CN111943805A - Preparation method of (R) -3-chloro-1, 2-propanediol - Google Patents
Preparation method of (R) -3-chloro-1, 2-propanediol Download PDFInfo
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- CN111943805A CN111943805A CN202010971610.1A CN202010971610A CN111943805A CN 111943805 A CN111943805 A CN 111943805A CN 202010971610 A CN202010971610 A CN 202010971610A CN 111943805 A CN111943805 A CN 111943805A
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- epoxypropane
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- SSZWWUDQMAHNAQ-VKHMYHEASA-N (R)-3-chloro-1,2-propanediol Chemical compound OC[C@@H](O)CCl SSZWWUDQMAHNAQ-VKHMYHEASA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims abstract description 20
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 claims abstract description 15
- 238000003756 stirring Methods 0.000 claims abstract description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000011259 mixed solution Substances 0.000 claims abstract description 11
- OWXJKYNZGFSVRC-NSCUHMNNSA-N (e)-1-chloroprop-1-ene Chemical compound C\C=C\Cl OWXJKYNZGFSVRC-NSCUHMNNSA-N 0.000 claims abstract description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- YSAVZVORKRDODB-UHFFFAOYSA-N Diethyl tartrate Chemical compound CCOC(=O)C(O)C(O)C(=O)OCC YSAVZVORKRDODB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000004821 distillation Methods 0.000 claims abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 6
- 239000012153 distilled water Substances 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 238000005194 fractionation Methods 0.000 claims abstract description 3
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 239000011541 reaction mixture Substances 0.000 claims abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 9
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical group OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 7
- 239000000463 material Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 229910001385 heavy metal Inorganic materials 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 4
- PTVWPYVOOKLBCG-ZDUSSCGKSA-N levodropropizine Chemical compound C1CN(C[C@H](O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-ZDUSSCGKSA-N 0.000 description 4
- 229960002265 levodropropizine Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- -1 3, 5-di-tert-butylsalicylidene Chemical group 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000000954 anitussive effect Effects 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- VZHHNBNSMNNUAD-UHFFFAOYSA-N cobalt 2-[2-[(2-hydroxyphenyl)methylideneamino]ethyliminomethyl]phenol Chemical compound [Co].OC1=CC=CC=C1C=NCCN=CC1=CC=CC=C1O VZHHNBNSMNNUAD-UHFFFAOYSA-N 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- HKJYVRJHDIPMQB-UHFFFAOYSA-N propan-1-olate;titanium(4+) Chemical compound CCCO[Ti](OCCC)(OCCC)OCCC HKJYVRJHDIPMQB-UHFFFAOYSA-N 0.000 description 2
- 238000005870 sharpless asymmetric epoxidation reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- PTVWPYVOOKLBCG-CYBMUJFWSA-N (2r)-3-(4-phenylpiperazin-1-yl)propane-1,2-diol Chemical compound C1CN(C[C@@H](O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-CYBMUJFWSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003426 co-catalyst Substances 0.000 description 1
- 229940011182 cobalt acetate Drugs 0.000 description 1
- 229910001429 cobalt ion Inorganic materials 0.000 description 1
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 description 1
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
- C07C29/103—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers
- C07C29/106—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers of oxiranes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/19—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic hydroperoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a preparation method of (R) -3-chloro-1, 2-propanediol, belonging to the technical field of chiral material preparation. Under the protection of nitrogen, adding chloroform into a reaction container, adding tetraisopropyltitanyl and L (-) -diethyl tartrate into the reaction container in sequence, dropwise adding chloropropene after fully stirring, then adding tert-butyl hydroperoxide into the reaction container, stirring for 12 hours, after the reaction is completed, carrying out reduced pressure distillation to prepare (S) -3-chloro-1, 2-epoxypropane, dissolving (S) -3-chloro-1, 2-epoxypropane into distilled water, dropwise adding a phase transfer catalyst into the solution, stirring and heating to 90 ℃, reacting for 24 hours, adding an alkali liquor into the mixed solution after the reaction, adjusting the pH value to 7, and carrying out reduced pressure fractionation on the reaction mixture to prepare the target product (R) -3-chloro-1, 2-propanediol. The raw materials needed by the invention are cheap and easy to obtain, and the preparation cost is lower; the method has the advantages of simple process, simple and convenient operation, high product yield and contribution to industrial popularization.
