CN117800872A - Synthesis method of 4-hydroxybutyronitrile - Google Patents
Synthesis method of 4-hydroxybutyronitrile Download PDFInfo
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- CN117800872A CN117800872A CN202311794248.5A CN202311794248A CN117800872A CN 117800872 A CN117800872 A CN 117800872A CN 202311794248 A CN202311794248 A CN 202311794248A CN 117800872 A CN117800872 A CN 117800872A
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- BAQQRABCRRQRSR-UHFFFAOYSA-N 4-hydroxybutylnitrile Chemical compound OCCCC#N BAQQRABCRRQRSR-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- 239000002253 acid Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 21
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims abstract description 18
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims abstract description 12
- 229940035437 1,3-propanediol Drugs 0.000 claims abstract description 12
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 239000002904 solvent Substances 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 238000004321 preservation Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 238000010791 quenching Methods 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 230000000171 quenching effect Effects 0.000 claims description 9
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000007333 cyanation reaction Methods 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 125000006239 protecting group Chemical group 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- 239000012074 organic phase Substances 0.000 description 19
- 239000008346 aqueous phase Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000007337 electrophilic addition reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing 4-hydroxybutyronitrile, which relates to the technical field of synthesis of 4-hydroxybutyronitrile and comprises the following steps: the 1, 3-propanediol is protected by a TBS protecting group, then a cyanation reaction is carried out under the action of protonic acid, and finally 4-hydroxybutyronitrile is obtained by deprotection. According to the synthesis method, 1, 3-propanediol is used as a starting material, and 4-hydroxybutyronitrile is obtained through three steps of reactions, cyanide is avoided in the reactions, and the synthesis method is environment-friendly, simple in post-treatment, low in labor cost and safe and reliable in reaction.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a method for synthesizing 4-hydroxybutyronitrile.
Background
The 4-hydroxybutyronitrile is a compound with very active chemical activity, is an important raw material and an intermediate in organic synthesis, can generate nucleophilic substitution, electrophilic addition and other reactions, and can be used for preparing organic compounds such as medicines, dyes, rubber additives and the like. In addition, 4-hydroxybutyronitrile can be used as a starter to prepare polymers in general because of the cyano group in the molecule. Thus, 4-hydroxybutyronitrile plays an important role in organic synthesis.
The traditional synthesis of 4-hydroxybutyronitrile can use sodium cyanide or cyanide, and the cyanide-containing waste liquid can cause great harm to the environment and does not meet the requirements of green chemistry, so the requirements on post-reaction treatment are severe, the synthesis cost can be greatly increased, and the method is not suitable for large-scale production. Here, a new route is designed, 1, 3-propanediol is protected by a method of applying TBS protecting groups, then cyanation reaction is carried out under the action of protonic acid, and finally 4-hydroxybutyronitrile is obtained by deprotection. The method avoids using cyanide and other highly toxic substances, is more environment-friendly, and is simple to operate and safe and reliable in reaction. In the invention, the proton acid is screened, the feeding ratio is optimized, the reaction yield is improved, and the method is more suitable for industrial production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of 4-hydroxybutyronitrile, which solves the problems in the prior art.
In order to achieve the above purpose, the invention is realized by the following technical scheme:
the synthesis method of the 4-hydroxybutyronitrile comprises the following steps:
s1: sequentially adding a solvent and 1, 3-propylene glycol into a reaction vessel, cooling, adding an acid binding agent and TBSCl, stirring, heating to room temperature, reacting, quenching, extracting, drying, filtering, concentrating under reduced pressure, and separating by column chromatography to obtain a first intermediate.
And S2, sequentially adding a solvent and a first intermediate into a reaction vessel, cooling under the protection of nitrogen, adding protonic acid and TMSCN, carrying out heat preservation reaction, then dropwise adding TMSOTF, carrying out heat preservation reaction, carrying out quenching reaction after the reaction is finished, extracting, drying, carrying out suction filtration, concentrating under reduced pressure, and rectifying to obtain a second intermediate.
And S3, sequentially adding a solvent and a second intermediate into a reaction container, adding a catalyst for reaction, quenching after the reaction is finished, extracting, drying, filtering, concentrating under reduced pressure, and rectifying to obtain the pure 4-hydroxybutyronitrile.
