CN114380727A - Preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile - Google Patents
Preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile Download PDFInfo
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 125000006125 ethylsulfonyl group Chemical group 0.000 title claims abstract description 18
- RFBXEQYQSIJAJL-UHFFFAOYSA-N azetidin-3-one;hydron;chloride Chemical compound Cl.O=C1CNC1 RFBXEQYQSIJAJL-UHFFFAOYSA-N 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 238000003756 stirring Methods 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 239000012074 organic phase Substances 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 12
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 11
- HQUIOHSYUKWGOM-UHFFFAOYSA-N 2-(1-ethylsulfonylazetidin-3-ylidene)acetonitrile Chemical compound CCS(=O)(=O)N1CC(=CC#N)C1 HQUIOHSYUKWGOM-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 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
- 239000007788 liquid Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 claims description 5
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 229960001701 chloroform Drugs 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004042 decolorization Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000006103 sulfonylation Effects 0.000 abstract description 3
- 238000005694 sulfonylation reaction Methods 0.000 abstract description 3
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 230000008030 elimination Effects 0.000 abstract description 2
- 238000003379 elimination reaction Methods 0.000 abstract description 2
- 230000004224 protection Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000000843 powder Substances 0.000 description 4
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 description 4
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- LDOZIDLMPNCNDI-UHFFFAOYSA-N 3-diethoxyphosphorylpropanenitrile Chemical compound CCOP(=O)(OCC)CCC#N LDOZIDLMPNCNDI-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XUZMWHLSFXCVMG-UHFFFAOYSA-N baricitinib Chemical compound C1N(S(=O)(=O)CC)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 XUZMWHLSFXCVMG-UHFFFAOYSA-N 0.000 description 1
- 229950000971 baricitinib Drugs 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile, in particular to a preparation method which takes 3-oxo-azetidine hydrochloride as a raw material and efficiently synthesizes the 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile by four steps of protection, sulfonylation, condensation and elimination.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile.
Background
2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile is one of the key intermediates for the synthesis of the oral JAK kinase 1 and 2 inhibitor baricitinib. The four-membered ring structure of the compound has instability and great synthesis difficulty.
The conventional synthetic route for 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile is as follows:
the method comprises the following steps:
in the method disclosed in US2019/135807, N-Boc-3-oxoazetidine is used as a starting material, and a target product is obtained by deprotection, sulfonylation and C-hydroxylation. The method has the advantages that the cost of the used initial raw material N-Boc-3-oxoazetidine is high, the last step of C-hydroxylation reaction uses tetrahydrofuran, potassium tert-butoxide and diethyl (2-cyanoethyl) phosphonate which are high in price as raw materials, and the yield is only 35%. The method has high overall cost and low industrialization value.
The method 2 comprises the following steps:
in the method disclosed in US2009/233903, a target product is obtained by C-hydroxylating, deprotecting and sulfonylating N-Boc-3-oxoazetidine as a starting material. The method has the advantages that the cost of raw materials N-Boc-3-oxo azetidine and diethyl (2-cyanoethyl) phosphonate is high, tetrahydrofuran and potassium tert-butoxide with high price are also used in the first step of C-hydroxylation reaction, the total yield is only 35.7 percent, the yield is low, and the method is not suitable for industrial production.
Disclosure of Invention
Aiming at the problems, the invention discloses a preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile, which specifically comprises the steps of taking 3-oxo-azetidine hydrochloride as a raw material, and efficiently synthesizing the 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile through four steps of protection, sulfonylation, condensation and elimination.