Description
The technical field is as follows:
the invention belongs to the technical field of chiral material preparation, and particularly relates to a preparation method of (R) -3-chloro-1, 2-propanediol.
Background art:
(R) -3-chloro-1, 2-propanediol is an important medical intermediate and can be used for synthesizing the antitussive levodropropizine. Levodropropizine (Levodropropizine) with the chemical name of S- (-) -3- (4-phenyl-1-piperazinyl) -1, 2-propanediol is a novel antitussive, and researches show that racemate R- (-) -3- (4-phenyl-1-piperazinyl) -1, 2-propanediol has the same effect on relieving cough, but has larger side effect, and particularly can cause adverse reaction in central nerves. If the pair of racemates can be separated, the pair of racemates has better medicinal effect on products with optically active enantiomers, but the industrial resolution of the racemates is very high in cost and difficult to realize industrial popularization. The reaction process for synthesizing levodropropizine by using (R) -3-chloro-1, 2-propanediol is as follows:
the current process for the production of (R) -3-chloro-1, 2-propanediol is as follows:
the method has low production efficiency and high cost, and uses Salen-Co catalyst ((R, R') - (-) -N, N-bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexyldiamine cobalt acetate (III)), (R) -3-chloro-1, 2-propanediol has serious standard exceeding of heavy metal ions, if the method is directly used for producing levo-hydroxypropyl piperazine, the heavy metal ions in the levo-hydroxypropyl piperazine can exceed the standard and can not reach the standard requirements of food and pharmaceutical additives, and if the levo-hydroxypropyl piperazine is recrystallized again to remove the heavy metal ions, the production cost can be correspondingly greatly increased.
The invention content is as follows:
the invention provides a preparation method of (R) -3-chloro-1, 2-propanediol aiming at the problems in the prior art. The method is simple and practical, has no pollution of heavy metal cobalt ions, and simultaneously the obtained (R) -3-chloro-1, 2-propanediol has high yield, high chiral purity and low water content, and has good industrial popularization value.
The preparation method of the (R) -3-chloro-1, 2-propanediol provided by the invention comprises the following specific steps:
(1) synthesis of (S) -3-chloro-1, 2-epoxypropane:
under the protection of nitrogen, adding a certain amount of reaction solvent into a reaction container, sequentially adding tetraisopropyltitanyl and L (-) -diethyl tartrate ((-) DET into the reaction container at the temperature of between 10 ℃ below zero and 0 ℃, dropwise adding chloropropene after fully stirring, adding tert-butyl hydroperoxide after fully mixing after dropwise adding, stirring the obtained mixed solution for 12 hours, monitoring the reaction process by TLC (thin layer chromatography) or HPLC (high performance liquid chromatography), and after the reaction is completed, carrying out reduced pressure distillation and fractionizing to obtain the (S) -3-chloro-1, 2-epoxypropane.
The reaction solvent is chloroform, and the mol ratio of chloropropene, tetraisopropyloxytitanium, L (-) -diethyl tartrate and tert-butyl hydroperoxide is as follows: chloropropene, tetraisopropyltitanyl, L (-) -diethyl tartrate and tert-butyl hydroperoxide are 1: 1.5-2.5; the reduced pressure distillation temperature is 60-65 ℃, and the pressure is-0.08 MPa; in the step, chloroform is used as a Sharpless asymmetric epoxidation reaction solvent, and tert-butyl hydroperoxide is used as an oxidant.
(2) Synthesis of (R) -3-chloro-1, 2-propanediol:
under the protection of nitrogen, dissolving (S) -3-chloro-1, 2-epoxypropane obtained in the step (1) in a certain amount of distilled water, after full dissolution, dropwise adding an aqueous solution of a phase transfer catalyst, stirring and heating to 90 ℃, reacting for 24h, monitoring the reaction process by TLC or HPLC, after the reaction is completed, adding an alkali liquor into the mixed solution after the reaction, adjusting the pH value to 7, stopping the reaction after the adjustment is completed, and separating water and a product (R) -3-chloro-1, 2-propanediol from the reaction mixture by reduced pressure fractionation.
