CN102115455A - Method for preparing psilocine key intermediate - Google Patents
Method for preparing psilocine key intermediate Download PDFInfo
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- CN102115455A CN102115455A CN2009102443855A CN200910244385A CN102115455A CN 102115455 A CN102115455 A CN 102115455A CN 2009102443855 A CN2009102443855 A CN 2009102443855A CN 200910244385 A CN200910244385 A CN 200910244385A CN 102115455 A CN102115455 A CN 102115455A
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Abstract
The invention discloses a method for preparing a psilocine key intermediate, which comprises the following steps of: 1, performing oxidation reaction on a compound I and dimethyl formamide (DMF) and POCl3 in an organic solvent to obtain a compound II; 2, reacting the compound II with hydroxylamine hydrochloride, and dehydrating to obtain a compound III; and 3, performing reduction reaction on the compound III to obtain the psilocine key intermediate, namely a compound IV. The invention provides a method for synthesizing the psilocine key intermediate. By the method, the steps of the conventional preparation method are reduced, the cost is reduced and the yield of the psilocine key intermediate is improved.
Description
Technical field
The present invention relates to the how hot key intermediate intermediates preparation of a kind of celo.
Background technology
Benign prostatic hyperplasia (BPH) is one of elderly men common disease, is feature with prostatic non-pernicious increase.In 60 years old or above the elderly, have and suffer from this disease more than 50%, and in 85 years old and above the elderly, 90% above person's morbidity is arranged.Its pathogenic factor is not illustrated as yet, it is generally acknowledged relevant with secretion, the Metabolic disorder of sexual hormoue and cholesterol etc.Someone thinks, the elderly weakens because of the action pathway of hypophysis-gonad-stimulating hormone-testis or because of endogenous changes, and makes that testis is degenerated, sexual function descends, testosterone value reduces, prostate gland increases because of reticular tissue, makes that glandular epithelium changes, prostate gland increases.Prostatic increase can be oppressed urethra, causes the bladder bradyuria, even stops up bladder outlet.Have α 1A-adrenoceptor in human benign prostatic, the activation of this receptor can increase the weight of urethral obstruction and misnicturition symptom.Therefore, the combination by blocking-up α 1A-adrenoceptor can make the prostate gland smooth muscle loosening that blocks, thereby improve symptom.
How hot celo is, chemistry (-)-1-(3-hydroxypropyl) by name-5-[2R-[2-[2-(2,2, the 2-trifluoro ethoxy) phenol oxygen base] ethylamine] propyl group] indoles-7-acid amides, develop jointly by Japanese Kissei and Daiichi pharmaceuticals, be the α 1A receptor antagonist of Japanese Kissei drugmaker invention, can be used for treatment and benign prostatic hyperplasia (BPH) or the loose dysuric symptom that causes, and other relevant symptoms.
Kissei company and the cooperation application of Daiichi Sankyo company obtain the listing approval in May, 2006 in Japan, and the trade(brand)name of use is Urief (R).Kissei company also licenses to silodosin U.S. Watson drugmaker, and the latter obtains FDA application listing recently in August, 2008.
The many sufferings of celo are α-1 receptor-blocking agent, by the suprarenin-1 acceptor onset in retardance prostate gland, bladder and the urethra.By this acceptor is produced retardance, loosen and organize unstriated muscle, thus the symptom of alleviation BPH.This medicine is taken once every day, and the normal patient's per daily dose of suggestion liver kidney is taken 8 milligrams, has the patient of moderate lesions of liver and kidney to take 4 milligrams per daily dose.Simultaneously, the patient does not advise taking in the serious lesions of liver and kidney, does not ratify child patient and uses.Use the how hot modal side effect defective ejaculation of celo, this side effect also disappears thereupon after the drug withdrawal.That other side effect also comprises is dizzy, dizzy, diarrhoea, orthostatic hypotension (blood pressure drops when standing), headache, rhinopharyngitis (viral infection of nasal cavity and larynx) and nasal obstruction.