The reaction equation is as follows:
the technical scheme for solving the technical problems is as follows: a preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile comprises the following steps:
(1) adding a solvent I into a reaction bottle, adding 1.0mol of 3-oxo-azetidine hydrochloride and 1.2-2.5mol of ethylene glycol under stirring, adding 0.05-0.15mol of acid, keeping the temperature at 110-140 ℃ after the addition is finished, reacting completely, cooling to room temperature, adding 1.1-1.5mol of potassium carbonate, reacting completely after the addition is finished, concentrating under reduced pressure to dryness, stirring and dissolving with dichloromethane and water, separating, drying, and concentrating under reduced pressure to dryness to obtain an intermediate I;
(2) adding a solvent II into a reaction bottle, adding 1.2-1.8mol of organic base and 0.87-0.92mol of the prepared intermediate I under stirring, keeping the temperature at minus 10-30 ℃, dropwise adding 0.96-1.38mol of ethylsulfonyl chloride, reacting completely after the addition is finished, washing with water, concentrating an organic phase to be dry, recrystallizing with ethyl acetate, filtering and drying to obtain an intermediate II;
(3) adding a solvent III into a reaction bottle, adding 0.79-0.87mol of an intermediate II, 1.2-1.7mol of ethyl cyanoacetate and 0.88-1.31 mol of alkali under stirring, heating to 50-110 ℃ after adding, reacting completely, concentrating under reduced pressure to dryness, adding ethyl acetate and water, stirring for dissolving and separating, drying an organic phase, and concentrating under reduced pressure to dryness to obtain an intermediate III;
(4) adding a solvent IV and water into a reaction bottle, adding 0.67-0.82mol of an intermediate III and 0.74-1.64mol of a catalyst under stirring, preserving heat at 80-120 ℃ for reaction, after the reaction is finished, concentrating under reduced pressure to dryness, adding dichloromethane and water, stirring for dissolution and liquid separation, drying an organic phase, concentrating under reduced pressure to dryness, heating to dissolve with ethyl acetate, adding activated carbon for decolorization, filtering under heat, concentrating, cooling for crystallization, filtering, and drying to obtain 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile.
In the step (1), the solvent I is one of toluene and xylene.
In the step (1), the acid is one of p-toluenesulfonic acid and sulfuric acid.
In the step (2), the solvent II is one of dichloromethane, trichloromethane and chlorobenzene.
In the step (2), the organic base is one of triethylamine, N-diisopropylethylamine and N-methylmorpholine.
In the step (3), the solvent III is one of tetrahydrofuran, toluene and N, N-dimethylformamide.
In the step (3), the alkali is one of sodium acetate, sodium carbonate and potassium carbonate.
In the step (4), the solvent IV is one of dimethyl sulfoxide, N-dimethylformamide and N-methylpyrrolidone.
In the step (4), the catalyst is one of lithium chloride, sodium chloride and sodium hydroxide.
The preparation method of the 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile has the advantages that: (1) the steps are short; (2) the three wastes are less; (3) the cost is low and the yield is high; (4) the product quality is good.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
A preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile specifically comprises the following steps:
(1) adding 1000ml of toluene into a reaction bottle, adding 107.5g of 3-oxo-azetidine hydrochloride and 155.1g of ethylene glycol under stirring, adding 25.8g of p-toluenesulfonic acid, keeping the temperature of 110 ℃ for reaction for 12 hours after the addition is finished, cooling to room temperature, adding 208.5g of potassium carbonate, stirring for 6 hours, concentrating under reduced pressure to dryness, stirring and dissolving with 800ml of dichloromethane and 400ml of water, drying with anhydrous sodium sulfate after liquid separation, and concentrating under reduced pressure to dryness to obtain intermediate I, 104.9g of off-white solid and 91.1 percent of yield.
(2) Adding 1000ml of dichloromethane into a reaction bottle, starting stirring, adding 181.8g of triethylamine and 104.9g of intermediate I, cooling to-10-0 ℃ by using an ice salt bath, slowly dropwise adding 177.5g of ethylsulfonyl chloride, reacting for 1 hour after the addition is finished, adding 400ml of water, washing, concentrating an organic phase until the organic phase is dry, recrystallizing by using 300ml of ethyl acetate, filtering and drying to obtain intermediate II, wherein the yield is 95.7 g of white-like powder.
(3) Adding 1500ml of tetrahydrofuran into a reaction bottle, adding 180.7g of intermediate II, 192.1g of ethyl cyanoacetate and 107.4g of sodium acetate under stirring, heating to 50-60 ℃ after the addition is finished, reacting for 24 hours, concentrating under reduced pressure to dryness, adding 800ml of ethyl acetate and 300ml of water, stirring, dissolving, separating, drying an organic phase by anhydrous sodium sulfate, and concentrating under reduced pressure to dryness to obtain intermediate III, 211.8g of light gray solid, wherein the yield is 94.1%.
