CN114560853A - Preparation method of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide - Google Patents
Preparation method of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide Download PDFInfo
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- CN114560853A CN114560853A CN202210189489.6A CN202210189489A CN114560853A CN 114560853 A CN114560853 A CN 114560853A CN 202210189489 A CN202210189489 A CN 202210189489A CN 114560853 A CN114560853 A CN 114560853A
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- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- PXXMSHBZYAOHBD-UHFFFAOYSA-N 3,3-diethoxypropan-1-amine Chemical compound CCOC(CCN)OCC PXXMSHBZYAOHBD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 238000001035 drying Methods 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000012074 organic phase Substances 0.000 claims description 20
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 229960001701 chloroform Drugs 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 7
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 230000003472 neutralizing effect Effects 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 4
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 238000006735 epoxidation reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000005805 hydroxylation reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 4
- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- KQEBGRLRYABJRL-DFWYDOINSA-N (2s)-3-aminopropane-1,2-diol;hydrochloride Chemical compound Cl.NC[C@H](O)CO KQEBGRLRYABJRL-DFWYDOINSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004042 decolorization Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 2
- 229960001148 rivaroxaban Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide, which specifically comprises the steps of taking 1-amino-3, 3-diethoxypropane as a raw material, and efficiently synthesizing 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide through three steps of isonitrification, C-hydroxylation and epoxidation.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide.
Background
5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-carboxamide is an important intermediate for the oral factor Xa inhibitor rivaroxaban (Rivaroxaban).
The main synthetic route for 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-carboxamide is now as follows:
the method comprises the following steps:
in the method disclosed in US2010/184767, 2-chlorothiophene-5-carboxylic acid is used as a starting material, and the target product is obtained through acyl chlorination, amidation, bromination and epoxidation. The raw material 2-chlorothiophene-5-formic acid used in the method needs to be synthesized by firstly acetylating and then oxidizing 2-chlorothiophene, so that the pollution is large; the preparation process is complicated to operate, and the (S) -3-amino-1, 2-propylene glycol hydrochloride in the raw material is high in price and high in overall cost.
The method 2 comprises the following steps:
in the method disclosed in EP2354128, 2-chlorothiophene-5-formic acid is used as a raw material, and a target product is obtained through acyl chlorination, amidation, sulfonic acid esterification and epoxidation. The method also needs the (S) -3-amino-1, 2-propanediol hydrochloride with higher price, and the steps of the sulfoacid esterification and the epoxidation have larger pollution and more three wastes.
Disclosure of Invention
The invention aims at the problems and discloses a preparation method of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide, which particularly takes 1-amino-3, 3-diethoxypropane as a raw material to efficiently synthesize the 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide through three steps of isonitrification, C-hydroxylation and epoxidation.
The reaction equation is as follows:
the technical scheme for solving the technical problems is as follows: a method for preparing 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide comprises the following steps:
(1) adding a solvent I into a reaction bottle, adding 1.0mol of 1-amino-3, 3-diethoxypropane and 1.1-2.1mol of alkali under stirring, adding 0.7-1.3mol of an isonitrification reagent in batches under the condition of keeping the temperature of 0-40 ℃, adding water after the reaction is completed, stirring, standing for liquid separation, drying an organic phase, and concentrating under reduced pressure to be dry to obtain an intermediate I;
(2) adding a solvent II into a reaction bottle, and adding 1.0-1.2mol of 2-chlorothiophene and 1.0-1.3mol of organic base II under stirring; firstly, 0.94-0.96mol of intermediate I is dissolved in a solvent II to form a mixed solution, then the mixed solution is dripped into a reaction bottle, the temperature of a reaction system is kept at 10-50 ℃, and the reaction is completed after the addition; adding water, stirring, separating, drying the organic phase, concentrating to dryness, decoloring and crystallizing with toluene, filtering and drying to obtain an intermediate II;
(3) adding 0.85-0.88mol of the intermediate II into tetrahydrofuran and water, stirring, adding 5ml of hydrochloric acid, stirring for 6 hours at 20-30 ℃ after the addition is finished, and concentrating under reduced pressure until the intermediate II is dried; dissolving by adding a solvent III, starting stirring, adding 0.1-0.3mol of L-prolinamide and 0.9-1.2mol of N-chlorosuccinimide under the condition of controlling the temperature to be 0-30 ℃, and reacting completely after the addition is finished; adding water, stirring and separating liquid, drying an organic phase, concentrating to dryness, adding ethanol, adding 1.1mol of sodium borohydride at 0-10 ℃, stirring and reacting completely after the addition, dropwise adding alkali liquor to alkalize until the pH is =12, reacting completely at 40-50 ℃, neutralizing with acetic acid until the pH is =7, concentrating to dryness under reduced pressure, adding dichloromethane and water, stirring and separating liquid, drying the organic phase, concentrating to dryness, decoloring and crystallizing with ethyl acetate, concentrating a filtrate until a large amount of precipitate is obtained, cooling and crystallizing, filtering and drying to obtain the 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide.
