Preparation method of exo-8-oxo-bicyclo [3.2. 1] octane-3-carboxylic acid methyl ester

Abstract

The invention discloses a preparation method of exo-8-oxo-bicyclo [3.2. 1] octane-3-carboxylic acid methyl ester, which comprises the following steps: carrying out deprotonation reaction on cyclopentanone under a strong alkali condition, and then carrying out ortho-alkylation reaction on the deprotonation product and 2-(bromomethyl) methyl acrylate to obtain 2-((2-oxo-cyclopentyl) methyl) methyl acrylate; 2-((2-oxocyclopentyl) methyl) methyl acrylate is subjected to a Michael addition cyclization reaction in a catalyst / organic solvent system, inner-8-oxobicyclo [3.2. 1] octane-3-carboxylic acid methyl ester is obtained, the reaction continues under the same conditions, and the inner-8-oxobicyclo [3.2. 1] octane-3-carboxylic acid methyl ester is obtained. And carrying out isomerization on the inner-8-oxo-bicyclo [3.2. 1] octane-3-carboxylic acid methyl ester until the inner-8-oxo-bicyclo [3.2. 1] octane-3-carboxylic acid methyl ester is completely converted into the outer-8-oxo-bicyclo [3.2. 1] octane-3-carboxylic acid methyl ester. The preparation method provided by the invention fills up the blank that the ex-8-oxo-bicyclo [3.2. 1] octane-3-carboxylic acid methyl ester cannot be synthesized in the prior art and the extrinsic derivative cannot be synthesized by using the extrinsic raw material in the actual research and development process.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic compound synthesis, and particularly relates to a preparation method of ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester. BACKGROUND

[0002] In recent years, 8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester has been widely used in the field of new drug research and development, which includes endo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester (CAS: 1036897-65-0) and ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester. Ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester has not been reported in the literature due to its special structure and structural stability. Therefore, the commercially available 8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester is actually an endo compound, not a mixture of endo and ex compounds.

[0003] At present, using endo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester as a raw material, a series of important endo derivatives have been synthesized in the actual process of new drug research and development. For example, US patent (publication number: US2015 / 23913) discloses that endo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester is subjected to ketone difluorination reaction with DAST, and finally P-44 is synthesized, as shown in the following synthesis route: Figure 2 WO2016 / 7185 discloses that endo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester is first hydrolyzed, and then subjected to Curtius rearrangement with DPPA and benzyl alcohol to obtain a Cbz-protected amino compound, and finally Compound 15 is obtained, as shown in the following synthesis route: Figure 2

[0004] Since the synthesis of ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester has not been reported, a series of important ex derivatives are missing in the actual research and development process. In view of this, the present application provides a preparation method of ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester to fill this gap. SUMMARY

[0005] In view of the problems existing in the prior art, the present application provides a preparation method of ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester.

[0006] In order to achieve the above-mentioned purpose, the present application adopts the following technical scheme:

[0007] The first aspect of the present application provides a preparation method of ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester, comprising the following steps:​

[0008]

[0009] S1, deprotonation reaction of cyclopentanone with structural formula as shown in formula (2) in aprotic solvent under the action of strong base;

[0010] S2, ortho-alkylation reaction of 2-(bromomethyl) methyl acrylate and deprotonation product to obtain 2-((2-oxocyclopentyl) methyl) methyl acrylate with structural formula as shown in formula (3);

[0011] S3, Michael addition cyclization reaction of the obtained 2-((2-oxocyclopentyl) methyl) methyl acrylate in a catalyst / organic solvent system to obtain (1R, 5S)-8-oxobicyclospiro[3.2.1]octane-3-carboxylic acid methyl ester with structural formula as shown in formula (4), and the same experimental conditions are continued to react until (1R, 5S)-8-oxobicyclospiro[3.2.1]octane-3-carboxylic acid methyl ester is completely isomerized into bridged ring compound with structural formula as shown in formula (1), i.e. exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester.

[0012] Preferably, the molar ratio of cyclopentanone, strong base and 2-(bromomethyl) methyl acrylate is 1:1-2:1-1.8.

[0013] Preferably, the strong base includes but is not limited to one or a combination of two or more of lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LHMDS), sodium bis(trimethylsilyl)amide (NaHMDS ) , potassium hexamethyldisilazane (KHMDS), lithium 2,2,6,6-tetramethylpiperidide (TMPLi), NaH, potassium tert-butoxide (t-BuOK).

[0014] Preferably, in step S1, the temperature of the deprotonation reaction is 0℃- -78℃, and the reaction time is 0.5-2.5h; when the strong base is one or a combination of two or more of lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LHMDS), sodium bis(trimethylsilyl)amide (NaHMDS ) , potassium hexamethyldisilazane (KHMDS), lithium 2,2,6,6-tetramethylpiperidide (TMPLi), potassium tert-butoxide (t-BuOK), the temperature of the deprotonation reaction is -20℃- -78℃; when the strong base is NaH, the temperature of the deprotonation reaction is 0℃.