(4) Adding 800ml of dimethyl sulfoxide and 80ml of water into a reaction bottle, adding 211.8g of intermediate III and 69.5g of lithium chloride under stirring, keeping the temperature at 90-100 ℃ for reaction for 16 hours, concentrating under reduced pressure to dryness after the reaction is finished, adding 800ml of dichloromethane and 300ml of water, stirring, dissolving and separating, drying an organic phase, concentrating under reduced pressure to dryness, heating to dissolve with 600ml of ethyl acetate, and activatingDecolorizing with charcoal, hot filtering, concentrating to 350ml, cooling, crystallizing, filtering, and oven drying to obtain 2- [1- (ethylsulfonyl) -3-azetidine]Acetonitrile, off-white powder 123.8g, yield 81.1%.1H NMR (400 MHz, DMSO- d6) δ 5.89 (d, J=2.4 Hz, 1H), 4.74-4.77 (m, 2H), 4.62-4.66 (m, 2H), 3.13-3.19 (m, 2H), 1.20-1.25 (m, 3H)
Example 2
A preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile specifically comprises the following steps:
(1) adding 700ml of xylene into a reaction bottle, adding 107.5g of 3-oxo-azetidine hydrochloride and 111.6g of ethylene glycol under stirring, adding 17.2g of p-toluenesulfonic acid, keeping the temperature of 120-125 ℃ after the addition for reaction for 12 hours, cooling to room temperature, adding 180.7g of potassium carbonate, stirring for 6 hours, concentrating under reduced pressure to dryness, stirring and dissolving with 800ml of dichloromethane and 400ml of water, separating the liquid, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness to obtain an intermediate I, 103.6g of a white-like solid, wherein the yield is 90.1%.
(2) Adding 700ml of trichloromethane into a reaction bottle, starting stirring, adding 193.8g of N, N-diisopropylethylamine and 103.6g of intermediate I, cooling to 5-10 ℃ in an ice water bath, slowly dropwise adding 147.9g of ethylsulfonyl chloride, reacting for 1 hour after the addition is finished, adding 400ml of water, washing, concentrating an organic phase to dryness, recrystallizing by 300ml of ethyl acetate, filtering and drying to obtain an intermediate II, wherein 174.1g of a white-like solid is obtained, and the yield is 93.2%.
(3) Adding 1100ml of toluene into a reaction bottle, adding 174.1g of intermediate II, 158.2g of ethyl cyanoacetate and 116.6g of sodium carbonate under stirring, heating to 70-80 ℃ after the addition is finished, reacting for 24 hours, concentrating under reduced pressure to dryness, adding 800ml of ethyl acetate and 300ml of water, stirring, dissolving, separating liquid, drying an organic phase by anhydrous sodium sulfate, and concentrating under reduced pressure to dryness to obtain intermediate III, 197.7g of light gray solid and 91.1 percent of yield.
(4) Adding 1100ml of N, N-dimethylformamide and 110ml of water into a reaction bottle, adding 197.7g of an intermediate III and 76.1g of sodium chloride under stirring, keeping the temperature at 110-120 ℃ for reacting for 48 hours, after the reaction is finished, concentrating under reduced pressure to dryness, adding 800ml of dichloromethane and 300ml of water, stirring, dissolving, separating, drying an organic phase, concentrating under reduced pressure to dryness, heating to dissolve with 600ml of ethyl acetate, adding activated carbon for decoloring, filtering under heat, concentrating to about 350ml, cooling, crystallizing, filtering, and drying to obtain 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile, 106.2g of white-like powder and 74.5% of yield.
Example 3
A preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile specifically comprises the following steps:
(1) adding 500ml of xylene into a reaction bottle, adding 107.5g of 3-oxo-azetidine hydrochloride and 74.4g of ethylene glycol under stirring, adding 4.9g of sulfuric acid with the mass concentration of 98%, preserving the temperature at 135-140 ℃ for 6 hours after the addition is finished, cooling to room temperature, adding 152.9g of potassium carbonate, stirring for 6 hours, concentrating under reduced pressure to dryness, stirring and dissolving with 800ml of dichloromethane and 400ml of water, drying with anhydrous sodium sulfate after liquid separation, and concentrating under reduced pressure to dryness to obtain an intermediate I, wherein the yield is 87.8 percent, and the intermediate I is an off-white solid 100.9 g.
(2) Adding 500ml of chlorobenzene into a reaction bottle, starting stirring, adding 121.2g of N-methylmorpholine and 100.9g of intermediate I, controlling the temperature to be 25-30 ℃, slowly dropwise adding 123.5g of ethylsulfonyl chloride, reacting for 1 hour after the addition is finished, adding 400ml of water, washing, concentrating an organic phase to be dry, recrystallizing with 300ml of ethyl acetate, filtering and drying to obtain intermediate II, 165.1g of a white-like solid, and the yield is 90.7%.
