventional methods under reduced pressure distillation It is more convenient and efficient to operate, and at the same time, it can reduce the formation of by-products, and it can synthesize high-purity and high-purity ecoate iodide; 5) In the method of the present invention, the prepared iococoate is high in yield and high in purity .
  • the invention provides a method for preparing dimethylaminoethylthiophosphoryl diethyl ester or a halide salt thereof, comprising the following steps:
  • 2-dimethylaminohaloethane is, for example, 2-dimethylaminochloroethane, 2-dimethylaminobromoethane, 2-dimethylaminoiodoethane, and 2-dimethylaminochloroethane is preferred.
  • 2-dimethylaminobromoethane more preferably 2-dimethylaminochloroethane.
  • Methyl iodide and dimethylaminoethylthiophosphoryl diethyl ester form trimethylammonium ethylthiophosphoryl diethyl iodide, iodoecol.
  • the reaction is performed in an organic solvent, preferably an anhydrous organic solvent.
  • the organic solvent is selected from organic solvents including ethyl acetate, methanol, ethanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, petroleum ether, diethyl ether, dimethyl sulfoxide, dioxane or a mixture thereof.
  • the preferred organic solvent may be selected from the group consisting of ethanol, ether, dichloromethane, acetonitrile, dimethyl sulfoxide, dioxane, tetrahydrofuran or a mixture thereof, preferably tetrahydrofuran, and more preferably anhydrous tetrahydrofuran. .
  • the reaction molar ratio of the sodium salt of O, O-diethyl thiophosphate and 2-dimethylaminochloroethane is, for example, about (0.5 to 3): 1, preferably about (1.2 to 2.8): 1 , More preferably about (1.2 to 2.5): 1, still more preferably about (1 to 2.5): 1, still more preferably about (1 to 2): 1, and most preferably about (1.6 to 1.7): 1.
  • the reaction temperature is, for example, about 30 ° C to 100 ° C, preferably about 40 ° C to 90 ° C, more preferably about 45 ° C to 80 ° C, and most preferably about 70 ° C.
  • reaction time varies depending on the amount of reactants used. Generally, the reaction time in step i is about 6 to 28 hours, preferably about 8 to 24 hours, more preferably about 10 to 22 hours, and most preferably about 18 to 20 hours.
  • the organic solvent used as the reaction solvent is, for example, a mixture of one or more members selected from the group consisting of methanol, ethanol, ether, acetonitrile, acetone, ethyl acetate, dimethyl sulfoxide, and tetrahydrofuran, preferably ether, especially Water ether.
  • ether especially Water ether.
  • the molar ratio of methyl iodide to dimethylaminoethylthiophosphoryl diethyl ester is, for example, about (1 to 3): 1, preferably about (1 to 2.8): 1, preferably (1.2 to 2.8): 1, more preferably (1.2 ⁇ 2.5): 1, more preferably about (1 ⁇ 2): 1, and most preferably 1.6 ⁇ 1.7: 1.
  • a post-treatment such as a recrystallization treatment is preferably performed.
  • the dimethylaminoethylthiophosphoryl diethyl ester and trimethylammonium ethylthiophosphoryl diethyl iodide obtained in step i and step ii are recrystallized.
  • the crude trimethylammonium ethylthiophosphoryl diethyl iodide is dissolved in an organic solvent, and if necessary, other organic solvents may be added for recrystallization together.
  • the temperature of recrystallization can be selected according to need, for example, it can be performed at a low temperature, such as below 0 ° C.
  • the recrystallization solvent is selected from organic solvents including methanol, ethanol, isopropanol, acetone, ethyl acetate, diethyl ether, tetrahydrofuran, and mixtures thereof.
  • a mixture of recrystallization solvents may be used.
  • the ratio of any two organic solvents is, for example, a volume ratio of about 1: (1 to 8); preferably, the ratio of any two organic solvents is about 1: (1 to 5).
  • a mixed solvent, or a mixed solvent of two solvents having a volume ratio of about 1: (1 to 3), and also a volume ratio of about 1: 1 is also preferred.
  • the mixture of the solvents is, for example, a mixture of methanol and diethyl ether.
  • the 2-methylaminohaloethane in step i can be obtained by step a, that is, the step of reacting N, N-dimethylaminoethanolamine and a sulfoxide halide to obtain 2-methylaminohaloethane.
  • step a the molar ratio of the halogenated sulfoxide to N, N-dimethylaminoethanolamine is about (0.5 to 3): 1, preferably about (1 to 2.5): 1, and more preferably about (1 to 2): 1, Most preferred is about 1.5: 1.
  • Step a can be performed in two steps, including a1) reacting N, N-dimethylaminoethanolamine with a sulfoxide halide, preferably sulfoxide, to obtain a 2-dimethylaminohaloethane salt, preferably a halide salt; and a2 ) Desalting 2-dimethylaminohaloethane halide to obtain 2-dimethylaminohaloethane.
  • the reaction of step a is performed in an organic solvent.
  • the organic solvent is, for example, selected from the group consisting of methanol, ethanol, diethyl ether, acetonitrile, acetone, ethyl acetate, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, or a mixture thereof.
  • the product obtained in steps a1) and a2) is recrystallized.
  • the solvent used in the recrystallization is selected from, for example, ethyl acetate, dichloromethane, methanol, ethanol, acetone, diethyl ether, acetonitrile, or a mixture thereof.
  • recrystallization uses a mixture of two or more solvents.
  • the volume ratio of the two solvents is, for example, 1: (1 to 10), preferably about 1:10, still more preferably about 1: 8, more preferably about 1: 5, and still more preferably about 1: 3, for example, about 1: 2.
  • the two solvents are, for example, ethanol and acetone.
  • the reaction time in step a is performed as needed, and may be, for example, 1 to 24 hours.
  • the O, O-diethyl thiophosphate sodium salt in step i can be obtained through step b, that is, the diethyl phosphite is reacted with sodium metal and sulfur powder in sequence.
  • the reaction molar ratio of diethyl phosphite, sodium metal and sulfur is, for example, about 1: (0.5 to 3): (0.5 to 3), preferably about 1: (1 to 2): (1 to 2). ), More preferably about 1: (1 to 1.5): (1 to 1.5), and specifically, about 1: 1.05: 1.3.
  • the metal sodium is preferably high-purity metal sodium, and sulfur powder can be selected according to needs.
  • the method provided herein has high reaction efficiency.
  • the post-processing operations in the reaction are mainly extraction and recrystallization.
  • the total yield can reach 42.1% by weight.
  • the purity of the product can reach 99.2% (HPLC).
  • the process is simple and the cost is low. Suitable for large-scale industrial production.
  • the ecoate iodide obtained by the method of the invention has high purity and can be used for preparing eye drops.
  • the O, O-diethyl thiophosphate sodium salt is reacted with 2-dimethylaminohaloethane in an organic solvent.
  • the halogen in 2-dimethylaminohaloethane may be fluorine, chlorine, bromine, iodine, preferably chlorine and bromine, and most preferably chlorine, such as 2-dimethylaminochloroethane.
  • the organic solvent is selected from the group consisting of methanol, ethanol, diethyl ether, dichloromethane, acetonitrile, dimethylsulfoxide, dioxane, and tetrahydrofuran or a mixture thereof, preferably tetrahydrofuran.
  • the organic solvent is preferably an anhydrous organic solvent.
  • the reaction molar ratio of the sodium salt of O, O-diethyl thiophosphate to 2-dimethylaminohaloethane is about (0.5 to 3): 1, preferably about (1.2 to 2.8): 1, It is more preferably about (1.2 to 2.5): 1, still more preferably about (1 to 2.5): 1, still more preferably about (1 to 2): 1, and most preferably about (1.6 to 1.7): 1.
  • the reaction temperature is about 30 ° C to 100 ° C, preferably about 40 ° C to 90 ° C, more preferably about 45 ° C to 80 ° C, and most preferably about 70 ° C.
  • the reaction time depends on the amount of reactants. In general, the reaction time is about 6 to 28 hours, preferably about 8 to 24 hours, more preferably about 10 to 22 hours, such as about 16 to 18 hours.
  • reaction formula of the above reaction is, for example:
  • 2-dimethylaminochloroethane and O, O-diethylthiophosphoric acid sodium salt are reacted in an organic solvent, such as tetrahydrofuran, preferably anhydrous tetrahydrofuran, thereby preparing dimethylaminoethylthiophosphine.
  • organic solvent such as tetrahydrofuran, preferably anhydrous tetrahydrofuran, thereby preparing dimethylaminoethylthiophosphine.
  • organic solvent such as tetrahydrofuran, preferably anhydrous tetrahydrofuran
  • the above intermediate dimethylaminoethylthiophosphoryl diethyl ester is reacted with methyl iodide in an organic solvent to obtain trimethylammonium ethylthiophosphoryl diethyl halide salt.
