CN102690223A - Preparation method for 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline - Google Patents
Preparation method for 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline Download PDFInfo
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- CN102690223A CN102690223A CN201210168752XA CN201210168752A CN102690223A CN 102690223 A CN102690223 A CN 102690223A CN 201210168752X A CN201210168752X A CN 201210168752XA CN 201210168752 A CN201210168752 A CN 201210168752A CN 102690223 A CN102690223 A CN 102690223A
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- acetyl
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- aminopropyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 10
- 150000001343 alkyl silanes Chemical class 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 39
- MCRFLQWSKTXBBS-UHFFFAOYSA-N 1-acetyl-5-(2-aminopropyl)-2,3-dihydroindole-7-carbonitrile Chemical compound N#CC1=CC(CC(N)C)=CC2=C1N(C(C)=O)CC2 MCRFLQWSKTXBBS-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical group CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 10
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical group N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 8
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 8
- 239000012954 diazonium Substances 0.000 claims description 8
- 150000001989 diazonium salts Chemical class 0.000 claims description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 229910017604 nitric acid Inorganic materials 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 235000010288 sodium nitrite Nutrition 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 claims description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 238000006396 nitration reaction Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 9
- PNCPYILNMDWPEY-QGZVFWFLSA-N silodosin Chemical compound N([C@@H](CC=1C=C(C=2N(CCCO)CCC=2C=1)C(N)=O)C)CCOC1=CC=CC=C1OCC(F)(F)F PNCPYILNMDWPEY-QGZVFWFLSA-N 0.000 abstract description 5
- 229960004953 silodosin Drugs 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- RNTCWULFNYNFGI-UHFFFAOYSA-N 1-(2,3-dihydroindol-1-yl)ethanone Chemical compound C1=CC=C2N(C(=O)C)CCC2=C1 RNTCWULFNYNFGI-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 abstract 1
- 238000005576 amination reaction Methods 0.000 abstract 1
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000005457 ice water Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- -1 compound (2)) Chemical compound 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000012267 brine Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- JEQDSBVHLKBEIZ-REOHCLBHSA-N (2s)-2-chloropropanoyl chloride Chemical compound C[C@H](Cl)C(Cl)=O JEQDSBVHLKBEIZ-REOHCLBHSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- MBXLGUFPIKCQTJ-UHFFFAOYSA-N 1,3,3-tribromopyrrolidin-2-one Chemical compound BrN1CCC(Br)(Br)C1=O MBXLGUFPIKCQTJ-UHFFFAOYSA-N 0.000 description 1
- JSMBGMRSUWECSH-UHFFFAOYSA-N 1-(1-acetyl-2,3-dihydroindol-5-yl)-2-chloropropan-1-one Chemical compound CC(Cl)C(=O)C1=CC=C2N(C(C)=O)CCC2=C1 JSMBGMRSUWECSH-UHFFFAOYSA-N 0.000 description 1
- UATXAXFBTKYPHT-UHFFFAOYSA-N C(C)(=O)N1CCC2=CC(=CC(=C12)C#N)CC(C)N1C(C=2C(C1=O)=CC=CC2)=O Chemical compound C(C)(=O)N1CCC2=CC(=CC(=C12)C#N)CC(C)N1C(C=2C(C1=O)=CC=CC2)=O UATXAXFBTKYPHT-UHFFFAOYSA-N 0.000 description 1
- CKZUHZPHILVPKU-UHFFFAOYSA-N C(C)(=O)N1CCC2=CC(=CC=C12)CC(C)N1C(C=2C(C1=O)=CC=CC2)=O Chemical compound C(C)(=O)N1CCC2=CC(=CC=C12)CC(C)N1C(C=2C(C1=O)=CC=CC2)=O CKZUHZPHILVPKU-UHFFFAOYSA-N 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
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- 238000004440 column chromatography Methods 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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- Indole Compounds (AREA)
Abstract
The invention provides a preparation method for synthesizing 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline which is a key intermediate of silodosin. The method comprises the following steps: 1-acetylindoline is adopted to serve as the material, and 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline can be obtained through the such 7 steps as friedel-crafts acylation reaction, phthalimide amination, alkylsilane reduction, nitrification, reduction, heavy nitrogen cyaniding and deprotection. According to the method, the materials in the whole synthesizing line are cost-saving and easy to obtain, the operation is simple and the operation cost is low. Moreover, the yield rate of each step of reaction is higher than that in the prior art. Therefore, the method provided by the invention is very suitable for industrial production and has larger industrial application value.
