CN112552222B - Preparation method of 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octane-5-yl) acetic acid - Google Patents
Preparation method of 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octane-5-yl) acetic acid Download PDFInfo
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Abstract
The invention discloses a preparation method of 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octane-5-yl) acetic acid, which comprises the following steps: dissolving the compound 1 and the compound 2 in 2-methyltetrahydrofuran, and dripping lithium bis (trimethylsilyl) amide into the mixture to react to obtain a compound 3; dissolving the compound 3 in acetone, and reacting with sodium iodide to obtain a compound 4; dissolving the compound 4 in 2-methyltetrahydrofuran, and then dropwise adding n-butyllithium to react to obtain a compound 5; dissolving a compound 5 in 2-methyltetrahydrofuran, adding a compound 6, a base and 1, 8-diazabicycloundecen-7-ene, and reacting at room temperature to obtain a compound 7; dissolving the compound 7 in ethyl acetate, adding a catalyst, and reacting in hydrogen to obtain a compound 8; dissolving the compound 8 in tetrahydrofuran and water, adding alkali for hydrolysis to obtain a final compound 9, and continuously optimizing the structure of a spiro compound to obtain the synthetic method suitable for industrial production.
Description
Technical Field
The invention relates to a synthesis method of a compound, in particular to a preparation method of a compound 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octane-5-yl) acetic acid.
Background
Compared with foreign competitors, Chinese medicine enterprises are frequently troubled by the problems of technology, fund and the like, new medicine development work cannot be effectively carried out, only foreign patent overdue medicines can be simply and repeatedly produced or imitated, the products lack international competitiveness, the domestic market is also seriously threatened by imported western medicines, and the discovery of a lead compound is a necessary way for discovering innovative medicines. Because the new drug development cycle is long (8-10 years) and the cost is high (8-10 hundred million dollars), most developed countries adopt a 'multi-, fast-, high-and provincial' method-combined chemical technology platform to accelerate the development and production of small molecular drug precursors, so that the new drug development cycle can be shortened by 5-7 years, and the foundation and cradle which can enable the platform to play a role are various high-quality template compounds. Through years of research, the novel spiro drug template compound is found to have various biological activities with wide prospects, but few compounds for new drug screening can be collected nationwide, and the requirement of innovative drug development cannot be met. The spirocyclic template compounds have few reports in documents, and pharmaceutical enterprises in China basically have no technical capability in design, research and development and production. The spiro compounds with novel chemical structures are just indispensable in the development of new drugs.
The compound 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid is a novel spiro compound that we have designed autonomously. No literature is available for the current synthetic method. Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production. The novel spiro compound structure is independently designed, a synthetic route is designed, and a synthetic method suitable for industrial production is found through continuous optimization. The breakthrough of the key technology of the project has important practical significance on the research and development of new drugs in China and has profound influence on the development of the new drugs.
Disclosure of Invention
The invention aims to solve the problem that the screening of new drugs is limited due to the fact that few novel spiro template compounds are used in China. The invention develops a preparation method of 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octane-5-yl) acetic acid, has the advantages of easily obtained raw materials, convenient operation, easy control of reaction and higher yield, and is suitable for industrial production.
In order to solve the technical problems, the invention provides the following technical scheme:
a process for the preparation of 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid comprising the steps of:
firstly, dissolving a compound 5 in 2-methyltetrahydrofuran, then adding a compound 6, alkali and 1, 8-diazabicycloundec-7-ene, and reacting to obtain a compound 7;
secondly, dissolving the compound 7 in ethyl acetate, adding a catalyst, and reacting in hydrogen to obtain a compound 8;
thirdly, dissolving the compound 8 in tetrahydrofuran and water, adding alkali for hydrolysis to obtain a final compound 9, namely 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octane-5-yl) acetic acid;
the reaction formula of the method is as follows:
as a preferred embodiment of the present invention, 1 to 3 molar equivalents of compound 6 and 1 to 3 molar equivalents of a base are added to 1 molar equivalent of compound 5 in the first step.
As a preferable technical scheme of the invention, the alkali in the first step is any one of cesium carbonate, sodium hydrogen and potassium carbonate.
As a preferred embodiment of the invention, 0.02 to 0.1 molar equivalent of the catalyst is added in the second step per 1 molar equivalent of the compound 7.
As the preferable technical scheme of the invention, the catalyst in the second step is selected from Pd/C (palladium carbon), Pd (OH) 2 (Palladium hydroxide), PtO 2 (platinum dioxide).
As a preferable technical scheme of the invention, the alkali in the third step is any one of sodium hydroxide, potassium hydroxide and lithium hydroxide.
As a preferable technical scheme of the invention, the reaction condition in the first step is that the temperature is 15-35 ℃ and the reaction lasts for 6-10 hours.
As a preferred technical scheme of the invention, the reaction conditions in the second step are that the temperature is 15-35 ℃, the pressure is 15-25Psi, and the reaction is carried out for 6-10 hours.
As a preferable technical scheme of the invention, the reaction condition in the third step is that the temperature is 15-35 ℃ and the reaction lasts for 16-24 hours.
