CN108341766B - Preparation method of 3-azabicyclo [3.1.0] hexane hydrochloride - Google Patents
Preparation method of 3-azabicyclo [3.1.0] hexane hydrochloride Download PDFInfo
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Abstract
The invention discloses a preparation method of 3-azabicyclo [3.1.0] hexane hydrochloride, which takes a compound II as a raw material, reacts with acetic acid solution and zinc powder under the heating condition to obtain reaction liquid containing a compound III, then is treated with alkali to obtain treatment liquid containing a compound IV, and then reacts with hydrogen chloride gas to obtain the 3-azabicyclo [3.1.0] hexane hydrochloride. Compared with the prior art, the preparation method has the advantages of simple preparation process, mild reaction conditions and lower cost. Meanwhile, the total yield of the preparation process can reach 71 percent.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of 3-azabicyclo [3.1.0] hexane hydrochloride.
Background
Overactive bladder is one of the most common causes of bladder control problems. It results from uncontrolled spontaneous detrusor activity during bladder filling, resulting in symptoms of frequent, urgent and incontinent urination and increased frequency of urination. Although there are some treatment options available, most of the current options still involve the selection of antimuscarinic drugs for the treatment of overactive bladder. Muscarinic receptors are widely distributed in the human body and currently five distinct subtypes are known (M1-M5). Human bladder smooth muscle contains the M2-and M3-muscarinic receptor subtypes, and although the M2-receptor is predominantly present in the bladder, it appears that the presence of a small amount of the M3-receptor is functionally most important, as they directly mediate detrusor contraction. However, due to the widespread distribution of muscarinic receptors in the human body, anticholinergic effects in organs other than the bladder can lead to dose-limiting side effects: including dry mouth, constipation, blurred vision, headache, lethargy and tachycardia.
The lack of selectivity of tolterodine and oxybutynin may be the result of internal interactions in different conformations of ligands of different receptor subtypes, thus subtype selective ligands, which recognize different regions and functions of receptor subtypes, raise the possibility of developing more ideal drugs. The use of 3-azabicyclo [3.1.0] hexane as a key fragment to replace the portion of the chain amine in tolterodine and oxybutynin has helped us study the configuration limitations of antimuscarinic drugs.
The process route which has been reported for 3-azabicyclo [3.1.0] hexane hydrochloride, Bioorganic & Medicinal chemistry letters.15(2005) 2093-2096 is as follows:
solvents and reagents: (a) NaH, toluene; (b) NaOH, 15% a.q., 5 h; (c) SOCl2Refluxing for 1 h; (d) benzylamine, heating; (e) lithium aluminum hydride, refluxing for 5 h; (f) i) H2，Pd/C；ii)HCl。
The process route is long, 6 steps of reaction are needed to prepare the 3-azabicyclo [3.1.0] hexane hydrochloride (I), hazardous reagents such as lithium aluminum hydride, palladium carbon, hydrogen and the like are needed to be used, the requirement on production equipment is high, and the total yield is low.
In addition, J.Med.chem.2005,48, 5009-one 5024 reported a synthesis method of compound ii:
solvents and reagents: (a) CHBr3，aq NaOH，CH2Cl2，BnEt3NCl, this step reaction reports a yield of only 50%.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a process method of 3-azabicyclo [3.1.0] hexane hydrochloride, which has the advantages of short process route, convenient operation, environmental protection, sufficient market supply of raw materials, high yield and suitability for large-scale production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a process for preparing 3-azabicyclo [3.1.0] hexane hydrochloride comprising the steps of:
(a) taking a compound II as a raw material, and reacting the compound II with acetic acid and zinc powder in a solvent under a heating condition to obtain a reaction solution containing a compound III;
(b) treating the reaction solution containing the compound III with alkali to obtain a treatment solution containing a compound IV;
(c) reacting the treatment solution containing the compound IV with hydrogen chloride gas to obtain 3-azabicyclo [3.1.0] hexane hydrochloride (compound I);
the step (c) can also comprise a step of preparing a compound V by reacting the treatment solution containing the compound IV with di-tert-butyl dicarbonate, introducing hydrogen chloride gas into a solvent to directly remove Boc protection and form hydrochloride,
the zinc powder in the step (a) is added in batches at the temperature of 50-85 ℃, preferably 65-80 ℃; the heating is carried out at the temperature of 80-100 ℃, and preferably at the temperature of 90-95 ℃; the molar ratio of the compound II, the zinc powder and the acetic acid is 1: 3-10: 3-5, and preferably 1: 7: 4; the solvent is any one of toluene and xylene, and benzene, preferably toluene.