In the step (1), the solvent I is one of dichloromethane, trichloromethane and chlorobenzene.
In the step (1), the base I is one of triethylamine, N-diisopropylethylamine and N-methylmorpholine.
The isonitrification reagent in the step (1) is one of diphosgene and triphosgene.
In the step (2), the solvent II is one of dichloromethane, dichloroethane and trichloromethane.
In the step (2), the organic base II is one of triethylamine, N-diisopropylethylamine and N-methylmorpholine.
In the step (3), the solvent III is one of dichloromethane, dichloroethane and chloroform.
And (4) the alkali liquor in the step (3) is one of a sodium hydroxide solution and a potassium hydroxide solution.
The preparation method of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide 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 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide specifically comprises the following steps:
(1) adding 800ml of dichloromethane into a reaction bottle, adding 147.2g of 1-amino-3, 3-diethoxypropane and 111.1g of triethylamine under stirring, adding 197.8g of diphosgene in batches under the condition of keeping the temperature of 0-10 ℃, reacting for 8 hours after the addition is finished, adding 400ml of water, stirring for 12 hours, standing for liquid separation, drying an organic phase, and concentrating under reduced pressure to be dry to obtain an intermediate I, 165.6g of a white-like solid, wherein the yield is 95.3%.
(2) Adding 700ml of dichloromethane into a reaction bottle, and adding 118.6g of 2-chlorothiophene and 101.1g of triethylamine under stirring; dissolving 165.6g of the intermediate I in 500ml of dichloromethane to form a mixed solution, dropwise adding the mixed solution into a reaction bottle, keeping the temperature of a reaction system at 10-20 ℃ during the period, and reacting for 36 hours after the addition is finished; 300ml of water is added, liquid separation is carried out by stirring, the organic phase is dried by anhydrous sodium sulfate and then concentrated to dryness, 400ml of toluene is used for decolorization and crystallization, and the intermediate II is obtained by filtering and drying, wherein 255.9g of yellowish solid is obtained, and the yield is 91.7%.
(3) Adding 255.9g of intermediate II into 1100ml of tetrahydrofuran and 110ml of water, stirring, adding 5ml of hydrochloric acid, stirring for 6 hours at 20-30 ℃ after the addition is finished, and concentrating under reduced pressure until the mixture is dry; adding 900ml of dichloromethane for dissolution, starting stirring, adding 11.5g of L-prolinamide and 120.2g of N-chlorosuccinimide under the condition of controlling the temperature to be 0-10 ℃, and reacting for 24 hours after the addition is finished; adding 400ml of water, stirring and separating, drying an organic phase, concentrating to be dry, adding 600ml of ethanol, adding 41.8g of sodium borohydride at 0-10 ℃, stirring and reacting for 12 hours after adding, dropwise adding a sodium hydroxide solution to alkalize to pH =12, reacting for 6 hours at 40-50 ℃, neutralizing to pH =7 with acetic acid, concentrating to be dry under reduced pressure, adding 900ml of dichloromethane and 200ml of water, stirring and separating, drying the organic phase, concentrating to be dry, decoloring and filtering with 400ml of ethyl acetate, concentrating a filtrate to be largely precipitated, cooling to crystallize, filtering and drying to obtain a product, wherein 157.9g of a white-like solid, the yield is 82.7%, and EE = 98.7%.1H-NMR (400 MHz, DMSO-d6) δ: 8.84 (t, 1H), 7.69 (d, 1H), 7.20 (d, 1H), 3.52-3.44 (m, 1H), 3.30-3.25(m, 1H), 3.11-3.07 (m, 1H), 2.78-2.75 (m, 1H), 2.59-2.57 (m, 1H).