Description
Technical Field
The invention relates to a preparation method of 1-acetyl-7-cyano-5- (2-aminopropyl) indoline, wherein the 1-acetyl-7-cyano-5- (2-aminopropyl) indoline is a key intermediate for synthesizing silodosin (silodosin) for treating prostatic hyperplasia.
Background
Silodosin is a1 adrenoceptor antagonist, has selective inhibitory effect on urethral smooth muscle contraction, can reduce intraurethral pressure, has no significant effect on blood pressure, and is useful for treating benign prostatic hyperplasia.
1-acetyl-7-cyano-5- (2-aminopropyl) indoline (i.e. compound (1)) is a key intermediate for the synthesis of silodosin. According to the literature reports, the prior art has two main synthetic routes for preparing 1-acetyl-7-cyano-5- (2-aminopropyl) indoline (1):
the first synthetic route is described in the european patent application with publication number EP0600675a 1:
the main drawbacks of this route are three: a. expensive tribromopyrrolidone is used during bromination; b. expensive catalyst platinum oxide is used in the two-step hydrogenation reduction reaction; c. the yield of the step of cyanidation is low, and column chromatography is used for separation and purification. Therefore, the implementation cost of the route is high, and the industrial production is not easy.
The second synthetic route is described in chinese patent application publication No. CN 101759627A:
the main disadvantages of this route are the poor selectivity of the bromination step, the low yield and the difficult purification. And the patent application text does not disclose specific process conditions, and only introduces a general introduction to the whole process flow, so the industrial value of the route is not high.
Disclosure of Invention
The invention aims to provide a preparation method of 1-acetyl-7-cyano-5- (2-aminopropyl) indoline, which is easy to purify, high in yield and low in implementation cost.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of 1-acetyl-7-cyano-5- (2-aminopropyl) indoline sequentially comprises the following 7 steps:
wherein,
(1) in the step a, Lewis acid is used as a catalyst, and X is halogen Cl, Br or I;
(2) in the step d, carrying out nitration reaction on the compound (5) and concentrated nitric acid in acid to prepare a compound (6);
(3) in the step f, the compound (7) is subjected to diazo reaction under the action of acid and sodium nitrite to generate diazonium salt, and then the diazonium salt reacts with a cyanating agent to prepare a compound (8);
further, in the step a: x is Cl; the reaction temperature is 0-120 ℃, and the reaction time is 3-10 hours; the solvent is selected from dichloromethane, chloroform, carbon tetrachloride or dichloroethane, preferably dichloroethane; the Lewis acid is anhydrous zinc chloride or aluminum trichloride, and preferably anhydrous zinc chloride; the molar ratio of the compound (2) to the 2-halogenopropionyl halide to the Lewis acid is 1 (1-1.5) to 2-5.
Further, in the step b: the reaction temperature is 50-150 ℃; the solvent is selected from DMF, DMSO, acetone or tetrahydrofuran, preferably DMF; the molar ratio of the compound (3) to the phthalimide potassium salt is 1 (1-2).
Further, in the step c: the alkylsilane is triethylsilane (Et)3SiH); the reaction temperature is 0-100 ℃, and the reaction time is 3-24 hours; the compound (4) is triethylsilane and trifluoroacetic acid in a molar ratio of 1 (1-5) to 5-100.