The alkali in the step (b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
Compound II can be prepared by the following reaction:
in the process of preparing the compound II from the compound VI, the base is any one of sodium tert-amylate, potassium tert-amylate and potassium tert-amylate, and sodium tert-amylate is preferred;
the solvent is any one of petroleum ether, n-hexane and n-heptane, preferably n-heptane;
the molar ratio of the compound VI, the alkali and the tribromomethane is 1: 5-8: 2-5, and preferably 1: 6-7: 3.
In the process of preparing the compound II from the compound VI, the reaction system is controlled at-15-10 ℃, and the tribromomethane is slowly added.
The general operating method comprises the following steps:
1. preparation of compound II: dissolving a compound VI in a solvent, adding alkali, controlling a reaction system at-15-10 ℃ under the protection of nitrogen, slowly adding tribromomethane, naturally heating to room temperature after dripping, monitoring the reaction, washing the reaction liquid with water, concentrating an organic layer under reduced pressure to obtain black oily liquid, cooling and crystallizing to obtain a compound II, wherein the yield is as follows: 86-95%.
2. Preparation of compound I:
(a) dissolving a compound II in acetic acid and a solvent, controlling the reaction system at 50-85 ℃, adding zinc powder in batches, controlling the reaction system at 80-100 ℃ for about 24-48 hours after the addition is finished, monitoring the reaction, cooling the reaction liquid to room temperature, separating out an organic phase, adding water into the residual jelly, stirring, and filtering to obtain a reaction liquid containing a compound III;
(b) adjusting the pH of the reaction liquid containing the compound III to be more than 12 by using sodium hydroxide, controlling the temperature to be less than 45 ℃, separating out a large amount of zinc hydroxide solids, and extracting by using 2-methyltetrahydrofuran to obtain a treatment liquid containing a compound IV;
(c) and (3) introducing hydrogen chloride gas into the treatment solution containing the compound IV, concentrating to remove 2-methyltetrahydrofuran after salifying, and crystallizing by using isopropanol/ethyl acetate to obtain the compound I.
The step (c) may further comprise the step of reacting with di-tert-butyl dicarbonate to prepare a compound V: adding di-tert-butyl dicarbonate (1.2eq.) into the treatment solution containing the compound IV, reacting at 10-30 ℃, and after monitoring the reaction, carrying out reduced pressure concentration on an organic phase to obtain a compound V; and (3) dissolving the compound V in methanol, introducing hydrogen chloride gas into the methanol, detecting the reaction, and concentrating to remove the methanol to obtain a compound I.
Has the advantages that: the preparation method of the 3-azabicyclo [3.1.0] hexane hydrochloride has the advantages of short reaction step, stable process, simple operation, sufficient supply of raw materials in the market and avoidance of the use of dangerous reagents, wherein the compound VI is used as the raw material for the preparation of the compound II to react with alkali, the conversion rate is greatly improved compared with that of the compound VI, and the yield can reach 95%; the total yield of the process route can reach 71 percent.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
Example 1
Preparation of compound II:
placing the compound VI (650g, 3.84mol, 1eq.) in a reaction flask, adding N-heptane (13L) and potassium tert-amyl alcohol (3394g, 26.89mol, 7eq.), stirring, cooling to-15 deg.C, and N2Under protection, slowly dropwise adding tribromomethane (2912g, 11.52mol, 3eq.) at the beginning, controlling the temperature to be-15 to-5 ℃, and making the reaction liquid become viscous in the reaction process. Stirring for 3 hours after dripping is finished, sampling and monitoring, finishing the reaction, washing the reaction liquid with water, drying and concentrating the organic phase to obtain brownish black oily matter, adding petroleum ether, freezing and crystallizing to obtain 1192g of coffee solid, and obtaining the yield: 91 percent.1HNMR(CDCl3,400MHz)(ppm)3.58(m,4H),2.40(m,2H),1.52(s,9H)。