The phase transfer catalyst is tetra-n-butyl ammonium bisulfate, and hydrogen sulfate radicals can be ionized to generate H in water+The quaternary ammonium salt cation can cause the phase transfer of the organic phase and the anion in the water, thereby accelerating the reaction rate; molar ratio of reactants: (S) -3-chloro-1, 2-epoxypropane and tetra-n-butyl ammonium hydrogen sulfate are respectively 100: 1-3; the reduced pressure distillation temperature is 60-65 ℃, and the pressure is-0.08MPa。
The reaction process is as follows:
the invention has the following technical characteristics:
1. the cheap and easily obtained chloropropene is used as the starting material, so that the production cost is lower.
2. Fully utilizes Sharpless asymmetric epoxidation to obtain a levorotatory or dextrorotatory enantiomer product with high yield, and mainly synthesizes a dextrorotatory intermediate product in the method.
3. Compared with the traditional catalyst Salen-Co, the acidic phase transfer catalyst is adopted, so that the phase transfer catalysis effect is achieved, the conversion rate in an acidic medium is high, and the problem that the content of heavy metal ions in a product exceeds the standard is solved.
4. High yield, easy separation and purification, high chiral purity and high added value.
The specific implementation mode is as follows:
example 1: the preparation method of the (R) -3-chloro-1, 2-propanediol provided by the invention comprises the following specific steps:
(1) preparation of (S) -3-chloro-1, 2-epoxypropane:
adding 30mL of chloroform into a 100mL three-neck round-bottom flask at-10 ℃, adding 0.344mL (0.412g,2mmol) of L (-) diethyl tartrate and 0.594mL (2mmol) of tetrapropyloxytitanium sequentially, fully stirring, adding 0.153g (2mmol) of chloropropene, stirring for 10min, adding 0.391mL (0.36g, 4mmol) of tert-butyl hydroperoxide, stirring the obtained mixed solution in a refrigerator at-10 to 0 ℃ for 12 hours, monitoring the reaction process by TLC or HPLC during the reaction, and after the reaction is completed, fractionating the product at 65 ℃ (-0.08MPa) to obtain a pure product. Yield 90.4%, purity: 99.3%, chiral purity: 99.5% e.e.
(2) Preparation of (R) -3-chloro-1, 2-propanediol:
20mL of distilled water and 0.78mL (0.92g,10mmol) of pure (S) -3-chloro-1, 2-epoxypropane are added into a 50mL three-neck flask, after the mixture is fully mixed, 3.4mg of tetra-N-butylammonium hydrogen sulfate is added into the mixed solution, the mixture is stirred and heated to 90 ℃, the reaction is carried out for 24 hours, the reaction progress is monitored by TLC or HPLC, after the reaction is finished, 0.1N sodium hydroxide is added into the mixed solution after the reaction, the pH is adjusted to 7, the reaction is stopped after the adjustment is finished, excessive water is distilled at 60 ℃ (-0.08MPa), and then the product (R) -3-chloro-1, 2-propanediol is distilled under high vacuum-0.1 MPa. Yield 96.4%, purity: 99.5%, chiral purity: 99.7% e.e.
Example 2: the preparation method of the (R) -3-chloro-1, 2-propanediol provided by the invention comprises the following specific steps:
(1) preparation of (S) -3-chloro-1, 2-epoxypropane
Adding 60mL of chloroform into a 250mL three-neck round-bottom flask at-10 ℃, adding 34.4mL (41.2g,0.2mol) of L (-) diethyl tartrate and 59.4mL (0.2mol) of tetrapropyloxytitanium sequentially, fully stirring, adding 15.3g (0.2mol) of chloropropene, stirring for 10min, adding 39.1mL (36g, 0.4mol) of tert-butyl hydroperoxide, stirring the obtained mixed solution in a refrigerator at-10 to 0 ℃ for 12 hours, monitoring the reaction process by TLC or HPLC during the reaction, and after the reaction is completed, fractionating the product at 65 ℃ (-0.08MPa) to obtain a pure product. Yield 90.1%, purity: 98.8%, chiral purity: 99.3% e.e.