As a preferred embodiment of the present invention, in the first step, the preparation method of the compound 5 comprises the following steps:
a, dissolving a compound 1 and a compound 2 in 2-methyltetrahydrofuran, and then dripping lithium bis (trimethylsilyl) amide to react to obtain a compound 3;
step B, dissolving the compound 3 in acetone, and reacting with sodium iodide to obtain a compound 4;
step C, dissolving the compound 4 in 2-methyltetrahydrofuran, and then dropwise adding n-butyllithium to react to obtain a compound 5;
the reaction scheme for the process for preparing compound 5 is as follows:
as a preferable technical scheme of the invention, in the step A, the compound 1 and the compound 2 are dissolved in 2-methyltetrahydrofuran, the temperature is reduced to-60 ℃ to-78 ℃, and then lithium bis (trimethylsilyl) amide is dropwise added and reacts for 2-4 hours.
As a preferable technical scheme of the invention, in the step B, the compound 3 is dissolved in acetone to react with sodium iodide for 12-16 hours at the temperature of 50-70 ℃.
As a preferable technical scheme of the invention, in the step C, the compound 4 is dissolved in 2-methyltetrahydrofuran, and then n-butyllithium is dropwise added under the reaction condition that the temperature is-60 ℃ to-78 ℃ and the reaction is carried out for 1-3 hours.
The technical scheme provided by the preparation method of the 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octane-5-yl) acetic acid has the following technical effects:
the reaction process is reasonable in design, the raw material 3-cyano azetidine-1-carboxylic acid tert-butyl ester which is easy to obtain and can be produced in a large scale is adopted to synthesize the 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octane-5-yl) acetic acid through six steps, the method is short in route, the reaction is easy to amplify, and the operation is convenient.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
The compounds or reagents used in the following examples are not specifically described, but are all commercial compounds or reagents.
The Chinese explanation of the invention is as follows: TLC: thin layer chromatography; LCMS: high performance liquid chromatograph.
Example 1:
the reaction formula of example 1 is as follows:
the present embodiment adopts the following steps:
the first step is as follows: A10L three-necked flask was prepared, with mechanical stirring, thermometer and dropping funnel. Dissolving the compound 1(191g, 1.05mol,1.00eq) and the compound 2(187g, 1.19mol, 1.13eq) in 2-methyltetrahydrofuran (2000mL), cooling to-60 ℃ with dry ice, then slowly adding dropwise lithium bistrimethylsilyl amide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq) at a temperature of not more than-60 ℃ for about 2 hours, and stirring at-70 ℃ for 2 hours after the dropwise addition. TLC showed the starting material reaction was complete. The reaction was quenched with 10% aqueous ammonium chloride (900mL), diluted with water (800mL), and extracted twice with methyl tert-butyl ether (600mL), and the combined organic phases were washed once with 20% aqueous citric acid (1500mL) and saturated brine (800mL), and the organic phases were dried over magnesium sulfate, filtered, and spun dry to give compound 3(348g, crude) as a pale yellow solid.
The second step: compound 3(551g, 2.13mol, 1.00eq) was dissolved in acetone (4500mL), followed by addition of sodium iodide (670g, 4.47mol,2.10eq) and heating to 50 ℃ with stirring for 12 hours. The reaction solution was diluted with water (2000mL) and methyl tert-butyl ether (2000mL), after separation, the aqueous phase was extracted twice with methyl tert-butyl ether (1200mL), the combined organic phases were washed once with 5% aqueous sodium bicarbonate (1000mL), 10% sodium thiosulfate (1100mL) and saturated brine (1200mL), the organic phase was dried over magnesium sulfate, filtered and spun to give a compound which was dissolved in ethyl acetate (4000mL), further washed with water (2000mL) and saturated brine (2000mL), dried, filtered and spun to give a pale yellow solid, which was slurried with a mixed solvent of methyl tert-butyl ether (500mL) and isopropyl ether (750mL) for 2 hours, and filtered to give clean compound 4(405g, 1.16mol, yield: 54.3%).
The third step: 2-methyltetrahydrofuran (1200mL) was added to a 5L three-necked flask, which was then cooled to-60 ℃ and n-butyllithium (2.5M n-hexane solution, 350mL, 2.19eq) was added dropwise. Compound 4(140g, 400mmol, 1.00eq) was dissolved in 2-methyltetrahydrofuran (1000mL) and added dropwise slowly to the above solution at a temperature below-60 ℃ over about 3 hours. After the completion of the dropping, the reaction was carried out at-60 ℃ for 1 hour. TLC showed complete consumption of starting material. The reaction solution was quenched with 10% aqueous oxalic acid (1100mL), the quenching temperature was below-40 ℃, after quenching was complete, the temperature was slowly raised to room temperature, water (1000mL) and methyl tert-butyl ether (1000mL) were added for dilution, after separation, the aqueous phase was extracted once with methyl tert-butyl ether (1200mL), the combined organic phases were washed once with 10% aqueous sodium thiosulfate (500mL), 5% aqueous sodium bicarbonate (500mL) and saturated brine (1000mL), the organic phases were dried over magnesium sulfate, filtered, spun-dried to give a crude product, and then purified by silica gel column to give compound 5 as a white solid (70.8g, 315mmol, yield: 78.7%).