Preparation of compound I:
placing a compound II (1800g, 5.28mol, 1eq.) in a reaction bottle, adding toluene (2.5L) and acetic acid (2218g, 36.95mol, 7eq.), stirring, heating to 65-80 ℃, adding zinc powder (1380g, 21.11mol, 4eq.) in batches, heating the system to 90-95 ℃ after the zinc powder is added, stirring for reaction for 22 hours, detecting the reaction completion, evaporating toluene and acetic acid under reduced pressure, adding 6L of water, stirring for 2 hours, filtering, and collecting filtrate;
cooling to 20 deg.C, adjusting pH to 12 with sodium hydroxide, separating out a large amount of zinc hydroxide solid, adding 2-methyltetrahydrofuran, extracting for 4 times, mixing organic layers, drying with anhydrous sodium sulfate, and filtering;
introducing hydrogen chloride gas into the filtrate, and reducingThe mixture was concentrated under reduced pressure to remove 2-methyltetrahydrofuran, and the residue was recrystallized (isopropanol: ethyl acetate: 1) to give 473.55g of off-white crystals, yield 75%.1HNMR(D2O,400MHz)(ppm)3.35(t,4H),1.75(m,2H),0.78(m,1H),0.32(m,1H)。
Example 2
Preparation of compound II:
placing compound VI (1000g, 5.91mol, 1eq.) in a reaction flask, adding N-heptane (20L) and potassium tert-amylate (4476g, 35.45mol, 6eq.), stirring, cooling to-5 deg.C, and cooling to N2Under protection, slowly dropwise adding tribromomethane (4480g, 17.73mol, 3eq.) at the beginning, controlling the temperature at-5-10 ℃, and making the reaction liquid become viscous in the reaction process. Stirring for 4 hours after dripping is finished, sampling and monitoring, finishing the reaction, washing the reaction liquid with water, drying and concentrating the organic phase to obtain brownish black oily matter, adding petroleum ether, freezing and crystallizing to obtain a coffee solid 1874g, and obtaining the yield: 93 percent.1HNMR(CDCl3,400MHz)(ppm)3.58(m,4H),2.40(m,2H),1.52(s,9H)。
Preparation of compound I:
putting a compound II (682g, 2.00mol, 1eq.) into a reaction bottle, adding toluene (1L) and acetic acid (360g, 6.00mol, 3eq.), stirring, heating to 70-85 ℃, adding zinc powder (392.3g, 6.00mol, 3eq.) in batches, finishing adding the zinc powder within 1 hour, heating the system to 80-90 ℃ after finishing adding the zinc powder, stirring for reacting for 26 hours, detecting that the reaction is finished, evaporating toluene and acetic acid under reduced pressure, adding 2.5L of water, stirring for 2 hours, filtering, and collecting filtrate;
cooling to 20 deg.C, adjusting pH to 12 with potassium hydroxide, separating out a large amount of zinc hydroxide solid, adding 2-methyltetrahydrofuran, extracting for 4 times, mixing organic layers, drying with anhydrous sodium sulfate, and filtering;
hydrogen chloride gas was introduced into the filtrate, and the filtrate was concentrated under reduced pressure to remove 2-methyltetrahydrofuran, and the residue was recrystallized (isopropanol: ethyl acetate: 1) to obtain 143.54g of off-white crystals, with a yield of 60%.1HNMR(D2O,400MHz)(ppm)3.35(t,4H),1.75(m,2H),0.78(m,1H),0.32(m,1H)。
Example 3
Preparation of compound II:
placing compound VI (1500g, 8.86mol, 1eq.) in a reaction flask, adding N-heptane (30L) and sodium tert-amylate (6833g, 62.05mol, 7eq.), stirring, cooling to-10 deg.C, and cooling to N2Under protection, slowly dropwise adding tribromomethane (6720g, 26.59mol, 3eq.) at the beginning, controlling the temperature at-10-0 ℃, and making the reaction liquid become viscous in the reaction process. Stirring for 6 hours after dripping, sampling and monitoring, finishing the reaction, washing the reaction liquid with water, drying and concentrating the organic phase to obtain brownish black oily matter, adding petroleum ether, freezing and crystallizing to obtain 2872g of coffee solid, and obtaining the yield: 95 percent.1HNMR(CDCl3,400MHz)(ppm)3.58(m,4H),2.40(m,2H),1.52(s,9H).