  • iodomethane and dimethylaminoethylthiophosphoryl diethyl ester are reacted to obtain trimethylammonium ethylthiophosphoryl diethyl iodide, ie, iodicolate.
  • the organic solvent used in the reaction is, for example, the organic solvents described above, such as methanol, ethanol, diethyl ether, dichloromethane, acetonitrile, dimethylsulfoxide, dioxane, and tetrahydrofuran, or a mixture thereof.
  • dimethylaminoethylthiophosphoryl diethyl ester is reacted with methyl iodide in, for example, diethyl ether, preferably anhydrous diethyl ether.
  • reaction formula of the above reaction is, for example:
  • the reaction molar ratio of methyl iodide to dimethylaminoethylthiophosphoryl diethyl ester is about (1 to 3): 1, preferably about (1 to 2.8): 1, and preferably (1.2 to 2.8): 1, More preferably (1.2 to 2.5): 1, more preferably about (1 to 2): 1, and most preferably (1.6 to 1.7): 1.
  • a crude trimethylammonium ethylthiophosphoryl diethyl iodide was obtained.
  • the crude trimethylammonium ethylthiophosphoryl diethyl iodide is post-treated, and the post-treatment method is, for example, recrystallization.
  • the trimethylammonium ethylthiophosphoryl diethyl iodide is recrystallized using the same organic solvent as the organic solvent used in the reaction, for example, to obtain purified trimethylammonium ethylthiophosphoryl dithioate. Ethyl iodide.
  • Recrystallization can also use a mixed solvent of two or more solvents, such as a mixture of two or more selected from the group consisting of methanol, ethanol, isopropanol, acetone, ethyl acetate, petroleum ether, ether, and tetrahydrofuran.
  • a mixed solvent of two or more solvents such as a mixture of two or more selected from the group consisting of methanol, ethanol, isopropanol, acetone, ethyl acetate, petroleum ether, ether, and tetrahydrofuran.
  • the crude trimethylammonium ethylthiophosphoryl diethyl iodide is recrystallized from a mixture of two solvents.
  • the crude trimethylammonium ethylthiophosphoryl diethyl iodide is dissolved in a mixture of two solvents, such as a mixture of two solvents with a volume ratio of about 1: 8; more preferably two of a volume ratio of about 1: 5 Recrystallization is performed in a mixed solvent of solvents, a mixed solvent of two solvents with a volume ratio of about 1: 3, or a mixed solvent of two solvents with a volume ratio of about 1: 3.
  • the recrystallization solvent is, for example, a mixed solvent of methanol and diethyl ether having a volume ratio of about 1: 8, preferably a mixed solvent of methanol and diethyl ether having a volume ratio of about 1: 5, and more preferably methanol and diethyl ether having a volume ratio of about 1: 3.
  • a mixed solvent of methanol and diethyl ether having a volume ratio of about 1: 8 preferably a mixed solvent of methanol and diethyl ether having a volume ratio of about 1: 5, and more preferably methanol and diethyl ether having a volume ratio of about 1: 3.
  • Mixed solvents for example, a mixed solvent of methanol and diethyl ether having a volume ratio of about 1: 8.
  • the 2-dimethylaminochloroethane used in the synthesis of dimethylaminoethylthiophosphoryl diethyl ester is commercially available, for example, in the form of dimethylaminochloroethane hydrochloride, and then desalted. It can also be prepared synthetically.
  • 2-dimethylaminochloroethane can be obtained, for example, by combining N, N-dimethylaminoethanolamine and a sulfoxide halide (SOX 2 ), such as sulfoxide, bromide, and sulfoxide, in an organic solvent.
  • SOX 2 sulfoxide halide
  • the reaction was obtained, whereby dimethylaminochloroethane halide was obtained.
  • the organic solvent may be selected from methanol, ethanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, diethyl ether, and mixtures thereof, such as dichloromethane.
  • reaction formula of the above reaction is, for example:
  • DCM dichloromethane
  • X is Cl or Br.
  • N, N-dimethylaminoethanolamine is added to an organic solvent to dissolve.
  • a sulfoxide halide preferably sulfoxide
  • 2-dimethylaminochloroethane hydrochloride. salt is added to the reaction to obtain 2-dimethylaminochloroethane hydrochloride. salt.
  • a recrystallization step is preferably performed. Recrystallization facilitates the progress of subsequent reactions and the improvement of purity, and the recrystallization is performed in a recrystallization solvent.
  • the recrystallization solvent is selected from ethyl acetate, dichloromethane, methanol, ethanol, acetone, diethyl ether, petroleum ether, acetonitrile, and mixtures thereof. Recrystallization can also be performed using a mixture of two or more solvents, such as a mixture of ethanol and acetone. When a mixture of two solvents is used, the volume ratio is at least about 1: 1 to each other to a ratio of about 1:10, such as about 1: 2, about 1: 3, about 1: 4, and about 1: 5. About 1: 6, about 1: 7, about 1: 8, and about 1: 9. After recrystallization, purified 2-dimethylaminochloroethane hydrochloride was obtained.
  • 2-dimethylaminochloroethane halide is desalted. Desalting can be performed by conventional procedures, such as sodium hydroxide neutralization. After desalting, 2-dimethylaminochloroethane was obtained.
  • 2-dimethylaminochloroethane halide is first dissolved in water, and the pH value of the aqueous solution is adjusted to 7-10 with sodium hydroxide solution, such as pH8, pH9, pH10, generally Not higher than pH 10, after the neutralized solution is separated, the upper oil phase is distilled. The lower aqueous phase is preferably extracted with an organic solvent. After the extraction, the organic phase is distilled to obtain 2-dimethylaminochloroethane.
  • N, N-dimethylaminoethanolamine is added to an organic solvent (anhydrous) dichloromethane, and sulfoxide is added at 0 ° C with stirring. After the addition is complete, heat to reflux for a period of time, such as 1 to 24 hours. The heating and reflux time can be adjusted as needed, for example, 2 to 18 hours, or 4 to 12 hours. After the reaction, 2-dimethylaminochloroethane halide salt is obtained, preferably after recrystallization, and desalted to obtain dimethylaminochloroethane.
  • the reaction molar ratio of sulfoxide and N, N-dimethylaminoethanolamine is about (0.5 to 3): 1, and the preferred molar ratio is about ( 1 to 2.5): 1, more preferably a reaction molar ratio of about (1 to 2): 1, and most preferably a reaction molar ratio of about 1.5: 1.
  • the recrystallization process is to dissolve the crude dimethylaminochloroethane hydrochloride in an organic solvent, and then add other organic solvents, and perform recrystallization at a low temperature, such as 0 ° C, preferably -5 ° C to -10 ° C. After recrystallization, purified dimethylaminochloroethane hydrochloride was obtained.
  • the recrystallization solvent may be two or more selected from the group consisting of ethanol, ethyl acetate, dichloromethane, methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, and petroleum ether; for example, ethanol and acetone in a volume ratio of about 1:10, Preference is given to ethanol and acetone in a volume ratio of about 1: 5, specifically ethanol and acetone in a volume ratio of about 1: 2.
  • the amount of the organic solvent can be selected as required.
  • the amount of the solvent (by volume) is preferably 10 times or less of the crude product, preferably about 8 times, more preferably about 6 times, and most preferably about 4 times. It is advisable that the product be sufficiently crystallized in a solvent.
  • the O, O-diethyl phosphorothioate sodium salt used in the synthesis of the above-mentioned intermediate dimethylaminoethylthiophosphoryl diethyl ester can be synthesized. For example, by sequentially reacting diethyl phosphite with sodium metal and sulfur powder, O, O-diethyl thiophosphate sodium salt is obtained. Diethyl phosphite is first reacted with sodium metal (Na) to obtain the diethyl phosphite sodium salt, and then diethyl phosphite sodium salt is reacted with sulfur powder (S 8 ) to obtain O, O-diethyl sulfur Phosphate sodium salt.
  • Na sodium metal
  • S 8 sulfur powder
  • the reaction is performed in an organic solvent as described above.
  • the organic solvent may be selected from the group consisting of methanol, ethanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, petroleum ether, ether, and mixtures thereof, such as ethanol, ether, or a mixture of ethanol and ether. If two organic solvents are selected, such as ethanol and ether, the volume ratio of ethanol and ether is about 1: 1-1: 3.
  • the reaction of diethyl phosphite with sodium and sulfur powder is continuously performed sequentially in the same organic solvent.
  • sulfur powder is added when the reaction of diethyl phosphite and sodium is completed to make the sodium salt of diethyl phosphite Reacts with sulfur powder.
  • O, O-diethyl thiophosphate sodium salt was obtained as a solid salt. If necessary, the O, O-diethylthiophosphate sodium salt may be washed with an organic solvent to obtain the washed O, O-diethylthiophosphate sodium salt and directly used in the next reaction.