Further, in the step d: the reaction temperature is 0-50 ℃, and the reaction time is 8-12 hours; the concentration of the concentrated nitric acid is more than 50 percent; the solvent is concentrated sulfuric acid or acetic acid, preferably acetic acid.
Further, in the step e: the reaction temperature is 0-80 ℃, and the reaction time is 5-12 hours; the reducing agent is iron powder; the solvent is selected from methanol, ethanol, glacial acetic acid aqueous solution or ammonium chloride aqueous solution; the molar ratio of the compound (6) to the iron powder is 1 (2.5-4).
Further, in step f: the reaction temperature is-5 to 50 ℃, and the reaction time is 5 to 12 hours; the acid is selected from sulfuric acid, hydrochloric acid or fluoroboric acid, preferably hydrochloric acid; the cyanating agent is selected from sodium cyanide, cuprous cyanide or a complex salt of sodium cyanide and cuprous cyanide, preferably sodium cyanide and cuprous cyanide.
Further, in the step g: the reaction temperature is 20-80 ℃, and the reaction time is 3-12 hours; the molar ratio of the compound (8) to the hydrazine hydrate is 1 (1-3).
The preparation method of 1-acetyl-7-cyano-5- (2-aminopropyl) indoline implemented according to the invention has the following advantages:
(1) the required raw materials and auxiliary materials are simple and cheap chemical raw materials sold in the market, and the purchase cost is low.
(2) The method overcomes the defects of low yield and difficult purification in the prior art, has high reaction yield, simple and convenient operation and low implementation cost, is favorable for realizing industrial production, and has extremely strong industrial application value.
Detailed Description
The following will describe embodiments of the present invention in detail with reference to examples. Embodiments of the present invention include, but are not limited to, the following examples, which should not be construed as limiting the scope of the invention.
The preparation of 1-acetyl-7-cyano-5- (2-aminopropyl) indoline according to the invention comprises the following 7 steps in sequence:
a: preparation of 1-acetyl-5- (2-chloropropionyl) indoline, compound (3):
example one: into a flask were charged 32.2g of 1-acetylindoline (i.e., compound (2)), 94.5g of anhydrous aluminum trichloride and 160ml of dichloroethane, and then 33g of 2-chloropropionyl chloride was added dropwise with stirring at room temperature.
After the completion of the dropwise addition, the reaction was allowed to proceed for 8 hours under heat preservation, and then the reaction mixture was poured into ice water and stirred for 30 minutes.
The aqueous layer was extracted with dichloroethane, the organic phases were combined, washed with water, then with saturated brine, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and ethanol was added to the residue to conduct recrystallization to obtain 40.3g of compound (3) in a yield of 80%.
Example two: into a flask were charged 32.2g of 1-acetylindoline (i.e., compound (2)), 100g of anhydrous zinc chloride and 160ml of methylene chloride, and then stirred at room temperature, 33g of 2-chloropropionyl chloride was added dropwise.
After the completion of the dropwise addition, the reaction was carried out at 50 ℃ for 10 hours, and then the mixture obtained by the reaction was poured into ice water and stirred for 30 minutes.
The aqueous layer was extracted with dichloromethane, the organic phases were combined, washed with water, then with saturated brine, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and ethanol was added to the residue to conduct recrystallization to obtain 38g of compound (3) in 78% yield.
b: preparation of 1-acetyl-5- (2-phthalimidopropionyl), compound (4):
50g of the compound (3), 48g of phthalimide potassium salt and DMF400ml were put into a flask, stirred and heated to 80 to 100 ℃ to react for 12 hours.
After the reaction was completed, the resulting mixture was poured into 1000g of ice water, extracted with ethyl acetate, the aqueous layer was extracted once with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate for dehydration, and concentrated by suction filtration to obtain 69g of compound (4) with a yield of 95%.
c: preparation of 1-acetyl-5- (2-phthalimidopropyl) indoline, compound (5):
into a reaction flask were charged 36.2g of compound (4) and 180ml of trifluoroacetic acid.