Further, the solvent in the step S1 is dichloromethane, and the acid binding agent in the step S1 is imidazole.
Further, the mass ratio of the solvent to the 1, 3-propanediol of step S1 is (3-5): 1.
Further, the charging ratio of the acid binding agent, the TBSCl and the 1, 3-propanediol in the step S1 is 1:1:1.
Further, the solvent in the step S2 is dichloromethane, and the proton acid in the step S2 is one of trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid.
Further, the mass ratio of the solvent and the first intermediate in step S2 is (3-5): 1.
Further, the feeding ratio of the protonic acid, the TMSCN, the TMSOTf and the first intermediate in the step S2 is (1-3): 2-4): 1.
Further, the solvent in the step S3 is THF, and the catalyst in the step S3 is TBAF.
Further, the mass ratio of the solvent to the second intermediate in step S3 is 1:1.
Further, the feed ratio of the catalyst and the second intermediate in step S3 is 2:1.
Compared with the prior art, the invention has the following beneficial effects:
1. the synthesis method of 4-hydroxybutyronitrile of the invention takes 1, 3-propanediol as an initial raw material, and obtains a target product through three steps of reactions.
2. The synthesis method of 4-hydroxybutyronitrile of the invention optimizes the feed ratio firstly, screens the protonic acid, effectively improves the yield, and has the condition of industrial production
Drawings
FIG. 1 is a synthetic route diagram of the present invention.
Detailed Description
In order to make the present application solution better understood by those skilled in the art, the following description will be made in detail and with reference to the accompanying drawings in the embodiments of the present application, it is apparent that the described embodiments are only some embodiments of the present application, not all embodiments. All other embodiments, which can be made by one of ordinary skill in the art based on the embodiments herein without making any inventive effort, shall fall within the scope of the present application.
The invention provides a method for synthesizing 4-hydroxybutyronitrile, referring to fig. 1, comprising the following steps:
s1: sequentially adding a solvent and 1, 3-propylene glycol into a reaction vessel, cooling, adding an acid binding agent and TBSCl, stirring, heating to room temperature, reacting, quenching, extracting, drying, filtering, concentrating under reduced pressure, and separating by column chromatography to obtain a first intermediate.
And S2, sequentially adding a solvent and a first intermediate into a reaction vessel, cooling under the protection of nitrogen, adding protonic acid and TMSCN, carrying out heat preservation reaction, then dropwise adding TMSOTF, carrying out heat preservation reaction, carrying out quenching reaction after the reaction is finished, extracting, drying, carrying out suction filtration, concentrating under reduced pressure, and rectifying to obtain a second intermediate.
And S3, sequentially adding a solvent and a second intermediate into a reaction container, adding a catalyst for reaction, quenching after the reaction is finished, extracting, drying, filtering, concentrating under reduced pressure, and rectifying to obtain the pure 4-hydroxybutyronitrile.
The solvent in the step S1 is dichloromethane, and the acid binding agent in the step S1 is imidazole.
The mass ratio of the solvent and the 1, 3-propanediol in the step S1 is (3-5): 1.
The feeding ratio of the acid binding agent, TBSCl and 1, 3-propanediol in the step S1 is 1:1:1.
The solvent of the step S2 is methylene dichloride, and the protonic acid of the step S2 is one of trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid.
The mass ratio of the solvent and the first intermediate in the step S2 is (3-5): 1.
The feeding ratio of the protonic acid, TMSCN, TMSOtf and the first intermediate in the step S2 is (1-3): 2-4): 1.
The solvent in the step S3 is THF, and the catalyst in the step S3 is TBAF.
The mass ratio of the solvent of S3 to the second intermediate is 1:1.
The feed ratio of the catalyst of S3 to the second intermediate was 2:1.
The TBSCl is tert-butyl dimethyl chlorosilane, TMSCN is trimethylcyano silane, also called trimethylcyano silane or trimethylsilyl cyanide, TMSOTf is trimethylsilyl trifluoro methanesulfonate, and TBAF is tetra-n-butyl ammonium fluoride.
The 1, 3-propanediol is firstly protected by a TBS protecting group, then is subjected to cyanation reaction with TMSCN under the action of acid, and finally is subjected to TBAF deprotection to obtain the 4-hydroxybutyronitrile.