  • reaction formula of the above reaction is, for example:
  • the reaction molar ratio of diethyl phosphite, sodium and sulfur is about 1: (0.5 to 3): (0.5 to 3), preferably about 1: (1 to 2): (1 to 2), and more It is preferably about 1: (1 to 1.5): (1 to 1.5), and most preferably about 1: 1.05: 1.3.
  • a method for preparing trimethylammonium ethylthiophosphoryl diethyl iodide including the following steps:
  • THF is tetrahydrofuran.
  • Dimethylaminoethylthiophosphoryl diethyl ester is reacted with methyl iodide in anhydrous diethyl ether, and trimethylammonium ethylthiophosphoryl diethyl iodide is obtained by recrystallization, wherein nitrogen has a positive charge and iodine has a negative charge.
  • the 2-dimethylaminochloroethane in step i can be synthesized as follows:
  • N, N-dimethylaminoethanolamine is reacted with sulfoxide to obtain 2-dimethylaminochloroethane hydrochloride.
  • the obtained 2-dimethylaminochloroethane hydrochloride is recrystallized by a mixed solvent such as ethanol and acetone, and then the pH is adjusted to 7 to 7 by an aqueous sodium hydroxide solution, such as a 50% aqueous sodium hydroxide solution. 10 and desalted to obtain 2-dimethylaminochloroethane.
  • the sodium salt of O, O-diethyl phosphorothioate in step i can be synthesized as follows:
  • diethyl phosphite sequentially reacts with sodium metal and sulfur powder.
  • the reaction of chemical formula (4) is reacted with sodium in an organic solvent, such as a mixed solvent of ethanol and diethyl ether, under the protection of nitrogen, and then reacted with sulfur powder at a low temperature, such as below room temperature, preferably below 0 ° C.
  • reaction equations in this article include the above reaction equations (1), (2), (3), and (4) to demonstrate the reaction process, not the reaction equations through chemical equilibrium.
  • a method for preparing icocoate iodo including the following steps:
  • step i The reactant in step i can be prepared by the following steps:
  • Diethyl phosphite is sequentially reacted with metallic sodium and sulfur powder to obtain O, O-diethyl thiophosphate sodium salt.
  • 2-dimethylaminochloroethane and O, O-diethyl thiophosphate sodium salt are synthesized to prepare the intermediate dimethylaminoethylthiophosphoryl diethyl ester, thereby obtaining iodoecol Esters, including, for example, the following steps:
  • SOX 2 is sulfoxide chloride
  • DCM is dichloromethane
  • Diethyl phosphite is reacted with metal sodium and sulfur powder in turn to obtain O, O-diethyl thiophosphate sodium salt;
  • THF tetrahydrofuran
  • O, O-diethyl thiophosphate sodium salt and 2-dimethylaminohaloethane are reacted in anhydrous tetrahydrofuran to obtain dimethylaminoethylthiophosphoryl diethyl ester;
  • the method provided in this paper is simple in reaction and easy to operate.
  • the post-processing operations in the reaction are mainly extraction and recrystallization.
  • the method has simple process and low cost, and is suitable for large-scale industrial production.
  • the total yield of iodocolate can reach 42.1% by weight, and the purity can reach 99.2% by weight, for example, and can be used to prepare eye drops.
  • a volume ratio is used, that is, based on volume; when the component and the amount percentage are used, it is a weight ratio, that is, by weight.
  • the crystals of 2-dimethylaminochloroethane hydrochloride were dissolved in water, and the solution was cooled to 0 ° C.
  • the pH value was adjusted to 10 with a 50% sodium hydroxide solution in a mass percentage concentration, and the solution was left to stand until it was separated.