Many suffering of celo are selectivity α 1A-suprarenal gland energy retarding agent, and preclinical study shows, its to the selective effect of urethra respectively than Prazosin (prazosin) and Tan Luoxingao 12 and 7.5 times.Xi Luoxin can obviously suppress the human prostate contraction that norepinephrine causes; The bladder hyperactivity of rat benign prostatauxe model there is the restraining effect of dose-dependently, and can improves the pressure threshold of bladder contracts.These Notes of Key Datas, Xi Luoxin is except that improving the bladder function, and is also effective to alleviating the benign prostatauxe related symptoms.
At present both at home and abroad openly the preparation method of the how hot key intermediate of celo (compound IV) is: Compound I is by reduction, oxidation, cyano group reaction, reduce and obtain the how hot key intermediate of celo (compound IV) once more.Long and yield is lower with this kind method steps, the 4 steps reaction that the improvement of our route via will be original changes 3 into and goes on foot and obtained the how hot key intermediate of celo (compound IV).
Summary of the invention
Technical problem to be solved by this invention has been to provide a kind of preparation method of the new how hot key intermediate of celo, productive rate and quality that it can the how hot key intermediate of obvious improved celo.
The preparation method of the how hot key intermediate of celo of the present invention, it comprises following step:
1. in organic solvent, Compound I and DMF and POCl
3Reaction obtains intermediate II.
2. Compound I I and oxammonium hydrochloride reaction obtains cyano compound III through dehydration again.
3. compound III obtains the how hot key intermediate of celo through reduction.Be compound IV, reaction equation is as follows:
Wherein, Compound I is 3-[5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] propyl benzoate.
Compound I I is 3-[7-formyl radical-5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] propyl benzoate.
Compound III is 3-[7-cyano group-5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] propyl benzoate.
Compound IV is 3-[7-cyano group-5-(2-aminopropyl)-2,3-dihydro-1H-indoles-1-yl] the phenylformic acid lactone.
1. step can adopt the method and the condition of the oxidizing reaction of this area routine to carry out preferred following condition: step temperature of reaction 1. is preferable to be-15～150 ℃, and better is-15～80 ℃; Reaction times preferable with detection reaction fully till, be generally 2～22h, that better is 3～10h.Described organic solvent be this area conventional use can dissolved compound I and solvent, that preferable is tetrahydrofuran (THF), methylene dichloride, toluene, acetone, chloroform, tetracol phenixin, methyl alcohol and N, in the dinethylformamide one or more, preferred tetrahydrofuran (THF), N, dinethylformamide; The consumption of solvent is 1～8 times of Compound I, and better is 2～4 times (ratio herein is the volume mass ratio).
2. step can adopt oxammonium hydrochloride to carry out the cyano group reaction, and preferred following condition: Compound I I carries out the cyano group reaction under the effect of oxammonium hydrochloride and dewatering agent, and what the temperature of reaction was preferable is 20～150 ℃, and better is 30～70 ℃; The time of reaction is preferable be (with detection reaction complete till), is generally 2～24h, preferred 2～10h.Described organic solvent is the solvent of the conventional energy dissolved compound II that uses in this area, and that preferable is tetrahydrofuran (THF), methylene dichloride, toluene, acetone, chloroform, tetracol phenixin, pyridine and N, one or more in the dinethylformamide, preferred pyridine; The consumption of solvent is 3～5 times of Compound I, and better is 3～5 times.Dewatering agent is the vitriol oil, acetic anhydride, and preferable is acetic anhydride.
3. step can adopt the method and the condition of the reduction reaction of this area routine to carry out preferred following condition: compound III is carried out reduction reaction with reductive agent under the effect of catalyzer, and what the temperature of reaction was preferable is-15～150 ℃, and better is 20～70 ℃; Reaction times preferable with detection reaction fully till, be generally 15～48h, preferred 20～36h.Described organic solvent be this area conventional use can dissolved compound III solvent, one or more that preferable is in tetrahydrofuran (THF), methylene dichloride, toluene, acetone, chloroform, tetracol phenixin, methyl alcohol and the ethanol, particular methanol and ethanol; The consumption of solvent is 2～15 times of compound III, and better is 3～6 times.Used reductive agent is sodium borohydride, H
2, that reductive agent is preferable is H
2The consumption of hydrogen is the consumption of this area double bond reduction reaction routine, and that preferable is 0.1～4MPa, and that better is 0.1～1MPa.Described catalyzer is the conventional catalyzer that uses of this area double bond reduction reaction, and preferable is palladium carbon, Raney's nickel, platinum, iron or zinc; Catalyst consumption is the conventional catalytic amount of this area, and is preferable for compound III is 0.5～100 times of catalyzer molar weight, and better is 0.5-4 doubly or 60～80 times.