(2) Preparation of (R) -3-chloro-1, 2-propanediol
50mL of distilled water and 78mL (92g,1mol) of pure (S) -3-chloro-1, 2-epoxypropane are added into a 250mL three-neck flask, the mixture is fully mixed, 0.35g of tetra-N-butyl ammonium hydrogen sulfate aqueous solution is added into the mixed solution dropwise, the mixture is stirred and heated to 90 ℃ and reacts for 24 hours, the reaction progress is monitored by TLC or HPLC, after the reaction is finished, 0.1N sodium hydroxide is added into the mixed solution after the reaction, the pH is adjusted to 7, the reaction is stopped after the adjustment is finished, excessive water is distilled at 60 ℃ (-0.08MPa), and then the product (R) -3-chloro-1, 2-propanediol is distilled under high vacuum-0.1 MPa. Yield 95.9%, purity: 98.5%, chiral purity: 99.6% e.e.
Claims (1)
1. A preparation method of (R) -3-chloro-1, 2-propanediol is characterized by comprising the following steps:
(1) synthesis of (S) -3-chloro-1, 2-epoxypropane:
under the protection of nitrogen, adding a certain amount of reaction solvent into a reaction container, sequentially adding tetraisopropyl titanyl and L (-) -diethyl tartrate into the reaction container at the temperature of between 10 ℃ below zero and 0 ℃, fully stirring, dropwise adding chloropropene into the mixture, after the dropwise adding and the full mixing are completed, adding tert-butyl hydroperoxide into the mixture, stirring the obtained mixed solution for 12 hours, monitoring the reaction process by TLC or HPLC, after the reaction is completed, carrying out reduced pressure distillation and fractionating to obtain (S) -3-chloro-1, 2-epoxypropane; the reaction solvent is chloroform, and the mol ratio of chloropropene, tetraisopropyloxytitanium, L (-) -diethyl tartrate and tert-butyl hydroperoxide is as follows: chloropropene, tetraisopropyltitanyl, L (-) -diethyl tartrate and tert-butyl hydroperoxide are 1: 1.5-2.5; the reduced pressure distillation temperature is 60-65 ℃, and the pressure is-0.08 MPa;
(2) synthesis of (R) -3-chloro-1, 2-propanediol:
under the protection of nitrogen, dissolving (S) -3-chloro-1, 2-epoxypropane obtained in the step (1) in a certain amount of distilled water, after full dissolution, dropwise adding an aqueous solution of a phase transfer catalyst, stirring and heating to 90 ℃, reacting for 24h, monitoring the reaction process by TLC or HPLC, after the reaction is completed, adding an alkali liquor into the mixed solution after the reaction, adjusting the pH value to 7, stopping the reaction after the adjustment is completed, and separating water and a product (R) -3-chloro-1, 2-propanediol from the reaction mixture by reduced pressure fractionation; the phase transfer catalyst is tetra-n-butyl ammonium hydrogen sulfate; the molar ratio of the (S) -3-chloro-1, 2-epoxypropane to the tetra-n-butyl ammonium hydrogen sulfate is as follows: (S) -3-chloro-1, 2-epoxypropane and tetra-n-butyl ammonium hydrogen sulfate are respectively 100: 1-3; the reduced pressure distillation temperature is 60-65 ℃, and the pressure is-0.08 MPa.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113943206A (en) * | 2021-10-25 | 2022-01-18 | 华今(山东)新材料科技有限公司 | Preparation method of high-quality (R) -3-chloro-1, 2-propanediol |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113943206A (en) * | 2021-10-25 | 2022-01-18 | 华今(山东)新材料科技有限公司 | Preparation method of high-quality (R) -3-chloro-1, 2-propanediol |
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