  • the upper oil phase was separated with a separating funnel, dried, filtered, and distilled to obtain 2-dimethylaminochloroethane.
  • the lower aqueous phase was extracted with ether, and dried, filtered, and distilled to obtain 2-dimethylaminochloroethane.
  • 116.20 g of 2-dimethylaminochloroethane was combined to obtain a yield of 90.01% and a boiling point of 58 ° C.
  • the method for preparing ecoate iodide according to the present invention brings the following benefits: 1) Avoid using the odorous and toxic intermediate dimethylaminoethyl mercaptan; 2) When using the intermediate O, O-diethylthio In the case of sodium phosphate, the starting material is diethyl phosphite, which is obtained by sequentially adding metallic sodium and sulfur powder in a one-pot method. Avoid the use of easily-toxic chemicals such as phosphorus oxychloride or phosphorus oxychloride, and avoid quenching and distillation.
  • the synthesis operation of each intermediate and product is mainly extraction and recrystallization. Compared with the conventional method of vacuum distillation, the operation is more convenient and effective, and the formation of by-products can be reduced. It is possible to synthesize iocoate iodide in high yield and purity; 5) In the method of the present invention, the yield is high and the purity is high.
  • the total yield of the four-step process is up to 42.1% and the product purity is as high as 99.2%; 6)
  • the method of the present invention has low process cost and is suitable for large-scale industrial production.

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Abstract

本文涉及三甲铵基乙硫磷酰二乙酯碘化物的制备方法,包括：将O,O-二乙基硫代磷酸钠盐与2-二甲氨基卤乙烷反应得到二甲氨基乙硫磷酰二乙酯；将二甲氨基乙硫磷酰二乙酯与碘甲烷反应得到三甲铵基乙硫磷酰二乙酯碘化物。此处提供的制备三甲铵基乙硫磷酰二乙酯碘化物的方法简单易行、成本低、收率高、适合大规模工业化生产。

Description

三甲铵基乙硫磷酰二乙酯碘化物的制备方法 技术领域
本领域属于医药技术和有机合成领域，具体涉及一种胆碱酯酶抑制剂，即三甲铵基乙硫磷酰二乙酯碘化物的制备方法。
背景技术
三甲铵基乙硫磷酰二乙酯碘化物，又名碘依可酯(Echothiopate Iodide)，别名碘磷灵，CAS号：513-10-0。本文中，碘依可酯和三甲铵基乙硫磷酰二乙酯碘化物可替代互换使用。三甲铵基乙硫磷酰二乙酯碘化物为胆碱酯酶强力抑制剂，主要用于开角型青光眼、前房液受阻引起的虹膜粘连、虹膜切除手术后及共转性内斜视，同时还可治疗重症肌无力，用途广泛。
现有技术中(发明专利Brit Patent No.738839)公开了一种碘依可酯的合成方法。该方法以N,N-二甲氨基乙醇胺为起始原料，通过三步反应得到第一中间体2-二甲氨基乙硫醇，该中间体合成收率较低，且该化合物奇臭又有剧毒。接下来，使用该第一中间体2-二甲氨基乙硫醇制备第二中间体二甲氨基乙硫磷酰二乙酯。同时，以三氯氧磷为起始原料，与乙醇反应生成第三中间体氯磷酸二乙酯。第二中间体二甲氨基乙硫醇在无水苯溶剂中加入金属钠反应后，滴加第三中间体氯磷酸二乙酯，通过减压蒸馏得到二甲氨基乙硫磷酰二乙酯。最后，二甲氨基乙硫磷酰二乙酯与碘甲烷反应得到碘依可酯。该方案合成收率较低，中间体二甲氨基乙硫醇奇臭且有剧毒，溶剂苯是致癌物质，还需通过减压蒸馏处理二甲氨基乙硫磷酰二乙酯，最终难以保证该化合物收率和纯度。
文献《碘磷灵的合成》(《中国医药工业》，1984年第5期，郭宗儒等)设计了一种碘依可酯的合成路线，以三氯硫磷为起始原料，与乙醇反应得到二乙氧硫磷酰氯，再与N,N-二甲氨基乙醇胺反应得到2-二甲氨基乙氧硫磷酰二乙酯，该2-二甲氨基乙氧硫磷酰二乙酯通过加热转位反应得到二甲氨基乙硫磷酰二乙酯，该转位反应收率约50％，之后加入碘甲烷进行反应得到碘依可酯。该路线虽然不使用有毒中间体二甲氨基乙硫醇，但前二步反应也使用 可致癌物质苯做溶剂，前三步反应均要用到减压蒸馏，且四步反应总收率很低，约为17.3％。
因此，需要一种能够制备碘依可酯的方法，避免使用有毒的中间体，工艺步骤操作简单，并且希望通过该方法得到的产品毒性低、纯度高、收率高。
碘依可酯可用于治疗青光眼。目前国内已经批准了多种治疗青光眼的药物，然而这些药物存在药效短暂、不良反应多、价格昂贵等诸多问题，药物疗效和安全性仍需要进一步提高。青光眼治疗市场仍旧是一个需求远未被满足的领域，具有很大的发展潜力。
碘依可酯可用来制备眼药水，能用于治疗一系列眼疾，包括青光眼、高眼压症、老年性黄斑病变、黄斑囊肿、黄斑裂孔、老花眼、近视眼、日光性视网膜病、糖尿病视网膜病，视网膜分支静脉阻塞、莱伯氏先天性黑矇、斜视、瞳孔扩张的视觉象差等。
发明内容
在此提供了一种三甲铵基乙硫磷酰二乙酯碘化物的制备方法，包含以下步骤：i、将O,O-二乙基硫代磷酸钠盐与2-二甲氨基卤乙烷反应，得到二甲氨基乙硫磷酰二乙酯；ii、将二甲氨基乙硫磷酰二乙酯与碘甲烷反应，得到三甲铵基乙硫磷酰二乙酯卤化物盐。步骤i中，O,O-二乙基硫代磷酸钠盐与2-二甲氨基卤乙烷的反应摩尔比为(0.5-3)：1。步骤ii中，碘甲烷与二甲氨基乙硫磷酰二乙酯的反应摩尔比为(1-3)：1。
步骤i中的O,O-二乙基硫代磷酸钠盐可以通过将亚磷酸二乙酯依次与金属钠和硫粉反应得到。亚磷酸二乙酯与金属钠和硫粉在氮气保护下依次反应，优选反应在低温下进行，如室温或0°及以下。
步骤i中的2-二甲氨基卤乙烷可以由N,N-二甲氨基乙醇胺和卤化亚砜反应得到。具体地，将N,N-二甲氨基乙醇胺和卤化亚砜反应，首先得到2-二甲氨基卤乙烷盐，之后通过脱盐，得到2-二甲氨基卤乙烷，其中根据需要进行重结晶。
上述的反应是在有机溶剂中进行的，该有机溶剂包括：乙酸乙酯、甲醇、乙醇、二氯甲烷、四氢呋喃、丙酮、乙腈、石油醚、乙醚、二甲基亚砜、二氧六环或其混合物。反应中，还可以使用有机溶剂的混合物，例如两种有机溶剂的混合物作为反应溶剂。优选，上述有机溶剂为无水有机溶剂。当使用 有机溶剂的混合物时，该有机溶剂混合物任何两种之间的体积比为约1:1～1:3。这些有机溶剂也可以用作重结晶溶剂或萃取剂。在重结晶、萃取中，该有机溶剂可以与其他溶剂，如无机溶剂组合而同时或先后使用。
根据本文，二甲氨基乙硫磷酰二乙酯可以如下制备：