But each the optimum condition arbitrary combination among the preparation method of the present invention promptly gets each preferred embodiment of the present invention.
Reagent that the present invention is used and raw material are all commercially available to be got.
Positive progressive effect of the present invention has been to provide a kind of preparation method of the new how hot key intermediate of celo, the productive rate that it can the how hot product of obvious improved celo.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Embodiment 1:3-[7-formyl radical-5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] preparation of propyl benzoate (Compound I I).
In the 500ml there-necked flask, add 56ml POCl
3With 12ml DMF, under 0 ℃, with 22.3g (60mmol) 3-[5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] the 20mlDMF solution of propyl benzoate (Compound I) joins in the reaction system, in 50 ℃ of reaction 4h down.Be cooled to room temperature, add 100ml water, separate out yellow solid, filtering-depositing, oven dry obtains white solid 19g, yield: 79%.
MS(+1)：381。
1HNMR：δ(ppm，CDCl
3)，9.95(s，1H)，8.12-8.10(m，2H)，7.62-7.59(m，1H)，7.47-7.45(m，2H)，7.22(s，1H)，6.93(brs，1H)，4.75-4.65(m，1H)，4.50-4.45(m，3H)，3.66-3.64(m，4H)，3.19(s，1H)，3.05-3.09(m，2H)，2.92(s，1H)，2.15-2.12(m，2H)，1.54-1.53(m，3H)。
Embodiment 2:3-[7-formyl radical-5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] preparation of propyl benzoate (compound III)
In the 250ml there-necked flask, add 4ml exsiccant tetrahydrofuran (THF), 8.6g (20mmol) 3-[7-formyl radical-5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] propyl benzoate (compound III), 1.8g (26mmol) oxammonium hydrochloride.7ml pyridine, 4ml acetic anhydride are in 50 ℃ of reactions 24 down
H is cooled to room temperature, adds 40ml water, add the 48ml ethyl acetate again, the extraction separatory, organic phase is received solution and saturated aqueous common salt with 1M hydrochloric acid soln, unsaturated carbonate hydrogen and is washed successively, uses concentrating under reduced pressure solvent after the anhydrous sodium sulfate drying organic phase again, add an amount of Virahol, separate out light yellow crystal, filter, oven dry, obtain faint yellow solid 5.4g, yield: 63%.
MS(+1)：406。
1HNMR：δ(ppm，CDCl
3)，8.01-7.97(m，2H)，7.48-7.46(m，1H)，7.37-7.35(m，2H)，6.89-6.84(m，1H)，6.49-6.46(m，1H)，4.66-4.65(m，2H)，4.45-4.41(m，3H)，3.54-3..50(m，4H)，3.03(s，1H)，2.93-2.90(m，2H)，2.85(s，1H)，2.03-1.99(m，2H)，1.47-1.44(m，3H)。
Embodiment 3:3-[7-cyano group-5-(2-aminopropyl)-2,3-dihydro-1H-indoles-1-yl] preparation of propyl benzoate (compound IV)
With 2g 3-[7-formyl radical-5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] propyl benzoate (compound III) places 500ml stainless steel hydrogenation still, adds 100ml ethanol; add 220mgPd/C; feed hydrogen to 0.1MPa., room temperature reaction 20h, filtration catalizer.Concentrate and obtain light yellow crystal 1g, yield: 53.7%.
