CN111171022B - Synthesis method of 1-hydroxy-pyrrolo [2,3-c ] piperidine - Google Patents
Synthesis method of 1-hydroxy-pyrrolo [2,3-c ] piperidine Download PDFInfo
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- CN111171022B CN111171022B CN202010000708.2A CN202010000708A CN111171022B CN 111171022 B CN111171022 B CN 111171022B CN 202010000708 A CN202010000708 A CN 202010000708A CN 111171022 B CN111171022 B CN 111171022B
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- C07—ORGANIC CHEMISTRY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a 1-hydroxy-pyrrolo [2,3-c]The synthesis method of piperidine comprises the following steps: (1) taking 1-nitro-5-chloro-1-pentene shown in a formula (IV) as an initial raw material, and reacting with TosMIC shown in a formula (V) under an alkaline condition to obtain a compound (VI); (2) carrying out catalytic hydrogenation on the compound (VI) to generate a compound (VII); (3) and (5) generating a compound (III) by the compound (VII) under the action of alkali. The 1-hydroxy-pyrrolo [2,3-c ] of the invention]The synthesis method of piperidine reduces the process cost and the production risk.
Description
Technical Field
The invention relates to the field of synthesis of medical intermediates, in particular to synthesis of 1-hydroxy-pyrrolo [2,3-c ] piperidine.
Background
Moxifloxacin (trade name: baefule) with the structure shown in formula (I) is a fourth-generation quinolone antibacterial drug and has a wide antibacterial spectrum: the product has strong antibacterial activity against common respiratory bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and part of Staphylococcus aureus. The medicine has good penetration ability, and can reach high concentration in lung tissue, so the treatment effect is good, and the treatment course is short. In recent years, the sales of moxifloxacin in China has been gradually increasing every year.
The key point of the synthesis of the moxifloxacin raw material medicine lies in the synthesis of seven-position side chain (S, S) -2, 8-diazabicyclo [4.3.0] nonane (the structure is shown as a formula (II)), and the side chain is the key point of the moxifloxacin with good antibacterial activity and antibacterial spectrum. The existing industrial production route mainly uses dipicolinic acid as a raw material, and a large amount of sodium borohydride is used in the production process, so that a large amount of borane is generated, the fire is easy, the production cost is high, and the danger is high.
It is therefore of great importance to develop a route for the synthesis of (S, S) -2, 8-diazabicyclo [4.3.0] nonane. The invention aims to provide a synthesis method of an intermediate for (S, S) -2, 8-diazabicyclo [4.3.0] nonane, namely 1-hydroxy-pyrrolo [2,3-c ] piperidine (III).
Disclosure of Invention
The invention aims to provide a synthetic method of 1-hydroxy-pyrrolo [2,3-c ] piperidine, so as to reduce the process cost and the production risk.
Therefore, the invention adopts the following technical scheme:
a method for synthesizing 1-hydroxy-pyrrolo [2,3-c ] piperidine comprises the following steps:
(1) taking 1-nitro-5-chloro-1-pentene shown in a formula (IV) as an initial raw material, and reacting with TosMIC shown in a formula (V) under an alkaline condition to obtain a compound (VI);
(2) carrying out catalytic hydrogenation on the compound (VI) to generate a compound (VII);
(3) the compound (VII) generates a compound (III) under the action of alkali;
the starting material used in the present invention is 1-nitro-5-chloro-1-pentene, which is simple and readily available, and which can be prepared according to the references eur.j.org.chem.1999, 2583-2591; molecules 2014,19,1150 and 1162 ].
Preferably, the base used in step (1) is potassium tert-butoxide, sodium hydroxide or sodium hydride, most preferably potassium tert-butoxide.
Preferably, in step (1), the molar ratio of 1-nitro-5-chloro-1-pentene to base charged is 1: 1-3.
Preferably, the reaction of step (1) is carried out in a reaction solvent which is tetrahydrofuran, DMSO or diethyl ether, most preferably tetrahydrofuran.
Preferably, the reaction temperature of the reaction in the step (1) is-20-25 ℃, and the reaction time is 1-3 h; more preferably, the reaction temperature is-10 ℃ and the reaction time is 1 h.
The invention is particularly preferably carried out in step (1) as follows: adding an alkali into a reaction container filled with a reaction solvent, wherein the alkali is potassium tert-butoxide, sodium hydroxide or sodium hydride (preferably potassium tert-butoxide), the reaction solvent is tetrahydrofuran, DMSO or diethyl ether (preferably tetrahydrofuran), cooling and stirring are carried out under an ice bath, when the temperature in a bottle reaches-20 ℃ -25 ℃ (preferably-10 ℃), TosMIC dissolved in the reaction solvent is slowly dripped, stirring is continuously carried out for 1-3 h (preferably 1h) under-20 ℃ -25 ℃ (preferably-10 ℃), and the obtained reaction solution is subjected to aftertreatment to obtain the compound (VI).