Figure PCTCN2019098001-appb-000001
其中，THF代表无水四氢呋喃，
将O,O-二乙基硫代磷酸钠盐与2-二甲氨基氯乙烷在无水四氢呋喃中反应，得到二甲氨基乙硫磷酰二乙酯。
根据需要，将二甲氨基乙硫磷酰二乙酯与碘甲烷反应，形成三甲铵基乙硫磷酰二乙酯碘化物：
Figure PCTCN2019098001-appb-000002
在乙醚中，将反应式(1)中得到的二甲氨基乙硫磷酰二乙酯与碘甲烷反应，得到三甲铵基乙硫磷酰二乙酯碘化物，其中N带正电荷，I带负电荷。
步骤i中的反应物O,O-二乙基硫代磷酸钠盐和2-二甲氨基氯乙烷可以通过如下反应制备：
Figure PCTCN2019098001-appb-000003
即，将亚磷酸二乙酯依次与金属钠和硫粉反应，制得O,O-二乙基硫代磷酸钠盐，该盐性质稳定，可以稳定存在；
以及
Figure PCTCN2019098001-appb-000004
其中，DCM代表二氯甲烷，
将N,N-二甲氨基乙醇胺在二氯甲烷中与氯化亚砜反应，得到2-二甲氨基氯乙烷。
根据以上方法，本文提供了制备三甲铵基乙硫磷酰二乙酯卤化物盐的方法，该方法工艺简单，(1)避免了使用奇臭有毒性的中间体二甲氨基乙硫醇；2)当使用中间体O,O-二乙基硫代磷酸钠盐时，起始原料为亚磷酸二乙酯，依次加入金属钠和硫粉一锅法得到，避免使用易制毒化学品三氯氧磷或三氯硫磷，同时避免淬灭与蒸馏操作三氯氧磷或三氯硫磷的废物，更容易控制该反应；3)避免使用可致癌的溶剂苯，减少副产物的形成，可以高产率、高纯度地获得二甲氨基乙硫磷酰二乙酯；4)在本发明的方法中，各中间体和产物的合成操作主要是萃取和重结晶，与常规方法减压蒸馏相比，操作更方便更有效，同时可以减少副产物的形成，可以高产率、高纯度地合成碘依可酯；5)在本发明的方法中，所制备的碘依可酯收率高，纯度高。
具体实施方式
本发明提供了一种二甲氨基乙硫磷酰二乙酯或其卤化物盐的制备方法，包含以下步骤：
i、将O,O-二乙基硫代磷酸钠盐与2-二甲氨基卤乙烷反应，得到二甲氨基乙硫磷酰二乙酯；
ii、将上述二甲氨基乙硫磷酰二乙酯与碘甲烷反应，得到三甲铵基乙硫磷酰二乙酯卤化物。
上述反应中，2-二甲氨基卤乙烷例如是2-二甲氨基氯乙烷、2-二甲氨基溴乙烷、2-二甲氨基碘乙烷，优选2-二甲氨基氯乙烷、2-二甲氨基溴乙烷，更优选是2-二甲氨基氯乙烷。碘甲烷与二甲氨基乙硫磷酰二乙酯，形成三甲铵基乙硫磷酰二乙酯碘化物，即碘依可酯。
反应在有机溶剂，优选无水有机溶剂中进行。该有机溶剂选自包括下列的有机溶剂：乙酸乙酯、甲醇、乙醇、二氯甲烷、四氢呋喃、丙酮、乙腈、石油醚、乙醚、二甲基亚砜、二氧六环或其混合物。步骤i中，优选有机溶剂可以选自包括下列的组：乙醇、乙醚、二氯甲烷、乙腈、二甲基亚砜、二氧六环、四氢呋喃或其混合物，优选四氢呋喃，更优选为无水四氢呋喃。
步骤i反应中，O,O-二乙基硫代磷酸钠盐与2-二甲氨基氯乙烷的反应摩尔比例如为约(0.5～3)：1，优选约(1.2～2.8)：1，更优选约(1.2～2.5)：1，还更优选约(1～2.5)：1，进一步优选约(1～2)：1，最优选约(1.6～1.7)：1。
步骤i中，反应温度例如为约30℃～100℃，优选约40℃～90℃，更优选约45℃～80℃，最优选在约70℃。
反应时间根据反应物的用量而有所不同。一般而言，步骤i的反应时间为约6～28小时，优选约8～24小时，更优选约10～22小时，最优选约18～20小时。
步骤ii中，用作反应溶剂的有机溶剂例如选自甲醇、乙醇、乙醚、乙腈、丙酮、乙酸乙酯、二甲基亚砜和四氢呋喃的一种或多种的混合物，优选乙醚，特别是无水乙醚。在碘甲烷与二甲氨基乙硫磷酰二乙酯的步骤ii反应中，优选碘甲烷过量。碘甲烷与二甲氨基乙硫磷酰二乙酯的摩尔比例如为约(1～3)：1，优选约(1～2.8)：1，优选(1.2～2.8)：1，更优选(1.2～2.5)：1，更优选约(1～2)：1，最优选1.6～1.7：1。
对于上述步骤得到的产品，优选进行后处理如重结晶处理。例如，将步骤i和步骤ii分别得到的二甲氨基乙硫磷酰二乙酯和三甲铵基乙硫磷酰二乙酯碘化物，进行重结晶处理。例如，将三甲铵基乙硫磷酰二乙酯碘化物粗品溶解在一种有机溶剂中，然后根据需要，可以加入其他有机溶剂，一起进行重结晶。重结晶的温度可以根据需要选择，例如可以在低温下，如0℃以下进行。
重结晶溶剂选自包括下列的有机溶剂：甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙醚、四氢呋喃及其混合物。重结晶溶剂可以使用混合物，当使用溶剂混合物时，其中任意两种有机溶剂的比例例如体积比约1：(1～8)；优选体积比为约1：(1～5)的两种溶剂的混合溶剂，或者体积比约1：(1～3)，还优选体积比约1:1的两种溶剂的混合溶剂。上述溶剂的混合物例如为甲醇和乙醚的混合物。
在步骤i中的2-甲氨基卤乙烷，可以通过步骤a，即将N,N-二甲氨基乙醇胺和卤化亚砜反应得到2-甲氨基卤乙烷的步骤。步骤a中，卤化亚砜和N,N-二甲氨基乙醇胺的摩尔比为约(0.5～3)：1，优选约(1～2.5)：1，更优选约(1～2)：1，最优选约1.5：1。
步骤a可以分两步进行，包括a1)将N,N-二甲氨基乙醇胺和卤化亚砜， 优选氯化亚砜反应，得到2-二甲氨基卤乙烷盐，优选卤酸盐；和a2)将2-二甲氨基卤乙烷卤酸盐脱盐，得到2-二甲氨基卤乙烷。步骤a的反应在有机溶剂中进行。该有机溶剂例如选自下列：甲醇、乙醇、乙醚、乙腈、丙酮、乙酸乙酯、二氯甲烷、二甲基亚砜、四氢呋喃或其混合物。优选，对步骤a1)和步骤a2)得到的产品进行重结晶。重结晶中用到的溶剂选自例如乙酸乙酯、二氯甲烷、甲醇、乙醇、丙酮、乙醚、乙腈或其混合物。优选，重结晶使用两种或多种溶剂的混合物。如使用两种溶剂的混合物时，该两种溶剂的体积比例如为1：(1～10)，优选约1：10，还优选约1：8，更优选约1：5，还更优选约1：3，具体例如约1：2。两种溶剂例如为乙醇和丙酮。步骤a的反应时间根据需要进行，例如可以持续1～24小时。
在步骤i中的O,O-二乙基硫代磷酸钠盐，可以通过步骤b，即将亚磷酸二乙酯依次同金属钠和硫粉反应得到。在步骤b中，亚磷酸二乙酯、金属钠和硫的反应摩尔比例如为约1：(0.5～3)：(0.5～3)，优选约1：(1～2)：(1～2)，更优选约1：(1～1.5)：(1～1.5)，具体例如为约1：1.05：1.3。金属钠优选高纯度的金属钠，硫粉可以根据需要选择。
本文提供的方法反应效率高，反应中的后处理操作主要是萃取和重结晶，总收率能够达到42.1％(重量)，产品纯度能够达到例如99.2％(HPLC)，工艺简单、成本较低，适合工业化大生产。本发明方法得到的碘依可酯纯度高，可用于制备滴眼液。
二甲氨基乙硫磷酰二乙酯的合成
在有机溶剂中，将O,O-二乙基硫代磷酸钠盐与2-二甲氨基卤乙烷反应。2-二甲氨基卤乙烷中的卤素可以是氟、氯、溴、碘，优选氯和溴，最优选是氯，例如为2-二甲氨基氯乙烷。
有机溶剂选自甲醇、乙醇、乙醚、二氯甲烷、乙腈、二甲基亚砜、二氧六环和四氢呋喃或其混合物，优选四氢呋喃。本文中，有机溶剂优选为无水的有机溶剂。
上述反应步骤中，O,O-二乙基硫代磷酸钠盐与2-二甲氨基卤乙烷的反应摩尔比为约(0.5～3)：1，优选约(1.2～2.8)：1，更优选约(1.2～2.5)：1，还更优选约(1～2.5)：1，进一步优选约(1～2)：1，最优选约(1.6～1.7)：1。
反应温度为约30℃～100℃，优选约40℃～90℃，更优选约45℃～80℃， 最优选约70℃。
反应时间取决于反应物的量，一般而言，反应时间为约6～28小时，优选约8～24小时，更优选约10～22小时，例如约16-18小时。
根据本文的一个实施方案，上述反应的反应式例如为：
Figure PCTCN2019098001-appb-000005
根据该反应式，将2-二甲氨基氯乙烷和O,O-二乙基硫代磷酸钠盐在有机溶剂，例如四氢呋喃，优选无水四氢呋喃中反应，由此制备二甲氨基乙硫磷酰二乙酯。
碘依可酯(三甲铵基乙硫磷酰二乙酯碘化物)的合成
在有机溶剂中，将上述中间体二甲氨基乙硫磷酰二乙酯与碘甲烷反应，得到三甲铵基乙硫磷酰二乙酯卤化物盐。为了制备碘依可酯，将碘甲烷和二甲氨基乙硫磷酰二乙酯反应，得到三甲铵基乙硫磷酰二乙酯碘化物，即碘依可酯。该反应中使用的有机溶剂例如为如上所述的有机溶剂，如甲醇、乙醇、乙醚、二氯甲烷、乙腈、二甲基亚砜、二氧六环和四氢呋喃或其混合物。优选，二甲氨基乙硫磷酰二乙酯在例如乙醚中，优选无水乙醚中，与碘甲烷反应。