The fourth step: compound 5(50g,222mmol, 1.00eq) and compound 6(66.5g, 297mmol, 1.34eq) were dissolved in 2-methyltetrahydrofuran (150mL) and cesium carbonate (145g,445mmol, 2.00eq) and 1, 8-diazabicycloundec-7-ene (3.4g, 22.3mmol, 0.10eq) were added and the reaction mixture was stirred at 15 ℃ for 6 hours. LCMS showed disappearance of starting material and a new spot formed. The reaction mixture was diluted with water (300mL) and methyl t-butyl ether (600mL), the layers were separated, the aqueous phase was extracted twice with methyl t-butyl ether (600mL), the combined organic phases were washed once with saturated brine (600mL), and the organic phase was dried over magnesium sulfate, filtered, dried by spin-drying, and purified by column chromatography to give compound 7(62.3g, 211mmol, yield: 87%) as a colorless oil.
The fifth step: compound 7(61g, 207mmol, 1.00eq) was dissolved in ethyl acetate (700mL), and then Pd/C (palladium on carbon) (6.1g, 10% purity, 10% of the raw material mass fraction) was added, replaced several times with hydrogen gas, and stirred at 15Psi for 6 hours at 15 ℃. TLC showed the reaction was complete. The reaction mixture was filtered to remove palladium on carbon, and the filtrate was concentrated under reduced pressure to give compound 8(56g, 189mmol, yield: 91.3%) as a colorless oily substance.
And a sixth step: compound 8(56g, 189mmol, 1.00eq) was added to a mixture of solvents tetrahydrofuran (350mL) and water (300 mL). Lithium hydroxide monohydrate (10.2g, 243mmol, 1.29eq) was added, followed by stirring at 15 ℃ for 6 hours. LCMS showed disappearance of starting material. The reaction mixture was diluted with isopropyl ether (300mL), extracted twice with water (200mL), and the combined aqueous phases were washed once with isopropyl ether (200mL) and adjusted to pH 3 with 10% aqueous citric acid (250 mL). The aqueous phase was then extracted three times with ethyl acetate (200mL), the combined organic phases were washed twice with saturated brine (200mL), and the organic phases were dried over magnesium sulfate, filtered, and spun dry to give final compound 9(51.2g, 189mmol, 100% yield).
1HNMR(400MHz,CDCl3)δ3.82(d,J＝8.8Hz,1H),3.78-3.69(m,2H),3.56(d,J＝8.8Hz,1H),2.67-2.54(m,1H),2.28-2.15(m,2H),1.99-1.90(m,1H),1.90-1.77(m,2H),1.62(quin,J＝7.6Hz,2H),1.44(s,9H),1.37-1.24(m,1H)。
Example 2:
the reaction formula of example 2 is as follows:
the present embodiment adopts the following steps:
the first step is as follows: A10L three-necked flask was prepared, with mechanical stirring, thermometer and dropping funnel. Dissolving the compound 1(191g, 1.05mol,1.00eq) and the compound 2(187g, 1.19mol, 1.13eq) in 2-methyltetrahydrofuran (2000mL), cooling to-60 ℃ with dry ice, then slowly adding dropwise lithium bistrimethylsilyl amide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq) at a temperature of not more than-60 ℃ for about 2 hours, and stirring at-70 ℃ for 2 hours after the dropwise addition. TLC showed the starting material reaction was complete. The reaction was quenched with 10% aqueous ammonium chloride (900mL), diluted with water (800mL), and extracted twice with methyl tert-butyl ether (600mL), and the combined organic phases were washed once with 20% aqueous citric acid (1500mL) and saturated brine (800mL), and the organic phases were dried over magnesium sulfate, filtered, and spun dry to give compound 3(348g, crude) as a pale yellow solid.
The second step is that: compound 3(551g, 2.13mol, 1.00eq) was dissolved in acetone (4500mL) followed by the addition of sodium iodide (670g, 4.47mol,2.10eq) and heated to 50 ℃ with stirring for 12 hours. The reaction solution was diluted with water (2000mL) and methyl t-butyl ether (2000mL), the layers were separated, the aqueous phase was extracted twice with methyl t-butyl ether (1200mL), the combined organic phases were washed once with 5% aqueous sodium bicarbonate (1000mL), 10% sodium thiosulfate (1100mL) and saturated brine (1200mL), the organic phase was dried over magnesium sulfate, filtered and dried by spinning to give a pale yellow solid, which was slurried with a mixed solvent of methyl t-butyl ether (500mL) and isopropyl ether (750mL) for 2 hours to give clean compound 4(405g, 1.16mol, yield: 54.3%).