The following are different embodiments:
embodiment one:
preparation of first intermediate
Into a dry and clean 5L reaction flask with stirrer and thermometer, 193g of 1, 3-propanediol and 1kg of methylene chloride were added in this order, and stirring was started. Cooling to 0 ℃, adding 172g of imidazole and 3831 g of TBSCl in portions, and stirring for 30min at 0 ℃. Then slowly warmed to room temperature and reacted for 3 hours. TLC monitoring, reaction completion, quench with saturated aqueous ammonium chloride (800 mL), separation of aqueous phase, extraction of aqueous phase with DCM (800 mL. Times.2), combining the extracted organic phases, drying over anhydrous sodium sulfate, suction filtration, concentration of the organic phase under reduced pressure, column chromatography (10% EtOAc/Hexane) afforded 458g of the first intermediate, with a GC purity of 99.6% and a yield of 95%.
Preparation of the second intermediate
To a dry and clean 5L reactor flask with stirrer and thermometer, 458g of the first intermediate and 1.37kg of methylene chloride were added in this order, and stirring was started. Under the protection of nitrogen, the temperature is reduced to 0 ℃, trifluoroacetic acid is added in batches for heat preservation reaction for 30min at 550g,716g TMSCN,0 ℃. Then 1.6kg TMSOTF is added dropwise at 0 ℃, and the temperature is kept for 3h after the addition is finished. Then the temperature is raised to 25 ℃ for reaction for 2 hours. TLC monitored the reaction, and quenched with saturated sodium bicarbonate solution (2L). The aqueous phase was separated and the aqueous phase was extracted with DCM (2 l x 2), the extracted organic phases combined, dried over anhydrous sodium sulphate, suction filtered and the organic phase concentrated under reduced pressure, finally distilled under reduced pressure by means of a water pump to give 403g of a second intermediate with a GC purity of 99.3% in 84% yield.
Preparation of the target product
A dry and clean 10L reaction flask with stirrer and thermometer was charged with 403g of the second intermediate and 403g of THF in this order, and stirring was turned on. TBAF (1M in THF) 4L was slowly added and stirred for 30min. TLC monitoring, reaction was completed, quenched with saturated aqueous ammonium chloride (1.5L), the aqueous phase was separated and the organic phase was spin-dried. The aqueous phase was extracted with ethyl acetate (1.5 l×3). The extracted organic phases are combined, dried by anhydrous sodium sulfate, filtered by suction, the organic phase is concentrated under reduced pressure, finally distilled under reduced pressure by a water pump, the oil temperature is 104-108 ℃, the top temperature is 74-76 ℃ and fractions are collected to obtain the pure product 162g, the GC purity is 99.5%, and the yield is 94.3%.
Embodiment two:
the first intermediate is prepared as described in example one.
Preparation of the second intermediate
To a dry and clean 10L reactor flask with stirrer and thermometer, 458g of the first intermediate and 1.37kg of methylene chloride were added in this order, and stirring was started. Under the protection of nitrogen, the temperature is reduced to 0 ℃, trifluoroacetic acid is added in batches for heat preservation reaction for 30min at 550g,955g TMSCN,0 ℃. 2.14kg TMSOTF is added dropwise at 0 ℃, and the temperature is kept for 3h after the addition. Then the temperature is raised to 25 ℃ for reaction for 2 hours. TLC monitored the reaction, and the reaction was quenched slowly with saturated sodium bicarbonate solution (2L). The aqueous phase was separated and the aqueous phase was extracted with DCM (2 l x 2), the extracted organic phases combined, dried over anhydrous sodium sulphate, suction filtered and the organic phase concentrated under reduced pressure, finally distilled under reduced pressure by means of a water pump to give 417g of a second intermediate, GC purity 99.5%, yield 87%.
The procedure for the preparation of the target product is as in example one, giving 169g of pure product with a GC purity of 99.7% and a yield of 95%.
Embodiment III:
the first intermediate is prepared as described in example one.