根据本文的一个实施方案，上述反应的反应式例如为：
Figure PCTCN2019098001-appb-000006
上述反应中，碘甲烷与二甲氨基乙硫磷酰二乙酯的反应摩尔比为约(1～3)：1，优选约(1～2.8)：1，优选(1.2～2.8)：1，更优选(1.2～2.5)：1，更优选约(1～2)：1，最优选(1.6～1.7)：1。
反应后，得到三甲铵基乙硫磷酰二乙酯碘化物粗品。对三甲铵基乙硫磷酰二乙酯碘化物粗品进行后处理，后处理方法例如为重结晶。重结晶中，使用与反应中使用的有机溶剂相同的有机溶剂，例如乙醚，对三甲铵基乙硫磷 酰二乙酯碘化物进行重结晶，由此得到纯化的三甲铵基乙硫磷酰二乙酯碘化物。重结晶也可以使用两种或多种溶剂的混合溶剂，例如选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、石油醚、乙醚、四氢呋喃中的两种或多种混合。
在本文的一个实施方案中，通过两种溶剂的混合物将三甲铵基乙硫磷酰二乙酯碘化物粗品进行重结晶。例如将三甲铵基乙硫磷酰二乙酯碘化物粗品溶解在两种溶剂的混合物中，如体积比约1：8的两种溶剂的混合物；更优选体积比为约1：5的两种溶剂的混合溶剂，或者体积比约1：3的两种溶剂的混合溶剂，或者体积比约1：3的两种溶剂的混合溶剂中，进行重结晶。例如，重结晶溶剂例如为体积比为约1：8的甲醇和乙醚的混合溶剂，优选体积比为约1：5的甲醇和乙醚混合溶剂，更优选体积比为约1：3的甲醇和乙醚混合溶剂。
2-二甲氨基氯乙烷的合成
二甲氨基乙硫磷酰二乙酯合成中用到的2-二甲氨基氯乙烷可以市售购得，例如以二甲氨基氯乙烷盐酸盐的形式购得，之后脱盐得到。也可以合成制备。
2-二甲氨基氯乙烷例如可以通过在有机溶剂中，将N,N-二甲氨基乙醇胺与卤化亚砜(SOX 2)，例如氯化亚砜、溴化亚砜，优选氯化亚砜反应得到，由此得到二甲氨基氯乙烷卤酸盐。有机溶剂可以选自甲醇、乙醇、二氯甲烷、四氢呋喃、丙酮、乙腈、乙醚及其混合物，例如二氯甲烷。
根据本文的一个实施方案，上述反应的反应式例如为：
Figure PCTCN2019098001-appb-000007
其中DCM为二氯甲烷；
X为Cl或Br。
在反应容器中，将N,N-二甲氨基乙醇胺加入有机溶剂中溶解，在所得到的溶液中，加入卤化亚砜，优选氯化亚砜，反应得到2-二甲氨基氯乙烷盐酸盐。优选在得到2-二甲氨基氯乙烷盐酸盐后，进行重结晶步骤。重结晶有利 于促进后续反应的进行和纯度的提高，该重结晶在重结晶溶剂中进行。重结晶溶剂选自乙酸乙酯、二氯甲烷、甲醇、乙醇、丙酮、乙醚、石油醚、乙腈及其混合物。重结晶也可以使用两种或多种溶剂的混合物，如乙醇和丙酮的混合物进行。当使用两种溶剂的混合物时，体积比为相互之间最低为约1:1，至比例为约1:10，例如为约1:2、约1:3、约1:4、约1:5、约1:6、约1:7、约1:8、约1:9。重结晶后，得到纯化的2-二甲氨基氯乙烷盐酸盐。
接下来，将纯化的2-二甲氨基氯乙烷卤酸盐进行脱盐。脱盐可以通过常规的步骤进行，例如氢氧化钠中和的方式。脱盐后，得到2-二甲氨基氯乙烷。在本文的一个实施方案中，例如首先将2-二甲氨基氯乙烷卤酸盐溶于水，用氢氧化钠溶液调节该水溶液的pH值为7-10，例如pH8、pH9、pH10，一般不高于pH10，待中和后的溶液分层后，蒸馏上层油相。对于下层水相，优选用有机溶剂萃取，萃取后，蒸馏有机相，由此得到2-二甲氨基氯乙烷。
在本文的一个技术方案中，在有机溶剂(无水)二氯甲烷中，加入N,N-二甲氨基乙醇胺，0℃下，搅拌加入氯化亚砜。加入完毕后，加热回流一段时间，例如1～24小时。加热回流时间可以根据需要调整，例如2～18小时，或者4～12小时。反应后，得到2-二甲氨基氯乙烷卤化物盐，优选将其重结晶后，经脱盐得到二甲氨基氯乙烷。
制备2-二甲氨基氯乙烷卤化物盐的反应中，氯化亚砜和N,N-二甲氨基乙醇胺的反应摩尔比为约(0.5～3)：1，优选反应摩尔比为约(1～2.5)：1，更优选反应摩尔比为约(1～2)：1，最优选反应摩尔比为约1.5：1。
重结晶过程为将二甲氨基氯乙烷盐酸盐粗品溶解在有机溶剂中，然后加入其他有机溶剂，在低温，例如为0℃，优选-5℃～-10℃，进行重结晶。重结晶后，得到纯化的二甲氨基氯乙烷盐酸盐。重结晶溶剂可以选自乙醇、乙酸乙酯、二氯甲烷、甲醇、乙醇、丙酮、乙腈、四氢呋喃、石油醚中的两种或多种混合；例如体积比为约1：10的乙醇和丙酮，优选体积比为约1：5的乙醇和丙酮，具体为体积比约1：2的乙醇和丙酮。
重结晶中，可以根据需要选择有机溶剂的量，优选溶剂的量(以体积计)为粗品的10倍以下，优选约8倍，更优选约6倍，最优选为约4倍，以能够使产品在溶剂中充分结晶为宜。
O,O-二乙基硫代磷酸钠盐的合成
上述中间体二甲氨基乙硫磷酰二乙酯合成中用到的O,O-二乙基硫代磷酸钠盐能够合成得到。例如，通过将亚磷酸二乙酯依次与金属钠和硫粉反应，得到O,O-二乙基硫代磷酸钠盐。亚磷酸二乙酯首先与金属钠(Na)反应，得到亚磷酸二乙酯钠盐，接下来亚磷酸二乙酯钠盐和硫粉(S 8)反应，得到O,O-二乙基硫代磷酸钠盐。
反应在上文所述的有机溶剂中进行。有机溶剂可以选自：甲醇、乙醇、二氯甲烷、四氢呋喃、丙酮、乙腈、石油醚、乙醚及其混合物，例如乙醇、乙醚或者乙醇和乙醚的混合物。如果选择两种有机溶剂时，例如乙醇和乙醚，乙醇和乙醚的体积比为约1:1-1:3。
反应中，亚磷酸二乙酯与钠和硫粉的反应在同样的有机溶剂中依次连续进行。优选，在亚磷酸二乙酯与钠的反应中，当金属钠完全溶解在有机溶剂中之后，则亚磷酸二乙酯与钠的反应完成时加入硫粉，使亚磷酸二乙酯的钠盐和硫粉反应。反应后，得到O,O-二乙基硫代磷酸钠盐，为固体盐。根据需要，可以通过用有机溶剂清洗该O,O-二乙基硫代磷酸钠盐，得到清洗后的O,O-二乙基硫代磷酸钠盐直接用到下一步的反应中。
根据本文的一个实施方案，上述反应的反应式例如为：
Figure PCTCN2019098001-appb-000008
上述反应中，亚磷酸二乙酯、钠和硫的反应摩尔比为约1：(0.5～3)：(0.5～3)，优选约1：(1～2)：(1～2)，更优选为约1：(1～1.5)：(1～1.5)，最优选为约1：1.05：1.3。
根据本文的一个具体实施方式，提供了一种制备三甲铵基乙硫磷酰二乙酯碘化物的方法，包括以下步骤：
i、二甲氨基乙硫磷酰二乙酯的合成：
Figure PCTCN2019098001-appb-000009
其中，THF是四氢呋喃。
O,O-二乙基硫代磷酸钠盐与2-二甲氨基氯乙烷在无水四氢呋喃中反应得到二甲氨基乙硫磷酰二乙酯；
ii、三甲铵基乙硫磷酰二乙酯碘化物的合成：
Figure PCTCN2019098001-appb-000010
二甲氨基乙硫磷酰二乙酯在无水乙醚中同碘甲烷反应，经重结晶得到三甲铵基乙硫磷酰二乙酯碘化物，其中的氮具有正电荷，碘具有负电荷。
本文的合成二甲氨基乙硫磷酰二乙酯或其卤化物盐的反应效率较高，后处理简单，产品收率最高可以达到42.1％，且最终得到的碘依可酯的纯度高，工艺成本低，适合工业化大生产。
根据本文的一个具体的实施方式，步骤i中的2-二甲氨基氯乙烷可如下合成：
Figure PCTCN2019098001-appb-000011
其中DCM是二氯甲烷。
即，将N,N-二甲氨基乙醇胺与氯化亚砜反应，得到2-二甲氨基氯乙烷盐酸盐。根据需要且优选，将得到2-二甲氨基氯乙烷盐酸盐通过例如乙醇和丙酮的混合溶剂进行重结晶，之后通过氢氧化钠水溶液，例如50％的氢氧化钠水溶液调节pH至7～10而脱盐，得到2-二甲氨基氯乙烷。
根据本文的一个具体的实施方式，步骤i中的O,O-二乙基硫代磷酸钠盐可如下合成：
Figure PCTCN2019098001-appb-000012
即，亚磷酸二乙酯依次与金属钠和硫粉反应。优选，化学式(4)的反应在氮气保护下，在有机溶剂，如乙醇和乙醚混合溶剂中，进行与钠的反应，之后在低温，如室温以下，优选0℃以下，与硫粉进行反应。
本文反应式，包括上述反应式(1)、(2)、(3)和(4)是为了演示反应流程，不是经过化学平衡的反应方程式。
在本文的又一个实施方式中，提供了包括如下步骤的制备碘依可酯的方法：
i、二甲氨基乙硫磷酰二乙酯的合成：
Figure PCTCN2019098001-appb-000013
O,O-二乙基硫代磷酸钠盐与2-二甲氨基氯乙烷在无水四氢呋喃中反应得到二甲氨基乙硫磷酰二乙酯；
ii、三甲铵基乙硫磷酰二乙酯碘化物的合成：
Figure PCTCN2019098001-appb-000014