The third step: 2-methyltetrahydrofuran (1200mL) was added to a 5L three-necked flask, which was then cooled to-60 ℃ and n-butyllithium (2.5M n-hexane solution, 350mL, 2.19eq) was added dropwise. Compound 4(140g, 400mmol, 1.00eq) was dissolved in 2-methyltetrahydrofuran (1000mL) and added dropwise slowly to the above solution at a temperature below-60 ℃ over about 3 hours. After the completion of the dropping, the reaction was carried out at-60 ℃ for 1 hour. TLC showed complete consumption of starting material. The reaction solution was quenched with 10% aqueous oxalic acid (1100mL), the quenching temperature was below-40 ℃, after quenching was complete, the temperature was slowly raised to room temperature, water (1000mL) and methyl tert-butyl ether (1000mL) were added for dilution, after separation, the aqueous phase was extracted once with methyl tert-butyl ether (1200mL), the combined organic phases were washed once with 10% aqueous sodium thiosulfate (500mL), 5% aqueous sodium bicarbonate (500mL) and saturated brine (1000mL), the organic phases were dried over magnesium sulfate, filtered, spun-dried to give a crude product, and then purified by silica gel column to give compound 5 as a white solid (70.8g, 315mmol, yield: 78.7%).
The fourth step: compound 5(5g,22.2mmol,1.00eq) and compound 6(4.98g, 22.2mmol,1.00eq) were dissolved in 2-methyltetrahydrofuran (150mL) followed by the addition of cesium carbonate (7.23g,22.2mmol,1.00eq) and 1, 8-diazabicycloundec-7-ene (0.34g,2.2mmol,0.1eq) and the reaction mixture was stirred at 15 ℃ for 6 hours. LCMS showed disappearance of starting material and a new spot was formed. The reaction mixture was diluted with water (30mL) and methyl t-butyl ether (60mL), and after separation, the aqueous phase was extracted twice with methyl t-butyl ether (100mL), the combined organic phases were washed once with saturated brine (100mL), and the organic phase was dried over magnesium sulfate, filtered, spin-dried, and purified by column chromatography to give compound 7(5g, yield: 76.3%) as a colorless oil.
The fifth step: compound 7(5g) was dissolved in ethyl acetate (100mL), then Pd/C (palladium on carbon) (0.5g, 10% pure) was added, replaced several times with hydrogen, and stirred at 15Psi, 15 ℃ for 6 hours. The reaction mixture was filtered to remove palladium on carbon, and the filtrate was concentrated under reduced pressure to give compound 8(4.5g, yield 90%) as a colorless oily substance.
And a sixth step: compound 8(4.5g,15.13mmol,1.00eq) was added to a mixed solvent of tetrahydrofuran (50mL) and water (50 mL). Lithium hydroxide monohydrate (0.64g,15.13mmol,1.00eq) was added, followed by stirring at 15 ℃ for 16 hours. LCMS showed disappearance of starting material. The reaction mixture was diluted with isopropyl ether (30mL), extracted twice with water (20mL), and the combined aqueous phases were washed once with isopropyl ether (20mL) and adjusted to pH 3 with 10% citric acid. The aqueous phase was then extracted three times with ethyl acetate (50mL), the combined organic phases were washed twice with saturated brine (100mL), and the organic phases were dried over magnesium sulfate, filtered, and spun dry to give final compound 9(4.0g, 98.1% yield).
1HNMR(400MHz,CDCl3)δ3.82(d,J＝8.8Hz,1H),3.78-3.69(m,2H),3.56(d,J＝8.8Hz,1H),2.67-2.54(m,1H),2.28-2.15(m,2H),1.99-1.90(m,1H),1.90-1.77(m,2H),1.62(quin,J＝7.6Hz,2H),1.44(s,9H),1.37-1.24(m,1H)。
Example 3:
the reaction formula of example 3 is as follows:
the present embodiment adopts the following steps:
the first step is as follows: a10-liter three-necked flask was prepared, and a mechanical stirrer, a thermometer and a dropping funnel were placed therein. Dissolving the compound 1(191g, 1.05mol,1.00eq) and the compound 2(187g, 1.19mol, 1.13eq) in 2-methyltetrahydrofuran (2000mL), cooling to-60 ℃ with dry ice, then slowly adding dropwise lithium bistrimethylsilyl amide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq) at a temperature of not more than-60 ℃ for about 2 hours, and stirring at-70 ℃ for 2 hours after the dropwise addition. TLC showed the starting material reaction was complete. The reaction was quenched with 10% aqueous ammonium chloride (900mL), diluted with water (800mL), and extracted twice with methyl tert-butyl ether (600mL), and the combined organic phases were washed once with 20% aqueous citric acid (1500mL) and saturated brine (800mL), and the organic phases were dried over magnesium sulfate, filtered, and spun dry to give compound 3(348g, crude) as a pale yellow solid.