The post-treatment in step (1) of the present invention may be performed as follows: and (3) pouring the reaction solution into an ammonium chloride aqueous solution for quenching, extracting the reaction solution by diethyl ether, taking a diethyl ether layer, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain the compound (VI).
Preferably, the catalyst used in step (2) is Pd/C, Ni or Pt/C, most preferably Pd/C.
Preferably, in the step (2), the mass amount of the catalyst is 2-10% of the mass amount of the compound (VI).
Preferably, the reaction of step (2) is carried out in a reaction solvent which is methanol, ethanol or ethyl acetate, most preferably the reaction solvent is methanol.
Preferably, the reaction temperature of the catalytic hydrogenation in the step (2) is 20-30 ℃, the hydrogen pressure is 1-4atm, and the reaction time is 15-20 h; more preferably, the reaction temperature is 25 ℃.
The invention particularly preferably implements said step (2) as follows: adding a compound (VI) into a three-neck flask filled with a reaction solvent, stirring and dissolving the reaction solvent which is methanol, ethanol or ethyl acetate (preferably the reaction solvent is methanol), adding a catalyst which is Pd/C, Ni or Pt/C, introducing hydrogen, hydrogenating at the temperature of 20-30 ℃ and the hydrogen pressure of 1-4atm, stirring for 15-20 h, filtering, taking filtrate, and concentrating to obtain the compound (VII).
Preferably, the base used in step (3) is cesium carbonate, potassium carbonate, sodium hydroxide or potassium tert-butoxide, most preferably potassium carbonate.
Preferably, in step (3), the molar ratio of the compound (VII) to the base is 1: 1.5-5.
Preferably, the reaction of step (3) is carried out in a reaction solvent, which is acetonitrile, water or tetrahydrofuran, most preferably tetrahydrofuran.
Preferably, the reaction temperature of the reaction in the step (3) is 20-50 ℃, and the reaction time is 4-18 h; most preferably, the reaction temperature is 25 ℃.
The present invention particularly preferably carries out said step (3) as follows: adding the compound (VII) into a reaction vessel filled with a reaction solvent, wherein the reaction solvent is acetonitrile, water or tetrahydrofuran (preferably the reaction solvent is tetrahydrofuran), stirring for dissolving, then adding a base, wherein the base is cesium carbonate, potassium carbonate, sodium hydroxide or potassium tert-butoxide (preferably potassium carbonate), stirring vigorously for 4h-18h from 20 ℃ to 50 ℃, and carrying out aftertreatment on the obtained reaction mixture to obtain the compound (III).
The post-treatment in step (3) of the present invention can be performed as follows: after cyclization, an appropriate amount of water was added to the reaction mixture, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound (III).
Compared with the prior art, the invention has the beneficial effects that:
1. compared with dipicolinic acid, the starting material is cheap and easy to obtain, and has cost advantage.
2. The reaction process has fewer steps and mild reaction conditions.
3. The reaction process is safer and more environment-friendly.
4. The invention has high yield.
Detailed Description
The technical solution of the present invention is illustrated by the following specific examples, but the scope of the present invention is not limited thereto:
example 1
Step (1) preparation of 3- (3' -chloropropyl) -4-nitro-1H-pyrrole
Adding potassium tert-butoxide (2.24g) into a three-necked flask containing 20mL of THF, starting cooling and stirring in an ice bath, starting slowly dropwise adding 1.95g of TosMIC (dissolved in 10mL of THF) when the temperature in the flask reaches-10 ℃, continuing stirring for 1h at-10 ℃, sampling during the reaction, detecting by TLC, pouring the reaction solution into an ammonium chloride aqueous solution for quenching after the reaction is finished, extracting the reaction solution by diethyl ether (30mL of 3), combining diethyl ether layers, washing the diethyl ether layer with water, taking the diethyl ether layer, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain 1.57g of compound (VI) with 84% yield. Nuclear magnetism (1H NMR,500MHz,CDCl3)δppm:1.84(m,2H)；2.51(t,2H)；3.68(t,2H)；6.61(s,1H)；7.57(s,1H)；9.7(s,1H)。
Step (2) preparation of 3- (N-hydroxy-amino) -4- (3' -chloropropyl) -1H-pyrrole:
the nitro compound (VI) (3.76g) prepared according to the method of the step (1) was charged into a three-necked flask containing methanol (20mL), dissolved by stirring, 2% Pd/C (0.106g) (Deqing county, Dede chemical Co., Ltd.) was added, hydrogen balloon was put on, hydrogenation was carried out at 25 ℃ under a pressure of 1atm, and after stirring for 20 hours, filtration was carried out to obtain a filtrate, which was concentrated to obtain 2.86g of the compound (VII) with a yield of 91%. Nuclear magnetism (1H NMR,500MHz,CDCl3)δppm 1.86(m,2H)；2.48(t,2H)；3.69(t,2H)；6.53(s,1H)；6.69(s,1H)；9.5(s,1H)；10.05(s,1H)；10.56(s,1H)。
And (3): preparation of 1-hydroxy-pyrrolo [2,3-c ] piperidine:
compound (VII) (0.158g) prepared according to the procedure of step (2) was charged into a three-necked flask charged with 3mL of DCM, dissolved with stirring, and thenPotassium carbonate (0.53g) powder was added, vigorous stirring was started at 25 ℃ for 18h, monitored by TLC, after cyclization, an appropriate amount of water was added to the reaction mixture, followed by extraction with ethyl acetate (10m L × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.115g of compound (III) in 85% yield. LRMS C7H17N2O,calculated142.1,found 142.1。
Claims (7)
1. A method for synthesizing 1-hydroxy-pyrrolo [2,3-c ] piperidine comprises the following steps:
(1) taking 1-nitro-5-chloro-1-pentene shown in a formula (IV) as an initial raw material, and reacting with TosMIC shown in a formula (V) under an alkaline condition to obtain a compound (VI);
(2) carrying out catalytic hydrogenation on the compound (VI) to generate a compound (VII);
(3) the compound (VII) generates a compound (III) under the action of alkali;
2. the method of synthesis of claim 1, wherein: the step (2) is implemented as follows: adding a compound (VI) into a three-neck flask filled with a reaction solvent, stirring and dissolving the reaction solvent which is methanol, ethanol or ethyl acetate, adding a catalyst which is Pd/C, Ni or Pt/C, introducing hydrogen, hydrogenating at the temperature of 20-30 ℃ and under the hydrogen pressure of 1-4atm, stirring for 15-20 h, filtering, taking filtrate, and concentrating to obtain a compound (VII).
3. A method of synthesis as claimed in claim 1 or 2, characterized in that: the catalyst used in the step (2) is Pd/C, and the organic solvent used is methanol.
4. A method of synthesis as claimed in claim 1 or 2, characterized in that: in the step (2), the mass usage of the catalyst is 2-10% of the mass usage of the compound (VI).
5. The method of synthesis of claim 1, wherein: the step (3) is implemented as follows: adding the compound (VII) into a reaction vessel filled with a reaction solvent, wherein the reaction solvent is acetonitrile, water or tetrahydrofuran, stirring for dissolving, then adding a base, wherein the base is cesium carbonate, potassium carbonate, sodium hydroxide or potassium tert-butoxide, stirring vigorously for 4-18 h at the temperature of 20-50 ℃, and carrying out aftertreatment on the obtained reaction mixture to obtain the compound (III).
6. The method of synthesis of claim 1 or 5, wherein: the base used in the step (3) is potassium carbonate, and the reaction solvent used is tetrahydrofuran.
7. The method of synthesis of claim 1 or 5, wherein: in the step (3), the molar ratio of the compound (VII) to the base is 1: 1.5-5.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5977146A (en) * | 1995-12-08 | 1999-11-02 | Basf Aktiengesellschaft | Pyridylcarbamates, process and intermediates for their preparation, and their use |
| CN109096276A (en) * | 2018-08-01 | 2018-12-28 | 上海博志研新药物技术有限公司 | The preparation method of moxifloxacin hydrochloride and its intermediate |
| CN110563725A (en) * | 2019-09-27 | 2019-12-13 | 哈尔滨珍宝制药有限公司 | preparation process of moxifloxacin |
| CN111320622A (en) * | 2018-12-15 | 2020-06-23 | 上虞京新药业有限公司 | Method for synthesizing moxifloxacin hydrochloride |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5977146A (en) * | 1995-12-08 | 1999-11-02 | Basf Aktiengesellschaft | Pyridylcarbamates, process and intermediates for their preparation, and their use |
| CN109096276A (en) * | 2018-08-01 | 2018-12-28 | 上海博志研新药物技术有限公司 | The preparation method of moxifloxacin hydrochloride and its intermediate |
| CN111320622A (en) * | 2018-12-15 | 2020-06-23 | 上虞京新药业有限公司 | Method for synthesizing moxifloxacin hydrochloride |
| CN110563725A (en) * | 2019-09-27 | 2019-12-13 | 哈尔滨珍宝制药有限公司 | preparation process of moxifloxacin |
Non-Patent Citations (1)
| Title |
|---|
| "Alkylation of Aryl N-(2-Pyridylsulfonyl)aldimines with Organozinc Halides: Conciliation of Reactivity and Chemoselectivity";Jorge Esquivias et al.;《Angew. Chem. Int. Ed.》;20071231;第46卷;第9257-9260页 * |
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