Triethylsilane was added dropwise with stirring at room temperature and reacted for 10 hours, then the resulting mixture was added to ice water and stirred for 30 minutes, extracted with ethyl acetate, the aqueous layer was extracted once with ethyl acetate, the organic phases were combined, washed with water, once with sodium carbonate solution and brine, and dried with anhydrous sodium sulfate, and the concentrated residue was filtered and recrystallized with anhydrous ethanol to obtain 29.6g of compound (5) with a yield of 85%.
d: preparation of 1-acetyl-7-nitro-5- (2-phthalimidopropyl) indoline, compound (6):
example one: into a flask, 35g of the compound (5) and 210ml of glacial acetic acid were placed, and 40ml of concentrated nitric acid was added dropwise with stirring at room temperature, followed by reaction with stirring for 10 hours.
After the reaction, the obtained mixture was poured into 500g of ice water to precipitate a solid, which was then filtered, washed with water and dried to obtain 37.4g of the compound (6) in a yield of 95%.
Example two: in a flask, 35g of the compound (5) and 105ml of concentrated sulfuric acid were charged, ice water was cooled to 5 ℃,40 ml of concentrated nitric acid was added dropwise with stirring, and after completion of the dropwise addition, the mixture was reacted at room temperature with stirring for 8 hours.
After the reaction, the obtained mixture was poured into 400g of ice water to precipitate a solid, which was then filtered, washed with water to neutrality, and dried to obtain 36g of the compound (6) with a yield of 93%.
e: preparation of 1-acetyl-7-amino-5- (2-phthalimidopropyl) indoline, compound (7):
example one: 240ml of an 80% ethanol solution and 20g of iron powder were put into a flask, and stirred and heated, 4ml of concentrated hydrochloric acid was added dropwise thereto, the internal temperature was raised to 60 ℃ and 39.3g of the compound (6) was added in portions.
Heating and refluxing for 8 hours, after the reaction is finished, adjusting the pH value to be neutral by using sodium carbonate, carrying out hot filtration, carrying out reduced pressure concentration on the filtrate to obtain a residue, and recrystallizing the residue with anhydrous ethyl acetate to obtain 32.7g of the compound (7) with the yield of 90%.
Example two: a flask was charged with 240ml of a saturated ammonium chloride solution and 20g of iron powder, and then the mixture was heated with stirring to an internal temperature of 60 ℃ and 39.3g of compound (6) was added in portions.
After the reaction was completed, the reaction was thermally filtered, and the filtrate was cooled to precipitate a solid, whereby 32.7g of the compound (7) was obtained in 88% yield.
f: preparation of 1-acetyl-7-cyano-5- (2-phthalimidopropyl) indoline, compound (8):
example one: 36.3g of the compound (7) and 108ml of concentrated hydrochloric acid were put into a flask, and stirred and dissolved for 30 minutes, 108ml of ice water was further added, and the mixture was cooled to an internal temperature of-5 ℃ with ice brine, and then 8.3g of an aqueous solution of sodium nitrite was added dropwise thereto over 20 minutes. And (3) preserving the temperature for reaction for 30 minutes, adding sodium bicarbonate solid to adjust the pH value to be neutral to obtain a diazonium salt solution, and preserving the temperature for later use.
In another flask, 19g of sodium cyanide and 20ml of water were charged, stirred and cooled with ice water, and then 12g of cuprous cyanide was added in portions. After the dissolution is finished, controlling the internal temperature at 0 ℃, and dropwise adding the prepared diazonium salt solution.
After the dropwise addition, the temperature was raised to room temperature, and the reaction was carried out for 8 hours.
After the reaction, dichloromethane was added for extraction, and the dichloromethane phase was washed with aqueous ammonia, water, and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated, and the residue was recrystallized from anhydrous ethanol to obtain 28g of compound (8) in a yield of 75%.