The second step is that: compound 3(551g, 2.13mol, 1.00eq) was dissolved in acetone (4500mL), followed by addition of sodium iodide (670g, 4.47mol,2.10eq) and heating to 50 ℃ with stirring for 12 hours. The reaction solution was diluted with water (2000mL) and methyl t-butyl ether (2000mL), the layers were separated, the aqueous phase was extracted twice with methyl t-butyl ether (1200mL), the combined organic phases were washed once with 5% aqueous sodium bicarbonate (1000mL), 10% sodium thiosulfate (1100mL) and saturated brine (1200mL), the organic phase was dried over magnesium sulfate, filtered and dried by spinning to give a pale yellow solid, which was slurried with a mixed solvent of methyl t-butyl ether (500mL) and isopropyl ether (750mL) for 2 hours to give clean compound 4(405g, 1.16mol, yield: 54.3%). The third step: 2-methyltetrahydrofuran (1200mL) was added to a 5L three-necked flask, which was then cooled to-60 ℃ and n-butyllithium (2.5M n-hexane solution, 350mL, 2.19eq) was added dropwise. Compound 4(140g, 400mmol, 1.00eq) was dissolved in 2-methyltetrahydrofuran (1000mL) and added dropwise slowly to the above solution at a temperature below-60 ℃ over about 3 hours. After the completion of the dropping, the reaction was carried out at-60 ℃ for 1 hour. TLC showed complete consumption of starting material. The reaction solution was quenched with 10% aqueous oxalic acid (1100mL), the quenching temperature was below-40 ℃, after quenching was complete, the temperature was slowly raised to room temperature, water (1000mL) and methyl tert-butyl ether (1000mL) were added for dilution, after separation, the aqueous phase was extracted once with methyl tert-butyl ether (1200mL), the combined organic phases were washed once with 10% aqueous sodium thiosulfate (500mL), 5% aqueous sodium bicarbonate (500mL) and saturated brine (1000mL), the organic phases were dried over magnesium sulfate, filtered, spun-dried to give a crude product, and then purified by silica gel column to give compound 5 as a white solid (70.8g, 315mmol, yield: 78.7%).
The fourth step: compound 5(5g,22.2mmol,1.00eq) and compound 6(14.93g, 66.6mmol,3.00eq) were dissolved in 2-methyltetrahydrofuran (150mL) and cesium carbonate (21.69g,66.6mmol,3.00eq) and 1, 8-diazabicycloundec-7-ene (0.34g,2.2mmol,0.1eq) were added and the reaction mixture was stirred at 35 ℃ for 10 hours. LCMS showed disappearance of starting material and a new spot was formed. The reaction mixture was diluted with water (100mL) and methyl t-butyl ether (100mL), the layers were separated, the aqueous phase was extracted twice with methyl t-butyl ether (100mL), the combined organic phases were washed once with saturated brine (100mL), and the organic phase was dried over magnesium sulfate, filtered, spin-dried, and purified by column chromatography to give compound 7(5.5g, yield: 83.9%) as a colorless oil.
The fifth step: compound 7(5g) was dissolved in ethyl acetate (100mL), then Pd/C (palladium on carbon) (0.5g, 10% pure) was added, replaced several times with hydrogen gas, and stirred at 25Psi, 35 ℃ for 10 hours. The reaction mixture was filtered to remove palladium on carbon, and the filtrate was concentrated under reduced pressure to give compound 8(4.6g, yield 92%) as a colorless oily substance.
And a sixth step: compound 8(4.5g,15.13mmol,1.00eq) was added to a mixed solvent of tetrahydrofuran (50mL) and water (50 mL). Lithium hydroxide monohydrate (1.9g,45.4mmol,3.00eq) was added, followed by stirring at 35 ℃ for 24 hours. LCMS showed disappearance of starting material. The reaction mixture was diluted with isopropyl ether (50mL), extracted twice with water (50mL), and the combined aqueous phases were washed once with isopropyl ether (20mL) and adjusted to pH 3 with 10% citric acid. The aqueous phase was then extracted three times with ethyl acetate (50mL), the combined organic phases were washed twice with saturated brine (100mL), and the organic phases were dried over magnesium sulfate, filtered, and spun dry to give final compound 9(3.8g, 93.2% yield).
1HNMR(400MHz,CDCl3)δ3.82(d,J＝8.8Hz,1H),3.78-3.69(m,2H),3.56(d,J＝8.8Hz,1H),2.67-2.54(m,1H),2.28-2.15(m,2H),1.99-1.90(m,1H),1.90-1.77(m,2H),1.62(quin,J＝7.6Hz,2H),1.44(s,9H),1.37-1.24(m,1H)。
Example 4:
the reaction formula of example 4 is as follows:
the present embodiment adopts the following steps:
the first step is as follows: A10L three-necked flask was prepared, with mechanical stirring, thermometer and dropping funnel. Dissolving the compound 1(191g, 1.05mol,1.00eq) and the compound 2(187g, 1.19mol, 1.13eq) in 2-methyltetrahydrofuran (2000mL), cooling to-60 ℃ with dry ice, then slowly adding dropwise lithium bistrimethylsilyl amide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq) at a temperature of not more than-60 ℃ for about 2 hours, and stirring at-70 ℃ for 2 hours after the dropwise addition. TLC showed the starting material reaction was complete. The reaction was quenched with 10% aqueous ammonium chloride (900mL), diluted with water (800mL), and extracted twice with methyl tert-butyl ether (600mL), the combined organic phases were washed once with 20% aqueous citric acid (1500mL) and saturated brine (800mL), and the organic phases were dried over magnesium sulfate, filtered, and spun to give compound 3(348g, crude) as a pale yellow solid.