Example 2
A preparation method of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide specifically comprises the following steps:
(1) adding 1000ml of trichloromethane into a reaction bottle, adding 147.2g of 1-amino-3, 3-diethoxypropane and 206.7g of N, N-diisopropylethylamine under stirring, adding 207.8g of triphosgene in batches under the condition of keeping the temperature of 10-20 ℃, reacting for 14 hours after the addition is finished, adding 400ml of water, stirring for 12 hours, standing for liquid separation, drying an organic phase, and concentrating under reduced pressure to dryness to obtain an intermediate I, wherein the yield is 94.1 percent, and the intermediate I is similar to white solid 162.9 g.
(2) Adding 900ml of dichloroethane into a reaction bottle, and adding 130.5g of 2-chlorothiophene and 155.1g of N, N-diisopropylethylamine while stirring; dissolving 162.9g of the intermediate I in 500ml of dichloroethane to form a mixed solution, dropwise adding the mixed solution into a reaction bottle, keeping the temperature of a reaction system at 20-30 ℃ during the period, and reacting for 28 hours after the addition is finished; 300ml of water is added, liquid separation is carried out by stirring, the organic phase is dried by anhydrous sodium sulfate and then concentrated to dryness, 400ml of toluene is used for decolorization and crystallization, and the intermediate II is obtained by filtering and drying, and is 248.4g of yellowish solid with the yield of 90.5%.
(3) Adding 248.4g of the intermediate II into 1100ml of tetrahydrofuran and 110ml of water, stirring, adding 5ml of hydrochloric acid, stirring for 6 hours at 20-30 ℃, and concentrating under reduced pressure until the intermediate is dried; adding 1100ml of dichloroethane for dissolving, starting stirring, adding 22.8g of L-prolinamide and 140.2g of N-chlorosuccinimide under the condition of controlling the temperature to be 10-20 ℃, and reacting for 20 hours after the addition is finished; adding 400ml of water, stirring and separating, drying an organic phase, concentrating to be dry, adding 700ml of ethanol, adding 41.8g of sodium borohydride at 0-10 ℃, stirring and reacting for 12 hours after the addition is finished, dropwise adding a potassium hydroxide solution to alkalize to pH =12, reacting for 6 hours at 40-50 ℃, neutralizing to pH =7 with acetic acid, concentrating to be dry under reduced pressure, adding 900ml of dichloromethane and 200ml of water, stirring and separating, drying the organic phase, concentrating to be dry, decoloring and filtering with 400ml of ethyl acetate, concentrating a filtrate to be largely precipitated, cooling to crystallize, filtering and drying to obtain a product, wherein the product is 154.6g of off-white solid, the yield is 83.4%, and the EE is precipitated into 98.9%.
Example 3
A preparation method of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide specifically comprises the following steps:
(1) 1400ml of chlorobenzene is added into a reaction bottle, 147.2g of 1-amino-3, 3-diethoxypropane and 212.1g of N-methylmorpholine are added under the condition of stirring, 385.7g of triphosgene is added in batches under the condition of keeping the temperature of 30-40 ℃, the reaction is carried out for 10 hours after the addition, 600ml of water is added, the mixture is stirred for 12 hours, then the mixture is kept stand and separated, an organic phase is dried and then is concentrated under reduced pressure to be dry, and an intermediate I, a white-like solid 165.4g is obtained, and the yield is 95.5%.
(2) 1200ml of trichloromethane is added into a reaction bottle, and 142.3g of 2-chlorothiophene and 131.3g of N-methylmorpholine are added under stirring; dissolving 165.4g of the intermediate I in 500ml of trichloromethane to form a mixed solution, dropwise adding the mixed solution into a reaction bottle, keeping the temperature of a reaction system at 40-50 ℃, reacting for 22 hours after the addition, adding 300ml of water, stirring, separating, drying an organic phase with anhydrous sodium sulfate, concentrating to be dry, decoloring and crystallizing with 400ml of toluene, filtering and drying to obtain 255.8g of a yellowish solid, wherein the yield is 91.8%.