其中步骤i中的反应物能够通过如下步骤制备得到：
a.合成2-二甲氨基氯乙烷
Figure PCTCN2019098001-appb-000015
将N,N-二甲氨基乙醇胺与氯化亚砜反应，得到2-二甲氨基氯乙烷盐酸盐，重结晶、脱盐后，得到2-二甲氨基氯乙烷；
或者
b.合成O,O-二乙基硫代磷酸钠盐：
Figure PCTCN2019098001-appb-000016
亚磷酸二乙酯依次与金属钠和硫粉反应，得到O,O-二乙基硫代磷酸钠盐。
在一个优选的实施方案中，合成2-二甲氨基氯乙烷和O,O-二乙基硫代磷酸钠盐，制备中间体二甲氨基乙硫磷酰二乙酯，进而得到碘依可酯，包括例如如下的步骤：
A、2-二甲氨基卤乙烷的合成：
Figure PCTCN2019098001-appb-000017
其中SOX 2为氯化亚砜；
DCM为二氯甲烷；
B、O,O-二乙基硫代磷酸钠盐的合成：
Figure PCTCN2019098001-appb-000018
亚磷酸二乙酯依次同金属钠和硫粉反应得到O,O-二乙基硫代磷酸钠盐；
C、二甲氨基乙硫磷酰二乙酯的合成：
Figure PCTCN2019098001-appb-000019
其中THF为四氢呋喃；
O,O-二乙基硫代磷酸钠盐与2-二甲氨基卤乙烷在无水四氢呋喃中反应得到二甲氨基乙硫磷酰二乙酯；
D、三甲铵基乙硫磷酰二乙酯碘化物的合成：
Figure PCTCN2019098001-appb-000020
通过上述反应步骤，可以制备得到碘依可酯。
本文提供的方法反应简便，易操作，反应中的后处理操作主要是萃取和重结晶。该方法工艺简单、成本较低，适合工业化大生产。根据本文的方法，碘依可酯的总收率能够达到42.1％(重量)，纯度能够达到例如99.2％(重量)， 可用于制备滴眼液。
以下实施例进一步描述本发明，但是这些实施例仅仅用于说明本发明，而不是对本发明范围的限制。本文中，未特别指明时，涉及溶剂时，使用的是体积比，即以体积为基础；涉及组分及用量百分数时，为重量比，即以重量计。
实施例
实施例1(制备例1) 2-二甲氨基氯乙烷的合成
将106.96g(1.20mol)N,N-二甲氨基乙醇胺和300ml二氯甲烷加入到1000ml的三口烧瓶中，缓慢滴加214.15g(1.80mol)氯化亚砜，滴加完毕继续搅拌加热回流反应8小时，旋干溶剂，得到2-二甲氨基氯乙烷盐酸盐粗品。用体积比1：2的乙醇和丙酮混合溶液重结晶2-二甲氨基氯乙烷盐酸盐粗品，得到纯化的2-二甲氨基氯乙烷盐酸盐。将2-二甲氨基氯乙烷盐酸盐晶体溶于水，再将溶液冷却到0℃，以质量百分比浓度为50％的氢氧化钠溶液调pH值为10，将溶液静置，待分层后，用分液漏斗分出上层油相，干燥、过滤、蒸馏得到2-二甲氨基氯乙烷。将下层水相用乙醚萃取，经干燥、过滤、精馏得到2-二甲氨基氯乙烷，合并得到2-二甲氨基氯乙烷116.20g，产率为90.01％，沸点58℃。HPLC检测纯度约98.9％。核磁共振 1H-NMR(400MHz，CDCl 3)：δ2.30(s，6H，CH 3)，2.66(t，J＝6.8Hz，2H)，3.57(t，J＝6.8Hz，2H)。
实施例2(制备例2) 2-二甲氨基氯乙烷的合成
将106.96g(1.20mol)N,N-二甲氨基乙醇胺和300ml二氯甲烷加入到1000ml的三口烧瓶中，缓慢滴加71.38g(0.60mol)氯化亚砜，滴加完毕继续搅拌加热回流反应8小时，旋干溶剂，得2-二甲氨基氯乙烷盐酸盐粗品，用体积比1：2的乙醇和丙酮重结晶得2-二甲氨基氯乙烷盐酸盐。将2-二甲氨基氯乙烷盐酸盐晶体溶于水，再将溶液冷却到0℃，以质量百分比浓度为50％的氢氧化钠溶液调pH值为10，将溶液静置，待分层后，用分液漏斗分出上层油相，干燥、过滤、蒸馏得到2-二甲氨基氯乙烷，将下层水相用乙醚萃取，经干燥、过滤、精馏得到2-二甲氨基氯乙烷，合并得到2-二甲氨基氯乙烷73.37g，产率为68.20％，HPLC检测纯度约98.7％。
实施例3(制备例3) 2-二甲氨基氯乙烷的合成
将106.96g(1.20mol)N,N-二甲氨基乙醇胺和300ml二氯甲烷加入到1000ml的三口烧瓶中，缓慢滴加428.29g(3.60mol)氯化亚砜，滴加完毕继续搅拌加热回流反应8小时，旋干溶剂，得2-二甲氨基氯乙烷盐酸盐粗品，用体积比1：2的乙醇和丙酮重结晶得2-二甲氨基氯乙烷盐酸盐。将2-二甲氨基氯乙烷盐酸盐晶体溶于水，再将溶液冷却到0℃，以质量百分比浓度为50％的氢氧化钠溶液调pH值为10，将溶液静置，待分层后，用分液漏斗分出上层油相，干燥、过滤、蒸馏得到2-二甲氨基氯乙烷，将下层水相用乙醚萃取，经干燥、过滤、精馏得到2-二甲氨基氯乙烷，合并得到2-二甲氨基氯乙烷118.21g，产率为91.57％，HPLC检测纯度约99.1％。
实施例4(制备例4) 2-二甲氨基溴乙烷氢溴酸盐的合成
将89.14g(1.00mol)N,N-二甲氨基乙醇胺和300ml二氯甲烷加入到1000ml的三口烧瓶中，缓慢滴加249.45g(1.20mol)溴化亚砜的二氯甲烷350ml，滴加完毕继续搅拌加热回流反应8小时，旋干溶剂，得2-二甲氨基溴乙烷氢溴酸盐粗品。用体积比1：2的乙醇和丙酮重结晶得白色固体217.8g，产率93.5％，HPLC检测纯度约98.7％， 1H-NMR(400MHz，Methanol-d 4)：δ2.99(s，6H，CH 3)，3.68(t，J＝6.4Hz，2H)，3.82(t，J＝6.4Hz，2H)。
实施例5(制备例5) O,O-二乙基硫代磷酸钠盐的合成
在1000ml三口烧瓶中加入100.00g(724.1mmol)亚磷酸二乙酯、250ml乙醇、250ml乙醚，充入氮气，搅拌下分批加入17.49g(760.1mmol)金属钠，当金属钠完全溶解时，用冰盐浴将溶液温度冷却到0℃以下，分批加入30.19g(941.3mmol)硫粉，1小时后升到室温搅拌过夜。反应液垫硅藻土过滤，滤液真空旋干，得到黄色固体，固体破碎，用乙醚搅洗，过滤，滤饼乙醚洗至灰白色，再冷冻干燥，得到灰白色粉末125.08g，产率89.9％， 1H-NMR(400MHz，d6-DMSO)：δ1.10(t，J＝7.2Hz，6H，CH 3)，3.65-3.80(m，4H，CH 2)； 13C-NMR(400MHz，d6-DMSO)：δ16.8(d，J＝31.2Hz，2C)，60.1(d，J＝23.2Hz，2C)； 13P-NMR(400MHz，d6-DMSO)：δ53.5(s，1P)。
实施例6(制备例6) O,O-二乙基硫代磷酸钠盐的合成
在1000ml三口烧瓶中加入100.00g(724.1mmol)亚磷酸二乙酯、250ml乙醇、250ml乙醚，充入氮气，搅拌下分批加入8.32g(362.1mmol)金属钠，当金属钠完全溶解时，用冰盐浴将溶液温度冷却到0℃以下，分批加入9.68g(362.1mmol)硫粉，1小时后升到室温搅拌过夜。反应液垫硅藻土过滤，滤液真空旋干，得黄色固体，固体破碎，用乙醚搅洗，过滤，滤饼乙醚洗至灰白色，再冷冻干燥，得到灰白色粉末50.78g，产率36.5％， 1H-NMR(400MHz，d6-DMSO)：δ1.10(t，J＝7.2Hz，6H，CH 3)，3.65-3.80(m，4H，CH 2)； 13C-NMR(400MHz，d6-DMSO)：δ16.8(d，J＝31.2Hz，2C)，60.1(d，J＝23.2Hz，2C)； 13P-NMR(400MHz，d6-DMSO)：δ53.5(s，1P)。
实施例7(制备例7) O,O-二乙基硫代磷酸钠盐的合成
在1000ml三口烧瓶中加入100.00g(724.1mmol)亚磷酸二乙酯、250ml乙醇、250ml乙醚，充入氮气，搅拌下分批加入49.94g(2.17mol)金属钠，当金属钠完全溶解时，用冰盐浴将溶液温度冷却到0℃以下，分批加入30.19g(2.17mol)硫粉，1小时后升到室温搅拌过夜。反应液垫硅藻土过滤，滤液真空旋干，得黄色固体，固体破碎，用乙醚搅洗，过滤，滤饼乙醚洗至灰白色，再冷冻干燥，得到灰白色粉末121.47g，产率87.3％， 1H-NMR(400MHz，d6-DMSO)：δ1.10(t，J＝7.2Hz，6H，CH 3)，3.65-3.80(m，4H，CH 2)； 13C-NMR(400MHz，d6-DMSO)：δ16.8(d，J＝31.2Hz，2C)，60.1(d，J＝23.2Hz，2C)； 13P-NMR(400MHz，d6-DMSO)：δ53.5(s，1P)。
实施例8 二甲氨基乙硫磷酰二乙酯的合成