Preparation of compound I:
placing a compound II (341g, 1.00mol, 1eq.) in a reaction bottle, adding toluene (0.6L) and acetic acid (600g, 10.00mol, 10eq.), stirring, heating to 50-85 ℃, adding zinc powder (326.9g, 5.00mol, 5eq.) in batches, heating the system to 95-100 ℃ after the zinc powder is completely added, stirring for reacting for 20 hours, detecting the reaction is completed, evaporating toluene and acetic acid under reduced pressure, adding 1.2L of water, stirring for 2 hours, filtering, and collecting filtrate;
cooling to 20 deg.C, adjusting pH to 12 with sodium carbonate, adding 2-methyltetrahydrofuran, extracting for 4 times, mixing organic layers, drying with anhydrous sodium sulfate, and filtering;
hydrogen chloride gas was introduced into the filtrate, and the filtrate was concentrated under reduced pressure to remove 2-methyltetrahydrofuran, and the residue was recrystallized (isopropanol: ethyl acetate: 1) to obtain 84.93g of off-white crystals, with a yield of 71%.1HNMR(D2O,400MHz)(ppm)3.35(t,4H),1.75(m,2H),0.78(m,1H),0.32(m,1H)。
Example 4
Preparation of compound II:
dissolving a compound VI (650g, 3.84mol, 1eq.) in 13L petroleum ether, adding sodium tert-amylate (2115g, 19.20mol, 5eq.), cooling to 0 ℃ under the protection of nitrogen, dropwise adding tribromomethane (1941g, 7.68mol, 2eq.), controlling the temperature at 0-10 ℃ for about 2 hours, naturally raising the temperature to room temperature, sampling and monitoring, and finishing the reaction. The reaction solution was centrifuged, the filtrate was washed with water for 2 times, concentrated under reduced pressure to give a black oily liquid, which was crystallized by cooling to give 1178.9g of a brown solid with a yield of 90%.
Preparation of compound I:
dissolving a compound II (682g, 2.00mol, 1eq.) in toluene (0.6L) and acetic acid (360g, 6.00mol, 3eq.), heating to 65-70 ℃, adding zinc powder (392.3g, 6.00mol, 3eq.) in batches, releasing heat, and controlling the internal temperature to be not more than 85 ℃ after about 0.5 hour. Stirring for two hours at 70 ℃, heating to 90-95 ℃ for reaction for 21 hours, discharging while the reaction is finished, cooling to room temperature, separating out a toluene phase, adding 1.2L of water into the residual jelly, stirring for 1 hour until a large amount of solid exists, and filtering;
adjusting pH of the filtrate to 12 with sodium hydroxide, controlling temperature to be less than 45 deg.C, releasing heat violently, precipitating a large amount of solid, and adding 2-methyltetrahydrofuran (1.5L);
add (Boc) with stirring2O (480g, 2.20mol, 1.1eq.) and reacting at 30 ℃ for 12 hours, TLC shows complete reaction, centrifuging, washing the solid with 2-methyltetrahydrofuran for 2 times, combining filtrates, separating liquid, extracting the aqueous phase with 2-methyltetrahydrofuran, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain about 238.2g of brown liquid;
adding 250mL of methanol, introducing hydrogen chloride gas, controlling the temperature to be 15-20 ℃, indicating complete reaction by TLC, concentrating to remove the methanol, pulping residues by using acetone, and filtering to obtain 146.64g of white-like solid with the yield of 61.3%.
Example 5
Preparation of compound II:
dissolving a compound VI (800g, 4.73mol, 1eq.) in 15L of n-hexane, adding sodium tert-amylate (4165g, 37.82mol, 8eq.), cooling to-10 ℃ under the protection of nitrogen, dropwise adding tribromomethane (5974g, 23.64mol, 5eq.), controlling the temperature to be-5 to-10 ℃ after about 3 hours of addition, naturally raising the temperature to room temperature, and detecting that the content of the compound VI is less than 10%. The reaction solution was centrifuged, the filtrate was washed with water for 2 times, concentrated under reduced pressure to give a black oily liquid, crystallized by cooling, and filtered to give 1515.4g of a brown solid with a yield of 94%.