(3) Adding 255.8g of intermediate II into 1100ml of tetrahydrofuran and 110ml of water, stirring, adding 5ml of hydrochloric acid, stirring for 6 hours at 20-30 ℃ after the addition is finished, and concentrating under reduced pressure until the mixture is dry; adding 1300ml of trichloromethane for dissolving, starting stirring, adding 34.35g of L-prolinamide and 160.2g of N-chlorosuccinimide under the condition of controlling the temperature to be 20-30 ℃, and reacting for 14 hours after the addition is finished; adding 400ml of water, stirring and separating, drying an organic phase, concentrating to be dry, adding 800ml of ethanol, adding 41.8g of sodium borohydride at 0-10 ℃, stirring and reacting for 12 hours after the addition is finished, dropwise adding a potassium hydroxide solution, alkalifying to pH =12, reacting for 6 hours at 40-50 ℃, neutralizing to pH =7 with acetic acid, concentrating to be dry under reduced pressure, adding 900ml of dichloromethane and 200ml of water, stirring and separating, drying the organic phase, concentrating to be dry, decoloring and filtering with 400ml of ethyl acetate, concentrating a filtrate until a large amount of filtrate is separated out, cooling and crystallizing, filtering and drying to obtain a product, 159.9g of white-like solid, 83.8% of yield and 99.1% of EE.
Claims (8)
1. A method for preparing 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide, which is characterized by comprising the following steps: the method specifically comprises the following steps:
(1) adding a solvent I into a reaction bottle, adding 1.0mol of 1-amino-3, 3-diethoxypropane and 1.1-2.1mol of alkali under stirring, adding 0.7-1.3mol of an isonitrification reagent in batches under the condition of keeping the temperature of 0-40 ℃, adding water after the reaction is completed, stirring, standing for liquid separation, drying an organic phase, and concentrating under reduced pressure to be dry to obtain an intermediate I;
(2) adding a solvent II into a reaction bottle, and adding 1.0-1.2mol of 2-chlorothiophene and 1.0-1.3mol of organic base II under stirring; firstly, 0.94-0.96mol of intermediate I is dissolved in a solvent II to form a mixed solution, then the mixed solution is dripped into a reaction bottle, the temperature of a reaction system is kept at 10-50 ℃, and the reaction is completed after the addition; adding water, stirring, separating, drying the organic phase, concentrating to dryness, decoloring and crystallizing with toluene, filtering and drying to obtain an intermediate II;
(3) adding 0.85-0.88mol of the intermediate II into tetrahydrofuran and water, stirring, adding 5ml of hydrochloric acid, stirring for 6 hours at 20-30 ℃ after the addition is finished, and concentrating under reduced pressure until the intermediate II is dried; dissolving by adding a solvent III, starting stirring, adding 0.1-0.3mol of L-prolinamide and 0.9-1.2mol of N-chlorosuccinimide under the condition of controlling the temperature to be 0-30 ℃, and reacting completely after the addition is finished; adding water, stirring and separating liquid, drying an organic phase, concentrating to dryness, adding ethanol, adding 1.1mol of sodium borohydride at 0-10 ℃, stirring and reacting completely after the addition, dropwise adding alkali liquor to alkalize until the pH is =12, reacting completely at 40-50 ℃, neutralizing with acetic acid until the pH is =7, concentrating to dryness under reduced pressure, adding dichloromethane and water, stirring and separating liquid, drying the organic phase, concentrating to dryness, decoloring and crystallizing with ethyl acetate, concentrating a filtrate until a large amount of precipitate is obtained, cooling and crystallizing, filtering and drying to obtain the 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide.
2. The process for the preparation of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-carboxamide according to claim 1, characterized in that: in the step (1), the solvent I is one of dichloromethane, trichloromethane and chlorobenzene.
3. The process for the preparation of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-carboxamide according to claim 1, characterized in that: in the step (1), the base I is one of triethylamine, N-diisopropylethylamine and N-methylmorpholine.
4. The process for the preparation of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-carboxamide according to claim 1, characterized in that: the isonitrification reagent in the step (1) is one of diphosgene and triphosgene.
5. The process for the preparation of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-carboxamide according to claim 1, characterized in that: in the step (2), the solvent II is one of dichloromethane, dichloroethane and trichloromethane.
6. The process for the preparation of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-carboxamide according to claim 1, characterized in that: in the step (2), the organic base II is one of triethylamine, N-diisopropylethylamine and N-methylmorpholine.
7. The process for the preparation of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-carboxamide according to claim 1, characterized in that: in the step (3), the solvent III is one of dichloromethane, dichloroethane and chloroform.
8. The process for the preparation of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-carboxamide according to claim 1, characterized in that: and (4) the alkali liquor in the step (3) is one of a sodium hydroxide solution and a potassium hydroxide solution.
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