The second step is that: compound 3(551g, 2.13mol, 1.00eq) was dissolved in acetone (4500mL), followed by addition of sodium iodide (670g, 4.47mol,2.10eq) and heating to 50 ℃ with stirring for 12 hours. The reaction solution was diluted with water (2000mL) and methyl t-butyl ether (2000mL), the layers were separated, the aqueous phase was extracted twice with methyl t-butyl ether (1200mL), the combined organic phases were washed once with 5% aqueous sodium bicarbonate (1000mL), 10% sodium thiosulfate (1100mL) and saturated brine (1200mL), the organic phase was dried over magnesium sulfate, filtered and dried by spinning to give a pale yellow solid, which was slurried with a mixed solvent of methyl t-butyl ether (500mL) and isopropyl ether (750mL) for 2 hours to give clean compound 4(405g, 1.16mol, yield: 54.3%).
The third step: 2-methyltetrahydrofuran (1200mL) was added to a 5L three-necked flask, which was then cooled to-60 ℃ and n-butyllithium (2.5M n-hexane solution, 350mL, 2.19eq) was added dropwise. Compound 4(140g, 400mmol, 1.00eq) was dissolved in 2-methyltetrahydrofuran (1000mL) and added dropwise slowly to the above solution at a temperature below-60 ℃ over about 3 hours. After the completion of the dropping, the reaction was carried out at-60 ℃ for 1 hour. TLC showed complete consumption of starting material. The reaction solution was quenched with 10% aqueous oxalic acid (1100mL), the quenching temperature was below-40 ℃, after quenching was complete, the temperature was slowly raised to room temperature, water (1000mL) and methyl tert-butyl ether (1000mL) were added for dilution, after separation, the aqueous phase was extracted once with methyl tert-butyl ether (1200mL), the combined organic phases were washed once with 10% aqueous sodium thiosulfate (500mL), 5% aqueous sodium bicarbonate (500mL) and saturated brine (1000mL), the organic phases were dried over magnesium sulfate, filtered, spun-dried to give a crude product, and then purified by silica gel column to give compound 5 as a white solid (70.8g, 315mmol, yield: 78.7%).
The fourth step: compound 5(5.0g,22.2mmol, 1.00eq) and compound 6(6.65g, 29.7mmol, 1.34eq) were dissolved in 2-methyltetrahydrofuran (100mL) and then NaH (sodium hydride) (1.78g,44.5mmol, 60%, 2.00eq) and 1, 8-diazabicycloundec-7-ene (0.34g, 2.23mmol, 0.10eq) were added and the reaction mixture was stirred at 35 ℃ for 10 hours. LCMS showed disappearance of starting material and a new spot formed. The reaction mixture was diluted with water (100mL) and methyl t-butyl ether (100mL), the layers were separated, the aqueous phase was extracted twice with methyl t-butyl ether (100mL), the combined organic phases were washed once with saturated brine (100mL), the organic phase was dried over magnesium sulfate, filtered, spun-dried, and purified by column chromatography to give compound 7(6.3g, yield: 88%) as a colorless oily compound.
The fifth step: compound 7(6.1g, 20.7mmol, 1.00eq) was dissolved in ethyl acetate (100mL) followed by the addition of Pd (OH) 2 (Palladium hydroxide) (0.6g, 10% by mass of the starting material) was replaced with hydrogen gas several times, and the mixture was stirred at 25Psi at 35 ℃ for 10 hours. TLC showed the reaction was complete. The reaction mixture was filtered to remove palladium on carbon, and the filtrate was concentrated under reduced pressure to give compound 8(5.5g, 18.5mmol, yield: 89.7%) as a colorless oily substance.
And a sixth step: compound 8(4.5g,15.13mmol,1.00eq) was added to a mixed solvent of tetrahydrofuran (50mL) and water (50 mL). Sodium hydroxide (1.21g,30.16mmol,2.00eq) was added, followed by stirring at 20 ℃ for 15 hours. LCMS showed disappearance of starting material. The reaction mixture was diluted with isopropyl ether (50mL), extracted twice with water (50mL), and the combined aqueous phases were washed once with isopropyl ether (20mL) and adjusted to pH 3 with 10% citric acid. The aqueous phase was then extracted three times with ethyl acetate (50mL), the combined organic phases were washed twice with saturated brine (100mL), and the organic phases were dried over magnesium sulfate, filtered, and spun dry to give final compound 9(3.7g, 90.8% yield).