Preparation of the second intermediate
To a dry and clean 10L reactor flask with stirrer and thermometer, 458g of the first intermediate and 1.37kg of methylene chloride were added in this order, and stirring was started. Under the protection of nitrogen, the temperature is reduced to 0 ℃, trifluoroacetic acid is added in batches for heat preservation reaction for 30min at 824g,716g TMSCN,0 ℃. Then 1.6kg TMSOTF is added dropwise at 0 ℃, and the temperature is kept for 3h after the addition is finished. Then the temperature is raised to 25 ℃ for reaction for 2 hours. TLC monitored the reaction, and quenched with saturated sodium bicarbonate solution (2L). The aqueous phase was separated and the aqueous phase was extracted with DCM (2 l x 2), the extracted organic phases combined, dried over anhydrous sodium sulphate, suction filtered and the organic phase concentrated under reduced pressure, finally distilled under reduced pressure by means of a water pump to give 408g of a second intermediate with GC purity 99.2% in 85% yield.
The procedure for the preparation of the target product is as in example one, which gives 165g of pure product with a GC purity of 99.4% and a yield of 94.5%.
Embodiment four:
the first intermediate is prepared as described in example one.
Preparation of the second intermediate
To a dry and clean 10L reactor flask with stirrer and thermometer, 458g of the first intermediate and 1.37kg of methylene chloride were added in this order, and stirring was started. Under the protection of nitrogen, the temperature is reduced to 0 ℃, and the trifluoromethanesulfonic acid is added in batches for heat preservation reaction for 30min at 723g,955g TMSCN,0 ℃. 2.14kg TMSOTF is added dropwise at 0 ℃, and the temperature is kept for 3h after the addition. Then the temperature is raised to 25 ℃ for reaction for 2 hours. TLC monitored the reaction, and quenched with saturated sodium bicarbonate solution (2L). The aqueous phase was separated and the aqueous phase was extracted with DCM (2 l x 2), the extracted organic phases combined, dried over anhydrous sodium sulphate, suction filtered and the organic phase concentrated under reduced pressure, finally distilled under reduced pressure by means of a water pump to give 360g of a second intermediate, GC purity 99.3%, yield 75%.
The procedure for the preparation of the target product is as in example I, 148g of pure product is obtained, the GC purity is 99.2%, and the yield is 96%.
Fifth embodiment:
the first intermediate is prepared as described in example one.
Preparation of the second intermediate
To a dry and clean 10L reactor flask with stirrer and thermometer, 458g of the first intermediate and 1.37kg of methylene chloride were added in this order, and stirring was started. Under the protection of nitrogen, the temperature is reduced to 0 ℃, p-toluenesulfonic acid is added in batches, and the temperature is kept at 829g,955g TMSCN,0 ℃ for 30min for reaction. 2.14kg TMSOTF is added dropwise at 0 ℃, and the temperature is kept for 3h after the addition. Then the temperature is raised to 25 ℃ for reaction for 2 hours. TLC monitored the reaction, and quenched with saturated sodium bicarbonate solution (2L). The aqueous phase was separated and the aqueous phase was extracted with DCM (2 l x 2), the extracted organic phases combined, dried over anhydrous sodium sulphate, suction filtered and the organic phase concentrated under reduced pressure, finally distilled under reduced pressure by means of a water pump to give 336g of a second intermediate, GC purity 99.1% in 70% yield.
The procedure for the preparation of the target product is as in example I, and gives 135g of pure product with a GC purity of 99.4% and a yield of 94%.
Example six:
the first intermediate is prepared as described in example one.
Preparation of the second intermediate
To a dry and clean 10L reactor flask with stirrer and thermometer, 458g of the first intermediate and 1.37kg of methylene chloride were added in this order, and stirring was started. Under the protection of nitrogen, the temperature is reduced to 0 ℃, methanesulfonic acid is added in batches, and the temperature is kept at 463g,955g TMSCN,0 ℃ for 30min for reaction. 2.14kg TMSOTF is added dropwise at 0 ℃, and the temperature is kept for 3h after the addition. Then the temperature is raised to 25 ℃ for reaction for 2 hours. TLC monitored the reaction, and quenched with saturated sodium bicarbonate solution (2L). The aqueous phase was separated and the aqueous phase was extracted with DCM (2 l x 2), the extracted organic phases combined, dried over anhydrous sodium sulphate, suction filtered and the organic phase concentrated under reduced pressure, finally distilled under reduced pressure by means of a water pump to give 374g of a second intermediate, GC purity 99.4%, yield 78%.
The preparation process of the target product is shown in example I, and the pure product 151g is obtained, the GC purity is 99.3%, and the yield is 94.5%.