MS(+1)：378。
1HNMR：δ(ppm，CDCl
3)8.06-8.02(m，1H)，7.63-7.57(m，1H)，7.50-7.47(m，2H)，6.94(s，1H)，6.90(brs，1H)，4.48-4.451(m，2H)，3.79-3.75(m，2H)，3.66-3.62(m，2H)，3.50(s，2H)，2.98-2.93(m，2H)，2.21-2.19(m，2H)，2.14(s，3H)。
Embodiment 4:3-[7-formyl radical-5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] preparation of propyl benzoate (compound III)
In the 250ml there-necked flask, add 4ml exsiccant tetrahydrofuran (THF), 8.6g (20mmol) 3-[7-formyl radical-5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] propyl benzoate (compound III), 1.8g (26mmol) oxammonium hydrochloride.7ml pyridine, the 10ml vitriol oil, reaction 24h is cooled to room temperature under 50 ℃, add 40ml water, add the 48ml ethyl acetate again, the extraction separatory, organic phase is received solution and saturated aqueous common salt with 1M hydrochloric acid soln, unsaturated carbonate hydrogen and is washed successively, use concentrating under reduced pressure solvent after the anhydrous sodium sulfate drying organic phase again, add an amount of Virahol, separate out light yellow crystal, filter, oven dry obtains faint yellow solid 5.4g, yield: 63%.
The nuclear-magnetism result is with embodiment 2.
Embodiment 5:3-[7-cyano group-5-(2-aminopropyl)-2,3-dihydro-1H-indoles-1-yl] preparation of propyl benzoate (compound IV)
With 2g 3-[7-formyl radical-5-(3-nitro-1-butylene base)-2,3-dihydro-1H-indoles-1-yl] propyl benzoate (compound III) places 500ml stainless steel hydrogenation still, adds 100ml methyl alcohol; add 220mgPd/C; feed hydrogen to 0.2MPa., room temperature reaction 20h, filtration catalizer.Concentrate and obtain light yellow crystal 0.8g, yield: 43%.
The nuclear-magnetism result is with embodiment 3.
Embodiment 6:3-[7-cyano group-5-(2-aminopropyl)-2,3-dihydro-1H-indoles-1-yl] preparation of propyl benzoate (compound IV)
With 2g 3-[7-formyl radical-5-(3-nitro-1-butylene base)-2; 3-dihydro-1H-indoles-1-yl] propyl benzoate (compound III) places the 500ml there-necked flask; add 100ml ethanol; add the freshly prepd Raney's nickel of 400mg; feed hydrogen to 0.2MPa.; room temperature reaction 24h, filtration catalizer.Concentrate and obtain light yellow crystal 0.9g, yield: 48%.
The nuclear-magnetism result is with embodiment 3.
Embodiment 7:3-[7-cyano group-5-(2-aminopropyl)-2,3-dihydro-1H-indoles-1-yl] preparation of propyl benzoate (compound IV)
With 2g 3-[7-formyl radical-5-(3-nitro-1-butylene base)-2; 3-dihydro-1H-indoles-1-yl] propyl benzoate (compound III) places 500ml stainless steel hydrogenation still; add 100ml methyl alcohol; add the freshly prepd Raney's nickel of 400mg; feed hydrogen to 0.2MPa.; room temperature reaction 24h, filtration catalizer.Concentrate and obtain light yellow crystal 0.8g, yield: 43%.
The nuclear-magnetism result is with embodiment 3.
Claims (12)
1. the preparation method of the how hot key intermediate of celo, it comprises following step:
1. in organic solvent, Compound I and DMF and POCl
3Reaction obtains intermediate II;
2. Compound I I and oxammonium hydrochloride reaction obtains cyano compound II through dehydration again;
3. compound III obtains the how hot key intermediate IV of celo through reduction.
2. the preparation method of the how hot key intermediate of celo according to claim 1 is characterized in that: step 1., step 2. or step temperature of reaction 3. be-50～150 ℃.
3. the preparation method of the how hot key intermediate of celo according to claim 1, it is characterized in that: step 1., step 2. or the organic solvent of step in 3. be tetrahydrofuran (THF), methylene dichloride, toluene, N, one or more in dinethylformamide, acetone, chloroform, pyridine, tetracol phenixin, methyl alcohol and the ethanol.