Example two: 36.3g of the compound (7) and 75ml of 80% sulfuric acid were put into a flask, and the mixture was dissolved by stirring for 30 minutes, then 75ml of ice water was added thereto, and the mixture was cooled to an internal temperature of-5 ℃ with ice brine, and then 8.3g of an aqueous solution of sodium nitrite was added dropwise thereto over 20 minutes. And (3) preserving the temperature for reaction for 30 minutes, adding sodium bicarbonate solid to adjust the pH value to be neutral to obtain a diazonium salt solution, and preserving the temperature for later use.
In another flask, 19g of sodium cyanide and 20ml of water were charged, stirred and cooled with ice water, and then 12g of cuprous cyanide was added in portions. After the dissolution is finished, controlling the internal temperature at 0 ℃, and dropwise adding the prepared diazonium salt solution.
After the dropwise addition, the temperature was raised to room temperature, and the reaction was carried out for 8 hours.
After the reaction, dichloromethane was added for extraction, and the dichloromethane phase was washed with aqueous ammonia, water, and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated, and the residue was recrystallized from anhydrous ethanol to give 26g of compound (8) in 70% yield.
g: preparation of 1-acetyl-7-cyano-5- (2-aminopropyl) indoline, compound (1):
37.3g of the compound (8), 300ml of ethanol and 15g of 80% hydrazine hydrate were put into a flask, and the mixture was refluxed at elevated temperature for 5 hours.
Cooling, filtering, concentrating the filtrate, drying, adding 80ml of absolute ethanol into the obtained residue, and separating out part of solid. Filtering, concentrating the filtrate to constant weight, standing and solidifying to obtain the target product 1-acetyl-7-cyano-5- (2-aminopropyl) indoline, namely the compound (1) 20.7 g. The yield thereof was found to be 85%.
The yield of each step is higher than 75%, generally higher than 85%, the operation is simple and convenient, the implementation cost is low, the industrial production is favorably realized, and the industrial application value is very high.
Claims (10)
1. A preparation method of 1-acetyl-7-cyano-5- (2-aminopropyl) indoline is characterized by comprising the following steps: the method sequentially comprises the following 7 steps:
wherein,
(1) in the step a, Lewis acid is used as a catalyst, and X is halogen Cl, Br or I;
(2) in the step d, carrying out nitration reaction on the compound (5) and concentrated nitric acid in acid to prepare a compound (6);
(3) and in the step f, the compound (7) is subjected to diazo reaction under the action of acid and sodium nitrite to generate diazonium salt, and then the diazonium salt is reacted with a cyanating agent to prepare the compound (8).
2. The method for producing 1-acetyl-7-cyano-5- (2-aminopropyl) indoline according to claim 1, characterized in that: in the step a, the step (c) is carried out,
x is Cl;
the reaction temperature is 0-120 ℃, and the reaction time is 3-10 hours;
the solvent is selected from dichloromethane or dichloroethane;
the Lewis acid is anhydrous zinc chloride or aluminum trichloride;
the molar ratio of the compound (2) to the 2-halogenopropionyl halide to the Lewis acid is 1 (1-1.5) to 2-5.
3. The method for producing 1-acetyl-7-cyano-5- (2-aminopropyl) indoline according to claim 1, characterized in that: in the step b, the step (c),
the reaction temperature is 50-150 ℃;
the solvent is selected from DMF, DMSO, acetone or tetrahydrofuran;
the molar ratio of the compound (3) to the phthalimide potassium salt is 1 (1-2).
4. The method for producing 1-acetyl-7-cyano-5- (2-aminopropyl) indoline according to claim 3, characterized in that: the solvent is DMF.