在250ml三口烧瓶中加入10.12g(52.7mmol)O,O-二乙基硫代磷酸钠盐和50ml无水四氢呋喃，搅拌下滴加3.34g(31.1mmol)2-二甲氨基氯乙烷，滴加完毕反应搅拌回流反应过夜。过滤，溶剂真空旋干，加入10％碳酸钠水溶液，用乙酸乙酯萃取4次，合并有机相，依次用10％碳酸钠溶液和饱和食盐水洗涤，有机相加无水硫酸钠干燥，过滤，旋干溶剂，加入乙醚，离心除去沉淀，再旋蒸除去乙醚，得到无色液体5.40g，产率约72％。 1H-NMR(400MHz，CDCl 3)：δ1.37(t，J＝6.8Hz，6H，CH 3)，2.27(s，6H)， 2.59(t，J＝7.2Hz，2H)，2.83-2.98(m，2H),4.11-4.23(m，4H)； 13C-NMR(400MHz，CDCl 3)：δ16.1(d，J＝28.8Hz，2C)，28.6(d，J＝14.4Hz，1C)，45.2(s，2C)，59.5(d，J＝23.2Hz，1C)，63.5(d，J＝24.4Hz，2C)； 13P-NMR(400MHz，CDCl 3)：δ28.2(s，1P)。
实施例9 二甲氨基乙硫磷酰二乙酯的合成
在250ml三口烧瓶中加入2.99g(15.56mmol)O,O-二乙基硫代磷酸钠盐和50ml无水四氢呋喃，搅拌下滴加3.34g(31.1mmol)2-二甲氨基氯乙烷，滴加完毕反应搅拌回流反应过夜。过滤，溶剂真空旋干，加入10％碳酸钠水溶液，乙酸乙酯萃取4次，合并有机相，依次用10％碳酸钠溶液和饱和食盐水洗涤，有机相加无水硫酸钠干燥，过滤，旋干溶剂，加入乙醚，离心除去沉淀，再旋蒸掉乙醚，得到无色液体1.86g，产率约49.7％。
实施例10 二甲氨基乙硫磷酰二乙酯的合成
在250ml三口烧瓶中加入17.93g(93.3mmol)O,O-二乙基硫代磷酸钠盐和50ml无水四氢呋喃，搅拌下滴加3.34g(31.1mmol)2-二甲氨基氯乙烷，滴加完毕反应搅拌回流反应过夜。过滤，溶剂真空旋干，加入10％碳酸钠水溶液，乙酸乙酯萃取4次，合并有机相，依次用10％碳酸钠溶液和饱和食盐水洗涤，有机相加无水硫酸钠干燥，过滤，旋干溶剂，加入乙醚，离心除去沉淀，再旋蒸掉乙醚，得到无色液体5.46g，产率约72.8％。
实施例11 二甲氨基乙硫磷酰二乙酯的合成
在250ml三口烧瓶中加入7.24g(31.1mmol)2-二甲氨基溴乙烷氢溴酸盐、5.16g(37.3mmol)无水碳酸钾和100ml无水四氢呋喃，搅拌半小时后加入10.12g(52.7mmol)O,O-二乙基硫代磷酸钠盐，搅拌回流反应过夜。过滤，溶剂真空旋干，加入10％碳酸钠水溶液，乙酸乙酯萃取4次，合并有机相，依次用10％碳酸钠溶液和饱和食盐水洗涤，有机相加无水硫酸钠干燥，过滤，旋干溶剂，加入乙醚，离心除去沉淀，再旋蒸掉乙醚，得到无色液体5.14g，产率约68.5％。
实施例12 三甲铵基乙硫磷酰二乙酯碘化物的合成
将5.40g(22.3mmol)二甲氨基乙硫磷酰二乙酯溶于10ml无水乙醚，缓慢滴加5.07g(35.7mmol)碘甲烷和无水乙醚50ml的溶液，滴加完毕，室温静置过夜，析出白色结晶性固体，过滤，滤饼乙醚洗，经干燥后，得碘依可酯粗品，用体积比1：3的甲醇和乙醚混合溶剂重结晶，过滤，乙醚洗涤固体，冷冻干燥至恒重，得白色粉末6.18g，产率约72.4％，HPLC检测纯度约99.2％， 1H-NMR(400MHz，d6-DMSO)：δ1.30(t，J＝7.2Hz，6H，CH 3)，3.11(s，9H)，3.17-3.26(m，2H)，3.56-3.60(m，2H)，4.07-4.20(m，2H)； 13C-NMR(400MHz，d6-DMSO)：δ16.4(d，J＝26.4Hz，2C)，23.2(d，J＝15.6Hz，1C)，52.9(s，3C)，64.4(d，J＝24.8Hz，2C)，65.2(s，1C)； 13P-NMR(400MHz，d6-DMSO)：24.9(s，1P)。
实施例13 三甲铵基乙硫磷酰二乙酯碘化物的合成
将5.40g(22.3mmol)二甲氨基乙硫磷酰二乙酯溶于10ml无水乙醚，缓慢滴加3.17g(22.3mmol)碘甲烷和无水乙醚50ml的溶液，滴加完毕，室温静置过夜，析出白色结晶性固体，过滤，滤饼乙醚洗，经干燥后，得碘依可酯粗品，用体积比1：3的甲醇和乙醚混合溶剂重结晶，过滤，乙醚洗涤固体，冷冻干燥至恒重，得白色粉末5.01g，产率约58.6％。
实施例14 三甲铵基乙硫磷酰二乙酯碘化物的合成
将5.40g(22.3mmol)二甲氨基乙硫磷酰二乙酯溶于10ml无水乙醚，缓慢滴加9.50g(66.9mmol)碘甲烷和无水乙醚50ml的溶液，滴加完毕，室温静置过夜，析出白色结晶性固体，过滤，滤饼乙醚洗，经干燥后，得碘依可酯粗品，用体积比1：3的甲醇和乙醚混合溶剂重结晶，过滤，乙醚洗涤固体，冷冻干燥至恒重，得白色粉末6.17g，产率约72.2％。
本发明的制备碘依可酯的方法带来了如下的益处：1)避免使用奇臭有毒性的中间体二甲氨基乙硫醇；2)当使用中间体O,O-二乙基硫代磷酸钠盐时，起始原料为亚磷酸二乙酯，依次加入金属钠和硫粉一锅法得到，避免使用易制毒化学品三氯氧磷或三氯硫磷，同时避免淬灭与蒸馏操作三氯氧磷或三氯硫磷的废物，更容易控制该反应；3)避免使用可致癌的溶剂苯，减少副产物 的形成，可以高产率、高纯度地获得二甲氨基乙硫磷酰二乙酯；4)在本发明的方法中，各中间体和产物的合成操作主要是萃取和重结晶，与常规方法减压蒸馏相比，操作更方便更有效，同时可以减少副产物的形成，可以高产率、高纯度地合成碘依可酯；5)在本发明的方法中，收率高，纯度高。例如在本发明的实施例中，例如从2-二甲氨基氯乙烷、O,O-二乙基硫代磷酸钠盐开始，四步法的总收率最高为42.1％且产品纯度高至99.2％；6)本发明的方法工艺成本较低，适合工业化大生产。

Claims (11)

  1. 三甲铵基乙硫磷酰二乙酯卤化物盐的制备方法，包含以下步骤：
    i、将O,O-二乙基硫代磷酸钠盐与2-二甲氨基卤乙烷反应，得到二甲氨基乙硫磷酰二乙酯；
    ii、将二甲氨基乙硫磷酰二乙酯与碘甲烷反应，得到三甲铵基乙硫磷酰二乙酯卤化物盐。
  2. 根据权利要求1的方法，其中步骤i中，O,O-二乙基硫代磷酸钠盐与2-二甲氨基卤乙烷的反应摩尔比为(0.5-3)：1。
  3. 根据权利要求1的方法，其中步骤ii中，卤代烃为氯甲烷或溴甲烷或碘甲烷，该卤代烃与二甲氨基乙硫磷酰二乙酯的反应摩尔比为(1-3)：1。
  4. 根据权利要求1的方法，其中步骤i中的O,O-二乙基硫代磷酸钠盐通过将亚磷酸二乙酯依次与金属钠和硫粉反应得到。
  5. 根据权利要求4的方法，其中亚磷酸二乙酯与金属钠和硫粉在氮气保护下依次反应。
  6. 根据权利要求1的方法，其中所述步骤i、步骤ii在有机溶剂中进行，所述有机溶剂选自包括下列的有机溶剂：乙酸乙酯、甲醇、乙醇、二氯甲烷、四氢呋喃、丙酮、乙腈、石油醚、乙醚、二甲基亚砜、二氧六环或其混合物。
  7. 根据权利要求6的方法，其中所述有机溶剂为至少两种有机溶剂的混合物。
  8. 根据权利要求6的方法，其中使用所述有机溶剂作为重结晶溶剂或萃取剂。
  9. 根据权利要求6的方法，其中当使用有机溶剂的混合物时，所述有机溶剂混合物任何两种之间的体积比为1:1-1:3。
  10. 根据权利要求1的方法，包括：
    i、形成二甲氨基乙硫磷酰二乙酯：
    Figure PCTCN2019098001-appb-100001
    O,O-二乙基硫代磷酸钠盐与2-二甲氨基氯乙烷在无水四氢呋喃中反应得到二甲氨基乙硫磷酰二乙酯；
    ii、根据需要，形成三甲铵基乙硫磷酰二乙酯碘化物：
    Figure PCTCN2019098001-appb-100002
    二甲氨基乙硫磷酰二乙酯在乙醚中与碘甲烷反应，得到三甲铵基乙硫磷酰二乙酯碘化物。
  11. 根据权利要求10的方法，还包括形成O,O-二乙基硫代磷酸钠盐或2-二甲氨基氯乙烷：
    Figure PCTCN2019098001-appb-100003
    将亚磷酸二乙酯依次与金属钠和硫粉反应，制得O,O-二乙基硫代磷酸钠盐；
    或者
    Figure PCTCN2019098001-appb-100004
    将N,N-二甲氨基乙醇胺在二氯甲烷中与氯化亚砜反应，得到2-二甲氨基氯乙烷。
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