1HNMR(400MHz,CDCl3)δ3.82(d,J＝8.8Hz,1H),3.78-3.69(m,2H),3.56(d,J＝8.8Hz,1H),2.67-2.54(m,1H),2.28-2.15(m,2H),1.99-1.90(m,1H),1.90-1.77(m,2H),1.62(quin,J＝7.6Hz,2H),1.44(s,9H),1.37-1.24(m,1H)。
Example 5:
the reaction formula of example 5 is as follows:
the present embodiment adopts the following steps:
the first step is as follows: A10L three-necked flask was prepared, with mechanical stirring, thermometer and dropping funnel. Dissolving the compound 1(191g, 1.05mol,1.00eq) and the compound 2(187g, 1.19mol, 1.13eq) in 2-methyltetrahydrofuran (2000mL), cooling to-60 ℃ with dry ice, then slowly adding dropwise lithium bistrimethylsilyl amide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq) at a temperature of not more than-60 ℃ for about 2 hours, and stirring at-70 ℃ for 2 hours after the dropwise addition. TLC showed the starting material reaction was complete. The reaction was quenched with 10% aqueous ammonium chloride (900mL), diluted with water (800mL), and extracted twice with methyl tert-butyl ether (600mL), and the combined organic phases were washed once with 20% aqueous citric acid (1500mL) and saturated brine (800mL), and the organic phases were dried over magnesium sulfate, filtered, and spun dry to give compound 3(348g, crude) as a pale yellow solid.
The second step is that: compound 3(551g, 2.13mol, 1.00eq) was dissolved in acetone (4500mL), followed by addition of sodium iodide (670g, 4.47mol,2.10eq) and heating to 50 ℃ with stirring for 12 hours. The reaction solution was diluted with water (2000mL) and methyl t-butyl ether (2000mL), the layers were separated, the aqueous phase was extracted twice with methyl t-butyl ether (1200mL), the combined organic phases were washed once with 5% aqueous sodium bicarbonate (1000mL), 10% sodium thiosulfate (1100mL) and saturated brine (1200mL), the organic phase was dried over magnesium sulfate, filtered and dried by spinning to give a pale yellow solid, which was slurried with a mixed solvent of methyl t-butyl ether (500mL) and isopropyl ether (750mL) for 2 hours to give clean compound 4(405g, 1.16mol, yield: 54.3%).
The third step: 2-methyltetrahydrofuran (1200mL) was added to a 5L three-necked flask, which was then cooled to-60 ℃ and n-butyllithium (2.5M n-hexane solution, 350mL, 2.19eq) was added dropwise. Compound 4(140g, 400mmol, 1.00eq) was dissolved in 2-methyltetrahydrofuran (1000mL) and added dropwise slowly to the above solution at a temperature below-60 ℃ over about 3 hours. After the completion of the dropping, the reaction was carried out at-60 ℃ for 1 hour. TLC showed complete consumption of starting material. The reaction solution was quenched with 10% aqueous oxalic acid (1100mL), the quenching temperature was below-40 ℃, after quenching was complete, slowly warmed to room temperature, diluted with water (1000mL) and methyl tert-butyl ether (1000mL), after layering, the aqueous phase was extracted once with methyl tert-butyl ether (1200mL), the combined organic phases were washed once with 10% aqueous sodium thiosulfate (500mL), 5% aqueous sodium bicarbonate (500mL), and saturated brine (1000mL), the organic phases were dried over magnesium sulfate, filtered, and spin-dried to give a crude product, which was then purified by silica gel column to give compound 5(70.8g, 315mmol, yield: 78.7%) as a white solid.
The fourth step: compound 5(5.0g,22.2mmol, 1.00eq) and compound 6(6.65g, 29.7mmol, 1.34eq) were dissolved in 2-methyltetrahydrofuran (100mL) and then potassium carbonate (1.69g,44.5mmol, 2.00eq) and 1, 8-diazabicycloundec-7-ene (0.34g, 2.23mmol, 0.10eq) were added and the reaction mixture was stirred at 35 ℃ for 10 hours. LCMS showed disappearance of starting material and new spot formed. The reaction mixture was diluted with water (100mL) and methyl t-butyl ether (100mL), the layers were separated, the aqueous phase was extracted twice with methyl t-butyl ether (100mL), the combined organic phases were washed once with saturated brine (100mL), and the organic phase was dried over magnesium sulfate, filtered, spin-dried, and purified by column chromatography to give compound 7(4.0g, yield: 55%) as a colorless oil.
The fifth step: compound 7(4.0g, 13.6mmol, 1.00eq) was dissolved in ethyl acetate (100mL) and PtO was added 2 (platinum dioxide) (0.4g, 10% by mass of the starting material), was replaced with hydrogen several times, and stirred at 25Psi at 35 ℃ for 10 hours. TLC showed the reaction was complete. The reaction mixture was filtered to remove palladium on carbon, and the filtrate was concentrated under reduced pressure to give colorless oily compound 8(3.5g,11.77mmol, yield: 86.5%).
And a sixth step: compound 8(3.5g,11.77mmol,1.00eq) was added to a mixed solvent of tetrahydrofuran (50mL) and water (50 mL). Potassium hydroxide (1.32g,23.54mmol,2.00eq) was added, followed by stirring at 20 ℃ for 15 hours. LCMS showed disappearance of starting material. The reaction mixture was diluted with isopropyl ether (50mL), extracted twice with water (50mL), and the combined aqueous phases were washed once with isopropyl ether (20mL) and adjusted to pH 3 with 10% citric acid. The aqueous phase was then extracted three times with ethyl acetate (50mL), the combined organic phases were washed twice with saturated brine (100mL), and the organic phases were dried over magnesium sulfate, filtered, and spun-dried to give final compound 9(3.0g, 11.14mmol, yield: 94.6%).