Preparation of compound I:
dissolving the compound II (5.4kg, 15.83mol, 1eq.) in toluene (7.6L) and acetic acid (9508g, 158.34mol, 10eq.), heating to 50-70 ℃, adding zinc powder (4141g, 63.34mol, 4eq.) in batches, releasing heat, and controlling the internal temperature to be not more than 85 ℃ after about 8 hours. Stirring for two hours at 70 ℃, heating to 90-95 ℃ for reaction for 24 hours, discharging while the reaction is finished, cooling to room temperature, separating a toluene phase, adding 20L of water into the residual jelly, stirring for 1 hour until a large amount of solid exists, and filtering;
adjusting pH of the filtrate to 12 with sodium hydroxide, controlling temperature to be less than 45 deg.C, releasing heat violently, precipitating a large amount of solid, and adding 2-methyltetrahydrofuran (10L);
add (Boc) with stirring2O (4146.9g, 19.00mol, 1.2eq.) and reacting at 30 ℃ for 12 hours, TLC shows complete reaction, centrifuging, washing the solid with 2-methyltetrahydrofuran for 2 times, combining filtrates, separating liquid, extracting the aqueous phase with 2-methyltetrahydrofuran, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain about 2060g of brown liquid;
adding 4L of methanol, introducing hydrogen chloride gas, controlling the temperature to be 15-20 ℃, displaying complete reaction by TLC, concentrating to remove the methanol, pulping residues by using acetone, and filtering to obtain 1277.6g of off-white solid with the yield of 67.45%.
Example 6
Preparation of compound II:
dissolving a compound VI (650g, 3.84mol, 1eq.) in 13L petroleum ether, adding potassium tert-butoxide (3448g, 30.73mol, 8eq.), cooling to 10 ℃ under the protection of nitrogen, dropwise adding tribromomethane (4854g, 19.20mol, 5eq.), naturally raising the temperature to room temperature after about 2 hours of addition, sampling, monitoring and ending the reaction. The reaction solution was centrifuged, the filtrate was washed with water for 2 times, concentrated under reduced pressure to give a black oily liquid, crystallized by cooling, and filtered to give 1126.5g of a brown solid with a yield of 86%.
Preparation of compound I:
dissolving the compound II (540g, 1.58mol, 1eq.) in toluene (0.6L) and acetic acid (665g, 11.08mol, 7eq.), heating to 65-80 ℃, adding zinc powder (517.7g, 7.92mol, 5eq.) in batches, releasing heat, and controlling the internal temperature to be not more than 85 ℃ after about 0.5 hour addition. Stirring for two hours at 70 ℃, heating to 90-95 ℃ for reaction for 24 hours, discharging while the reaction is finished, cooling to room temperature, separating out a toluene phase, adding 1.2L of water into the residual jelly, stirring for 1 hour until a large amount of solid exists, and filtering;
adjusting pH of the filtrate to 12 with sodium hydroxide, controlling temperature to be less than 45 deg.C, releasing heat violently, precipitating a large amount of solid, and adding 2-methyltetrahydrofuran (1.5L);
add (Boc) with stirring2O (362.85g, 1.66mol, 1.05eq.) and reacting at 30 ℃ for 12 hours, TLC shows complete reaction, centrifuging, washing the solid with 2-methyltetrahydrofuran for 2 times, combining filtrates, separating liquid, extracting the water phase with 2-methyltetrahydrofuran, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain about 232.13g of brown liquid;
adding 250mL of methanol, introducing hydrogen chloride gas, controlling the temperature to be 15-20 ℃, displaying complete reaction by TLC, concentrating to remove the methanol, pulping residues by using acetone, and filtering to obtain 141.99g of white-like solid with the yield of 75%.