5. The method for producing 1-acetyl-7-cyano-5- (2-aminopropyl) indoline according to claim 1, characterized in that: in the step c, in the step of the method,
the alkylsilane is triethylsilane (Et)3SiH）；
The reaction temperature is 0-100 ℃, and the reaction time is 3-24 hours;
the compound (4) is triethylsilane and trifluoroacetic acid in a molar ratio of 1 (1-5) to 5-100.
6. The method for producing 1-acetyl-7-cyano-5- (2-aminopropyl) indoline according to claim 1, characterized in that: in the step d, the step of the method comprises the following steps,
the reaction temperature is 0-50 ℃, and the reaction time is 8-12 hours;
the concentration of the concentrated nitric acid is more than 50 percent;
the solvent is concentrated sulfuric acid or acetic acid.
7. The method for producing 1-acetyl-7-cyano-5- (2-aminopropyl) indoline according to claim 1, characterized in that: in the step e, the step (c),
the reaction temperature is 0-80 ℃, and the reaction time is 5-12 hours;
the reducing agent is iron powder;
the solvent is selected from methanol, ethanol, glacial acetic acid aqueous solution or ammonium chloride aqueous solution;
the molar ratio of the compound (6) to the iron powder is 1 (2.5-4).
8. The method for producing 1-acetyl-7-cyano-5- (2-aminopropyl) indoline according to claim 1, characterized in that: in the step f, the step of the method comprises the following steps,
the reaction temperature is-5 to 50 ℃, and the reaction time is 5 to 12 hours;
the acid is selected from sulfuric acid, hydrochloric acid or fluoroboric acid;
the cyanating agent is selected from sodium cyanide, cuprous cyanide or complex salts of sodium cyanide and cuprous cyanide.
9. The method for producing 1-acetyl-7-cyano-5- (2-aminopropyl) indoline according to claim 8, characterized in that: the acid is hydrochloric acid; the cyanating agent is complex salt of sodium cyanide and cuprous cyanide.
10. The method for producing 1-acetyl-7-cyano-5- (2-aminopropyl) indoline according to claim 1, characterized in that: in the step g, the step (c),
the reaction temperature is 20-80 ℃, and the reaction time is 3-12 hours;
the molar ratio of the compound (8) to the hydrazine hydrate is 1 (1-3).
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| CN103848772A (en) * | 2012-11-30 | 2014-06-11 | 苏州四同医药科技有限公司 | Preparation method of important intermediate of Silodosin |
| CN104974072A (en) * | 2014-04-10 | 2015-10-14 | 江苏和成新材料有限公司 | Preparation method of silodosin intermediate |
| CN108033906A (en) * | 2017-12-28 | 2018-05-15 | 常州瑞明药业有限公司 | A kind of preparation method of Silodosin intermediate |
| CN108047116A (en) * | 2017-12-28 | 2018-05-18 | 常州瑞明药业有限公司 | The preparation method of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines |
| WO2018205919A1 (en) | 2017-05-10 | 2018-11-15 | 浙江天宇药业股份有限公司 | Method for synthesizing silodosin and intermediate thereof |
| US10421719B2 (en) | 2015-09-30 | 2019-09-24 | Urquima S.A. | Maleic acid salt of a silodosin intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848772A (en) * | 2012-11-30 | 2014-06-11 | 苏州四同医药科技有限公司 | Preparation method of important intermediate of Silodosin |
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| CN108033906A (en) * | 2017-12-28 | 2018-05-15 | 常州瑞明药业有限公司 | A kind of preparation method of Silodosin intermediate |
| CN108047116A (en) * | 2017-12-28 | 2018-05-18 | 常州瑞明药业有限公司 | The preparation method of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines |
| CN108033906B (en) * | 2017-12-28 | 2021-07-06 | 常州瑞明药业有限公司 | Preparation method of silodosin intermediate |
| CN108047116B (en) * | 2017-12-28 | 2021-08-13 | 常州瑞明药业有限公司 | Preparation method of R-5- (2-aminopropyl) -1- (3-hydroxypropyl) -7-nitrilindoline |
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