Embodiment seven:
the first intermediate is prepared as described in example one.
Preparation of the second intermediate
To a dry and clean 100L reactor with stirrer and thermometer, 4.6kg of the first intermediate and 14kg of methylene chloride were added in this order, and stirring was started. Under the protection of nitrogen, the temperature is reduced to 0 ℃, trifluoroacetic acid is added in batches for heat preservation reaction for 30min at 5.5kg,9.5kg TMSCN,0 ℃. Then 21kg TMSOTF is added dropwise at 0 ℃, and the temperature is kept for 3 hours after the addition is finished. Then the temperature is raised to 25 ℃ for reaction for 2 hours. TLC monitored the reaction, and quenched with saturated sodium bicarbonate solution (20L). The aqueous phase was separated and the aqueous phase was extracted with DCM (20 l x 2), the extracted organic phases combined, dried over anhydrous sodium sulphate, suction filtered and the organic phase concentrated under reduced pressure, finally distilled under reduced pressure by means of a water pump to give 3.8kg of a second intermediate with GC purity of 99.3% in 80% yield.
The preparation process of the target product is shown in the first example, 1.5kg of pure product is obtained, the GC purity is 99.4%, and the yield is 95.1%.
In the experiment of preparing the second intermediate, the invention screens the feeding ratio through the first to third embodiments; then screening protonic acid through the orthogonal comparison experiments of the fourth to sixth embodiments, and finding that the trifluoroacetic acid has the best catalytic effect; finally, in example seven, an enlarged production was performed. The method avoids cyanide, has simple post-treatment, can obtain 4-hydroxybutyronitrile through three-step chemical reaction, and meets the basic requirements of the pharmaceutical industry.
The foregoing is merely a preferred embodiment of the present application and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present application and are intended to be comprehended within the scope of the present application.
Claims (10)
1. The synthesis method of the 4-hydroxybutyronitrile is characterized by comprising the following steps:
s1: sequentially adding a solvent and 1, 3-propylene glycol into a reaction vessel, cooling, adding an acid binding agent and TBSCl, stirring, heating to room temperature, reacting, quenching, extracting, drying, filtering, concentrating under reduced pressure, and separating by column chromatography to obtain a first intermediate.
And S2, sequentially adding a solvent and a first intermediate into a reaction vessel, cooling under the protection of nitrogen, adding protonic acid and TMSCN, carrying out heat preservation reaction, then dropwise adding TMSOTF, carrying out heat preservation reaction, carrying out quenching reaction after the reaction is finished, extracting, drying, carrying out suction filtration, concentrating under reduced pressure, and rectifying to obtain a second intermediate.
And S3, sequentially adding a solvent and a second intermediate into a reaction container, adding a catalyst for reaction, quenching after the reaction is finished, extracting, drying, filtering, concentrating under reduced pressure, and rectifying to obtain the pure 4-hydroxybutyronitrile.
2. The method for synthesizing 4-hydroxybutyronitrile according to claim 1, wherein the solvent in step S1 is methylene chloride, and the acid-binding agent in step S1 is imidazole.
3. The method according to claim 1, wherein the mass ratio of the solvent and the 1, 3-propanediol in step S1 is (3-5): 1.
4. The method for synthesizing 4-hydroxybutyronitrile according to claim 1, wherein the feeding ratio of the acid binding agent, TBSCl and 1, 3-propanediol in step S1 is 1:1:1.
5. The method according to claim 1, wherein the solvent in the step S2 is dichloromethane, and the protonic acid in the step S2 is one of trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid.
6. The method according to claim 1, wherein the mass ratio of the solvent to the first intermediate in the step S2 is (3-5): 1.
7. The method according to claim 1, wherein the feed ratio of the protonic acid, the TMSCN, the TMSOTf and the first intermediate in the step S2 is (1-3): 2-4): 1.
8. The method for synthesizing 4-hydroxybutyronitrile according to claim 1, wherein the solvent in step S3 is THF and the catalyst in step S3 is TBAF.
9. The method according to claim 1, wherein the mass ratio of the solvent to the second intermediate in step S3 is 1:1.
10. The method according to claim 1, wherein the catalyst and the second intermediate in step S3 are fed in a ratio of 2:1.
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