Example 7
Preparation of compound I:
dissolving a compound II (682g, 2.00mol, 1eq.) in benzene (0.6L) and acetic acid (720.5g, 12.00mol, 6eq.), heating to 65-80 ℃, adding zinc powder (523g, 8.00mol, 4eq.) in batches, releasing heat, and controlling the internal temperature to be not more than 85 ℃ after about 0.5 hour. Stirring for two hours at 70 ℃, heating to 90-95 ℃ for reaction for 24 hours, discharging while the reaction is finished, cooling to room temperature, separating a benzene phase, adding 1.2L of water into the remaining jelly, stirring for 1 hour until a large amount of solid exists, and filtering;
adjusting pH of the filtrate to 11 with sodium carbonate, controlling temperature to be less than 45 deg.C, releasing heat violently, adding 2-methyltetrahydrofuran (1.5L);
add (Boc) with stirring2O (654.7g, 3.00mol, 1.5eq.) and reacting at 30 ℃ for 12 hours, TLC shows complete reaction, centrifuging, washing the solid with 2-methyltetrahydrofuran for 2 times, combining filtrates, separating liquid, extracting the water phase with 2-methyltetrahydrofuran, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain about 274.84g of brown liquid;
adding 300mL of acetone, introducing hydrogen chloride gas, controlling the temperature to be 15-20 ℃, displaying complete reaction by TLC, filtering, pulping residues by using acetone, and filtering to obtain 161.84g of white-like solid with the yield of 67.6%.
Example 8
Preparation of compound I:
dissolving the compound II (341g, 1.00mol, 1eq.) in benzene (0.6L) and acetic acid (420.3g, 7.00mol, 7eq.), heating to 65-80 ℃, adding zinc powder (261.5g, 4.00mol, 4eq.) in batches, releasing heat, controlling the internal temperature not to exceed 85 ℃, and finishing the addition for about 0.5 hour. Stirring for two hours at 70 ℃, heating to 80-90 ℃ for reaction for 23 hours, discharging while the reaction is finished, cooling to room temperature, separating a benzene phase, adding 1.2L of water into the remaining jelly, stirring for 1 hour until a large amount of solid exists, and filtering;
adjusting pH of the filtrate to 12 with potassium carbonate, controlling temperature to be less than 45 deg.C, releasing heat violently, adding 2-methyltetrahydrofuran (1.5L);
add (Boc) with stirring2O (261.87g, 1.20mol, 1.2eq.) at 30 ℃ for 12 h, TLC showed complete reaction, centrifugation and application of solidWashing with 2-methyltetrahydrofuran for 2 times, combining filtrates, separating liquid, extracting water phase with 2-methyltetrahydrofuran, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain about 131.92g of brown liquid;
adding 300mL of THF, introducing hydrogen chloride gas, controlling the temperature to be 15-20 ℃, indicating complete reaction by TLC, concentrating to remove THF, pulping residues by using acetone, and filtering to obtain 79.84g of off-white solid with the yield of 66.7%.
Example 9
Preparation of compound I:
dissolving a compound II (682g, 2.00mol, 1eq.) in dimethylbenzene (0.6L) and acetic acid (720.5g, 12.00mol, 6eq.), heating to 65-80 ℃, adding zinc powder (523g, 8.00mol, 4eq.) in batches, releasing heat, and controlling the internal temperature to be not more than 85 ℃ after about 0.5 hour addition. Stirring for two hours at 70 ℃, heating to 95-100 ℃ for reaction for 20 hours, discharging while the reaction is finished, cooling to room temperature, separating out a dimethylbenzene phase, adding 1.2L of water into the residual jelly, stirring for 1 hour until a large amount of solid exists, and filtering;
adjusting pH of the filtrate to 12 with potassium carbonate, controlling temperature to be less than 45 deg.C, releasing heat violently, adding 2-methyltetrahydrofuran (1.5L);
add (Boc) with stirring2O (523.7g, 2.40mol, 1.2eq.) and reacting at 30 ℃ for 12 hours, TLC shows complete reaction, centrifuging, washing the solid with 2-methyltetrahydrofuran for 2 times, combining filtrates, separating liquid, extracting the water phase with 2-methyltetrahydrofuran, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain about 252.86g of brown liquid;
adding 300mL of THF, introducing hydrogen chloride gas, controlling the temperature to be 15-20 ℃, indicating complete reaction by TLC, concentrating to remove THF, pulping residues by using acetone, and filtering to obtain 156.82g of off-white solid with the yield of 65.5%.