4. the preparation method of the how hot key intermediate of celo according to claim 1 is characterized in that: the step 1. consumption of middle Compound I is POCl
3The mol ratio of consumption is about 1: 2.2.
5. the preparation method of the how hot key intermediate of celo according to claim 1 is characterized in that: the method for step cyano group reaction 2. is under the effect of dewatering agent, and Compound I I and oxammonium hydrochloride carry out the cyano group reaction.
6. the preparation method of the how hot key intermediate of celo according to claim 1 is characterized in that: the method for step nitro-reduction reaction 3. is under the effect of catalyzer, and compound III and reductive agent react.
7. the preparation method of the how hot key intermediate of celo according to claim 5 is characterized in that: described reductive agent is a hydrogen.
8. the preparation method of the how hot key intermediate of celo according to claim 6 is characterized in that: the consumption of described hydrogen be make system pressure at least maintenance system pressure at the consumption of 0.1Mpa.
9. the preparation method of the how hot key intermediate of celo according to claim 5 is characterized in that: described catalyzer is palladium carbon, Raney's nickel, platinum, iron or zinc.
10. the preparation method of the how hot key intermediate of celo according to claim 1 is characterized in that: described Compound I by with POCl
3Carrying out oxidizing reaction makes;
Wherein, the consumption of temperature of reaction, organic solvent and compound is described with in the claim 2～4 each.
11. the preparation method of the how hot key intermediate of celo according to claim 1 is characterized in that: in organic solvent, Compound I I and oxammonium hydrochloride reaction carrying out cyano group reaction get compound III;
Wherein, the consumption of temperature of reaction, organic solvent and compound is described with in the claim 2～5 each.
12. the preparation method of the how hot key intermediate of celo according to claim 1 is characterized in that: in organic solvent, compound III is carried out reduction reaction under catalyst action, gets how hot key intermediate of celo and compound IV;
Wherein, the consumption of temperature of reaction, organic solvent and compound is described with in the claim 2～8 each.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2015533501A (en) * | 2012-10-18 | 2015-11-26 | サンド・アクチエンゲゼルシヤフト | Method for preparing indoline derivatives |
| US10421719B2 (en) | 2015-09-30 | 2019-09-24 | Urquima S.A. | Maleic acid salt of a silodosin intermediate |
| US11724985B2 (en) | 2020-05-19 | 2023-08-15 | Cybin Irl Limited | Deuterated tryptamine derivatives and methods of use |
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| CN101585798A (en) * | 2008-05-20 | 2009-11-25 | 浙江华海药业股份有限公司 | Optical active compound of 1-(3-benzoyloxy-propyl)-5-(2-(1-phenyl ethyl amine) propyl-7-cyano indoline as well as preparation method and application thereof |
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2009
- 2009-12-30 CN CN2009102443855A patent/CN102115455A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585798A (en) * | 2008-05-20 | 2009-11-25 | 浙江华海药业股份有限公司 | Optical active compound of 1-(3-benzoyloxy-propyl)-5-(2-(1-phenyl ethyl amine) propyl-7-cyano indoline as well as preparation method and application thereof |
Non-Patent Citations (1)
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| 吴建才等: ""西洛多辛合成路线图解"", 《中国医药工业杂志》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015533501A (en) * | 2012-10-18 | 2015-11-26 | サンド・アクチエンゲゼルシヤフト | Method for preparing indoline derivatives |
| US10421719B2 (en) | 2015-09-30 | 2019-09-24 | Urquima S.A. | Maleic acid salt of a silodosin intermediate |
| US11724985B2 (en) | 2020-05-19 | 2023-08-15 | Cybin Irl Limited | Deuterated tryptamine derivatives and methods of use |
| US11746088B2 (en) | 2020-05-19 | 2023-09-05 | Cybin Irl Limited | Deuterated tryptamine derivatives and methods of use |
| US11834410B2 (en) | 2020-05-19 | 2023-12-05 | Cybin Irl Limited | Deuterated tryptamine derivatives and methods of use |
| US11958807B2 (en) | 2020-05-19 | 2024-04-16 | Cybin Irl Limited | Deuterated tryptamine derivatives and methods of use |
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Application publication date: 20110706 |