(3) Adding 800ml of N, N-dimethylformamide into a reaction bottle, adding 165.1g of an intermediate II, 135.6g of ethyl cyanoacetate and 122.3g of potassium carbonate under stirring, heating to 100-110 ℃ after the addition is finished, reacting for 16 hours, concentrating under reduced pressure to dryness, adding 800ml of ethyl acetate and 300ml of water, stirring, dissolving, separating, drying an organic phase by anhydrous sodium sulfate, and concentrating under reduced pressure to dryness to obtain an intermediate III, 175.7g of a light gray solid, wherein the yield is 85.4%.
(4) Adding 1500ml of N-methyl pyrrolidone and 150ml of water into a reaction bottle, adding 175.7g of an intermediate III and 29.6g of sodium hydroxide under stirring, preserving heat at 80-90 ℃ for reaction for 12 hours, after the reaction is finished, concentrating under reduced pressure to dryness, adding 800ml of dichloromethane and 300ml of water, stirring for dissolution and liquid separation, drying an organic phase, concentrating under reduced pressure to dryness, heating to dissolve with 600ml of ethyl acetate, adding activated carbon for decolorization, filtering under heat and concentrating to about 350ml, cooling for crystallization, filtering, and drying to obtain 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile, 85.9g of white-like powder and 67.8% of yield.
Claims (9)
1. A preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile is characterized in that: the method specifically comprises the following steps:
adding a solvent I into a reaction bottle, adding 1.0mol of 3-oxo-azetidine hydrochloride and 1.2-2.5mol of ethylene glycol under stirring, adding 0.05-0.15mol of acid, keeping the temperature at 110-140 ℃ after the addition is finished, reacting completely, cooling to room temperature, adding 1.1-1.5mol of potassium carbonate, reacting completely after the addition is finished, concentrating under reduced pressure to dryness, stirring and dissolving with dichloromethane and water, separating, drying, and concentrating under reduced pressure to dryness to obtain an intermediate I;
adding a solvent II into a reaction bottle, adding 1.2-1.8mol of organic base and 0.87-0.92mol of the prepared intermediate I under stirring, keeping the temperature at minus 10-30 ℃, dropwise adding 0.96-1.38mol of ethylsulfonyl chloride, reacting completely after the addition is finished, washing with water, concentrating an organic phase to be dry, recrystallizing with ethyl acetate, filtering and drying to obtain an intermediate II;
adding a solvent III into a reaction bottle, adding 0.79-0.87mol of an intermediate II, 1.2-1.7mol of ethyl cyanoacetate and 0.88-1.31 mol of alkali under stirring, heating to 50-110 ℃ after adding, reacting completely, concentrating under reduced pressure to dryness, adding ethyl acetate and water, stirring for dissolving and separating, drying an organic phase, and concentrating under reduced pressure to dryness to obtain an intermediate III;
adding a solvent IV and water into a reaction bottle, adding 0.67-0.82mol of an intermediate III and 0.74-1.64mol of a catalyst under stirring, preserving heat at 80-120 ℃ for reaction, after the reaction is finished, concentrating under reduced pressure to dryness, adding dichloromethane and water, stirring for dissolution and liquid separation, drying an organic phase, concentrating under reduced pressure to dryness, heating to dissolve with ethyl acetate, adding activated carbon for decolorization, filtering under heat, concentrating, cooling for crystallization, filtering, and drying to obtain 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile.
2. The process for the preparation of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile according to claim 1 characterized in that: in the step (1), the solvent I is one of toluene and xylene.
3. The process for the preparation of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile according to claim 1 characterized in that: in the step (1), the acid is one of p-toluenesulfonic acid and sulfuric acid.
4. The process for the preparation of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile according to claim 1 characterized in that: in the step (2), the solvent II is one of dichloromethane, trichloromethane and chlorobenzene.
5. The process for the preparation of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile according to claim 1 characterized in that: in the step (2), the organic base is one of triethylamine, N-diisopropylethylamine and N-methylmorpholine.
6. The process for the preparation of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile according to claim 1 characterized in that: in the step (3), the solvent III is one of tetrahydrofuran, toluene and N, N-dimethylformamide.
7. The process for the preparation of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile according to claim 1 characterized in that: in the step (3), the alkali is one of sodium acetate, sodium carbonate and potassium carbonate.
8. The process for the preparation of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile according to claim 1 characterized in that: in the step (4), the solvent IV is one of dimethyl sulfoxide, N-dimethylformamide and N-methylpyrrolidone.
9. The process for the preparation of 2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile according to claim 1 characterized in that: in the step (4), the catalyst is one of lithium chloride, sodium chloride and sodium hydroxide.
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