1HNMR(400MHz,CDCl3)δ3.82(d,J＝8.8Hz,1H),3.78-3.69(m,2H),3.56(d,J＝8.8Hz,1H),2.67-2.54(m,1H),2.28-2.15(m,2H),1.99-1.90(m,1H),1.90-1.77(m,2H),1.62(quin,J＝7.6Hz,2H),1.44(s,9H),1.37-1.24(m,1H)。
In conclusion, the technical scheme provided by the invention is reasonable in reaction process design, the raw material 3-cyanoazetidine-1-carboxylic acid tert-butyl ester which is easy to obtain and can be produced in a large scale is adopted to synthesize the 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octane-5-yl) acetic acid through six steps, and the method is short in route, easy to amplify in reaction and convenient to operate.
Specific embodiments of the invention have been described above. It is to be understood that the invention is not limited to the particular embodiments described above, in that devices and structures not described in detail are understood to be implemented in a manner common in the art; various changes or modifications may be made by one skilled in the art within the scope of the claims without departing from the spirit of the invention, and without affecting the spirit of the invention.
Claims (13)
1. A process for the preparation of 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid comprising the steps of:
firstly, dissolving a compound 5 in 2-methyltetrahydrofuran, and then adding a compound 6, alkali and 1, 8-diazabicycloundec-7-ene to react to obtain a compound 7; in the first step, the alkali is any one of cesium carbonate and sodium hydrogen;
secondly, dissolving the compound 7 in ethyl acetate, adding a catalyst, and reacting in hydrogen to obtain a compound 8;
thirdly, dissolving the compound 8 in tetrahydrofuran and water, adding alkali for hydrolysis to obtain a final compound 9, namely 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octane-5-yl) acetic acid;
the reaction formula of the method is as follows:
2. the process for producing 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid according to claim 1, characterized by comprising: in the first step, 1 to 3 molar equivalents of compound 6 and 1 to 3 molar equivalents of base are added per 1 molar equivalent of compound 5.
3. The process for producing 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid according to claim 1, characterized by comprising: in the second step, 0.02 to 0.1 molar equivalent of the catalyst is added per 1 molar equivalent of the compound 7.
4. 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] according to claim 3]Method for preparing octane-5-base) acetic acid, wherein the catalyst in the second step is Pd/C, Pd (OH) 2 、PtO 2 Any one of them.
5. The process for producing 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid according to claim 1, which comprises: in the third step, the alkali is any one of sodium hydroxide, potassium hydroxide and lithium hydroxide.
6. The process for producing 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid according to any one of claims 1 to 5, characterized by comprising: the reaction conditions in the first step are 15-35 ℃ and 6-10 hours.
7. The process for producing 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid according to any one of claims 1 to 5, characterized by comprising: the reaction conditions in the second step are that the temperature is 15-35 ℃, the pressure is 15-25Psi, and the reaction is carried out for 6-10 hours.
8. The process for producing 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid according to any one of claims 1 to 5, characterized by comprising: the reaction condition in the third step is that the temperature is 15-35 ℃, and the reaction lasts for 16-24 hours.
9. The process for producing 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid according to any one of claims 1 to 5, characterized by comprising: in the first step, the preparation method of the compound 5 comprises the following steps:
a, dissolving a compound 1 and a compound 2 in 2-methyltetrahydrofuran, and then dripping lithium bis (trimethylsilyl) amide into the solution to react to obtain a compound 3;
step B, dissolving the compound 3 in acetone, and reacting with sodium iodide to obtain a compound 4;
step C, dissolving the compound 4 in 2-methyltetrahydrofuran, and then dropwise adding n-butyllithium to react to obtain a compound 5;
the reaction scheme for the process for preparing compound 5 is as follows:
10. the process for producing 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid according to claim 9, characterized by comprising: in the step A, the compound 1 and the compound 2 are dissolved in 2-methyltetrahydrofuran, the temperature is required to be reduced to-60 ℃ to-78 ℃, and then lithium bistrimethylsilyl amide is dripped into the mixture to react for 2 to 4 hours.
11. The process for producing 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid according to claim 9, characterized by comprising: in the step B, the compound 3 is dissolved in acetone to react with sodium iodide at the temperature of 50-70 ℃ for 12-16 hours.
12. The process for producing 2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.4] octan-5-yl) acetic acid according to claim 9, characterized by comprising: in the step C, the compound 4 is dissolved in 2-methyltetrahydrofuran, and then n-butyllithium is dripped into the mixture under the reaction condition that the temperature is between 60 ℃ below zero and 78 ℃ below zero, and the reaction is carried out for 1 to 3 hours.
13. A method for preparing a compound 8, which is characterized by comprising the following steps: comprises the following steps:
firstly, dissolving a compound 5 in 2-methyltetrahydrofuran, then adding a compound 6, alkali and 1, 8-diazabicycloundec-7-ene, and reacting to obtain a compound 7; in the first step, the alkali is any one of cesium carbonate and sodium hydrogen;
secondly, dissolving the compound 7 in ethyl acetate, adding a catalyst, and reacting in hydrogen to obtain a compound 8;
the reaction formula of the method is as follows:
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