Example 10
Preparation of compound ii:
dissolving a compound vi (10g, 49.2mmol, 1eq.) in 100mL of n-heptane, adding sodium tert-amylate (16.3g, 148mmol, 3eq.), cooling to-15 ℃ under the protection of nitrogen, dropwise adding tribromomethane (87.0g, 344.4mmol, 7eq.), controlling the temperature to-15 ℃ to-5 ℃, finishing the addition within about 15 minutes, naturally raising the temperature to 18 ℃ for reaction for 12 hours,1HNMR detects the content of the compound vi to be about 50 percent, prolongs the reaction for 12 hours,1the HNMR detected the vi content of the compound to be about 50%, and the reaction did not proceed any more.
Claims (11)
1. A method for preparing 3-azabicyclo [3.1.0] hexane hydrochloride comprising the steps of:
(a) taking a compound II as a raw material, and reacting the compound II with acetic acid and zinc powder in a solvent under a heating condition to obtain a reaction solution containing a compound III;
(b) treating the reaction solution containing the compound III with alkali to obtain a treatment solution containing a compound IV;
(c) reacting the treatment solution containing the compound IV with hydrogen chloride gas to obtain 3-azabicyclo [3.1.0] hexane hydrochloride shown as a compound I;
2. the method according to claim 1, wherein the step (c) further comprises a step of reacting the treated solution containing the compound IV with di-tert-butyl dicarbonate to obtain a compound V, wherein the compound V is dissolved in a solvent and then reacted with hydrogen chloride gas to obtain 3-azabicyclo [3.1.0] hexane hydrochloride represented by the compound I,
3. the preparation method according to claim 1 or 2, characterized in that the zinc powder in step (a) is added in portions by controlling the reaction system at 50-85 ℃; the heating is carried out under the condition of 80-100 ℃.
4. The preparation method of claim 1 or 2, wherein the molar ratio of the compound II, zinc powder and acetic acid is 1: 3-10: 4-5.
5. The method according to claim 1 or 2, wherein the solvent in the step of synthesizing the compound III from the compound II is any one of toluene, xylene, or benzene.
6. The method according to claim 1 or 2, wherein the base in step (b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
7. The process according to claim 1 or 2, wherein compound II is prepared by the reaction of:
8. the process according to claim 7, wherein in the preparation of compound II from compound VI, the base is any one of sodium tert-amylate, potassium tert-amylate or potassium tert-amylate.
9. The method according to claim 7, wherein the solvent used in the preparation of compound II from compound VI is any one of petroleum ether, n-hexane and n-heptane.
10. The preparation method according to claim 7, wherein in the process of preparing the compound II from the compound VI, the molar ratio of the compound VI, the base and the tribromomethane is 1: 5-8: 2-5.
11. The preparation method according to claim 7, wherein during the preparation of the compound II from the compound VI, the temperature of a reaction system is controlled to be-15-10 ℃, and the bromoform is slowly added.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4183857A (en) * | 1978-07-06 | 1980-01-15 | Shell Oil Company | 3-Benzyl-3-azabicyclo(3.1.0)hexane-2,4-dione |
| CN101318925A (en) * | 2007-06-04 | 2008-12-10 | 上海恒瑞医药有限公司 | Pyrrolidine-tetratomic ring derivants, preparation method and medical uses thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4183857A (en) * | 1978-07-06 | 1980-01-15 | Shell Oil Company | 3-Benzyl-3-azabicyclo(3.1.0)hexane-2,4-dione |
| CN101318925A (en) * | 2007-06-04 | 2008-12-10 | 上海恒瑞医药有限公司 | Pyrrolidine-tetratomic ring derivants, preparation method and medical uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| Conformational Constraint in Oxazolidinone Antibacterials. Synthesis and Structure-Activity Studies of (Azabicyclo[3.1.0]hexylphenyl)oxazolidinones;Adam R. Renslo,等;《Journal of Medicinal Chemistry》;20050622;第48卷(第15期);第5009-5024页尤其是第5010页方案3，第5015页右栏第2段 * |
| Design, synthesis and activity of novel derivatives of Oxybutynin and Tolterodine;Kirandeep Kaur,等;《Bioorganic & Medicinal Chemistry Letters》;20050319;第15卷(第8期);第2093-2096页尤其是第2094页方案1 * |
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