[0015] Preferably, in step S2, the temperature of the ortho-alkylation reaction is -70℃- -78℃, and the reaction time is 1-3h.

[0016] Preferably, in step S1, the aprotic solvent is any one or a combination of two or more of tetrahydrofuran, diethyl ether, dioxane, methyl tetrahydrofuran, and further preferably tetrahydrofuran.

[0017] Preferably, in step S3, the catalyst in the catalyst / organic solvent system for the Michael addition-cyclization reaction is any one or a combination of two or more of tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium fluoride (TBAF), 1,8-diazabicycloundec-7-ene (DBU), K2CO3, Na2CO3, and the organic solvent is any one or a combination of two or more of toluene, chlorobenzene, xylene, diphenyl ether, tetrahydrofuran (THF), so the catalyst / organic solvent system for the Michael addition-cyclization reaction includes but is not limited to the following combinations: TBAB / organic solvent, TBAB / potassium carbonate / organic solvent, TBAC / organic solvent, TBAF / organic solvent, DBU / organic solvent, potassium carbonate / organic solvent, and the like, and further preferably TBAB / potassium carbonate / toluene and TBAB / THF.

[0018] Preferably, in step S3, the molar ratio of the methyl 2-((2-oxocyclopentyl)methyl)acrylate to the catalyst is 1:1-5.

[0019] Preferably, in step S3, the temperature for the Michael addition-cyclization reaction is 60-120°C, and the reaction time is 20-50 h. It is to be noted that the reaction time for each step in the synthetic method of the present application is determined according to the reaction raw materials and their usage amount, reaction temperature, and the like, and can be tracked by TLC or GC-MS to determine whether each reaction raw material is completely reacted.

[0020] Compared with the prior art, the present application has the following beneficial effects:

[0021] (1) The application provides a synthesis method of ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester, which comprises the following steps: firstly, deprotonation of cyclopentanone under strong alkaline conditions, then ortho-alkylation reaction of the protonated product and 2-(bromomethyl)propenoic acid methyl ester to obtain 2-((2-oxocyclopentyl)methyl)propenoic acid methyl ester; Michael addition and cyclization reaction of 2-((2-oxocyclopentyl)methyl)propenoic acid methyl ester in a catalyst / organic solvent system to obtain endo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester, namely (1R, 5S)-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester, and under the same experimental conditions, further reaction is continued until the endo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester is isomerized and all converted into ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester. The preparation method fills the blank of the prior art that ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester cannot be synthesized, and also fills the blank that in the actual research and development process, ex-type raw materials cannot be used to synthesize ex-type derivatives.

[0022] (2) According to actual requirements, by controlling the reaction node in step S3 of the application, endo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester, ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester and a mixture of endo and ex type 8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester can also be synthesized.

[0023] (3) The preparation method has the characteristics of simple operation and high yield, and therefore has excellent application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0024] In order to more clearly illustrate the technical solutions in the embodiments of the application, the drawings needed to be used in the embodiments will be briefly introduced as follows. Obviously, the drawings in the following description are only some embodiments of the application, and other drawings can also be obtained by those skilled in the art without any creative effort on the basis of these drawings.

[0025] Figure 1 A synthesis route diagram of ex-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester provided by the application;

[0026] Figure 2 A synthesis route diagram of corresponding endo-type derivatives synthesized by using endo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester in the prior art;

[0027] Figure 3 A nuclear magnetic resonance hydrogen spectrum diagram of endo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester;

[0028] Figure 4 The nuclear magnetic hydrogen spectrum of exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester. DETAILED DESCRIPTION

[0029] In the following description, for purposes of explanation and not limitation, specific details are set forth such as particular architectures, techniques, etc. in order to provide a thorough understanding of the embodiments of the present application. However, it will be apparent to those skilled in the art that the present application can be practiced in other embodiments that depart from these specific details.

[0030] Example 1

[0031] Reference Figure 1 , synthesis of exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester:

[0032] (1) Preparation of 2-((2-oxocyclopentyl)methyl) methyl acrylate:

[0033] Cyclopentanone (17 g, 0.202 mol) was dissolved in anhydrous tetrahydrofuran (140 mL) under nitrogen protection and cooled to -78 °C in a dry ice acetone bath, then LDA (151.58 mL, 0.303 mol) was slowly added dropwise into the above reaction solution, and the temperature was controlled not to exceed -70 °C, the dropwise time was 1 h, after the dropwise addition was completed, the reaction solution was continuously stirred at -78 °C for 1 h; then 2- (bromomethyl) methyl acrylate (47 g, 0.26 mol) was added dropwise into the reaction solution, and the temperature was controlled not to exceed -70 °C, the dropwise time was 0.5 h, after the dropwise addition was completed, the reaction was continuously stirred at -78 °C for 1 h, the reaction was monitored by TLC, after the reaction was completed, the temperature was slowly increased to 0 °C, and then quenched with saturated ammonium chloride solution (500 mL), then extracted with ethyl acetate (300 mL x 2), the organic phase was dried with anhydrous sodium sulfate, filtered with a Buchner funnel, and then concentrated to dryness, the crude product was column chromatographed with ethyl acetate and petroleum ether (1:20) to obtain 22 g of the target product 2-((2-oxocyclopentyl) methyl) methyl acrylate. 1 H NMR (300 MHz, CDCl3) δ 6.20 (s, 1H), 5.59 (s, 1H), 3.76 (s, 3H), 2.88 (dd, J = 14.1, 3.9 Hz, 1H), 2.42-2.25 (m, 2H), 2.22-2.10 (m, 3H), 2.08-1.95 (m, 1H), 1.85-1.70 (m, 1H), 1.55-1.43 (m, 1H).

[0034] (2) Preparation of exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester, the structure of which is shown below:

[0035]

[0036] Methyl 2-((2-oxocyclopentyl)methyl)acrylate (10 g, 54.9 mmol) was dissolved in 500 ml of toluene under nitrogen protection, then tetrabutylammonium bromide (17.69 g, 55.9 mmol) and potassium carbonate (22.75 g, 0.165 mol) were added at one time, and the reaction was carried out under stirring at 105°C for 48 h, then cooled to room temperature, filtered to remove insoluble matter, and then ethyl acetate (500 ml) was added to the obtained filtrate to obtain an organic phase, which was washed with water (800 ml), saturated brine (800 ml) in turn, then dried with anhydrous sodium sulfate, filtered, concentrated, and the obtained crude product was purified by column chromatography with ethyl acetate and petroleum ether (1:25) to obtain 4 g of the target product, methyl exo-8-oxobicyclo[3.2.1]octane-3-carboxylate, with a yield of 40%.

[0037] GCMS (EI + ) = 182; 1 H NMR (300 MHz, CDC13) δ 3.68 (s, 3H), 3.00

[0038] (m, 1H), 2.32-2.24 (m, 2H), 2.22-2.12 (m, 4H), 2.10-1.95 (m, 2H), 1.85-1.76 (m, 2H).

[0039] The progress of the above reaction was monitored by GC-MS, and it was found that when the reaction was carried out for 30 h, the raw material was basically consumed, and the main reaction product detected by GCMS was the endo product, i.e. methyl endo-8-oxobicyclo[3.2.1]octane-3-carboxylate (its nuclear magnetic hydrogen spectrum is shown in Figure 3 ), and only a small amount of the target exo product. When the reaction was carried out for 48 h, the reaction product composition detected by GCMS was the target exo product, i.e. methyl exo-8-oxobicyclo[3.2.1]octane-3-carboxylate (its nuclear magnetic hydrogen spectrum is shown in Figure 4 ).

[0040] It is also pointed out here that endo and exo are a kind of names of stereostructure, and the one close to the bridge ring system is endo, and the one far from the bridge ring system is exo. Since the hydrogen spectrum of endo and exo products is quite different, the non-chiral structure can be confirmed by hydrogen spectrum. In addition, since the target molecule is a new product, there is no literature hydrogen spectrum data to verify it at present, and the test shows that the target molecule is an axial symmetry structure, and the optical rotation data is 0.

[0041] Example 2

[0042] (1) Preparation of methyl 2-((2-oxocyclopentyl)methyl)acrylate Same as Example 1;

[0043] (2) Preparation of exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester: under nitrogen protection, 2-((2-oxocyclopentyl)methyl) methyl acrylate (1 g, 5.5 mmol) was dissolved in 50 mL of tetrahydrofuran, then TBAB (1.77 g, 5.5 mmol) was added at one time, and the temperature was raised to 65°C under stirring, and continued for 40 h, and then cooled to room temperature, filtered, removed the insoluble, and then added ethyl acetate (50 mL) to the obtained filtrate to obtain an organic phase, which was washed with water (80 mL), saturated brine (80 mL), dried with anhydrous sodium sulfate, filtered, concentrated to dryness, and the crude product was purified by column chromatography with ethyl acetate and petroleum ether (volume ratio 1:25), and finally 390 mg of the target product, exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester, was obtained, with a yield of 39%.

[0044] GCMS (EI + ) = 182; 1 H NMR (300 MHz, CDCl3): (s, 3H), 3.00 (m, 1H), 2.32-2.24 (m, 2H), 2.22-2.12 (m, 4H), 2.10-1.95 (m, 2H), 1.85-1.76 (m, 2H).

[0045] The progress of the above reaction was also monitored by GC-MS, and it was found that when the reaction was 24 h, the raw material was basically consumed, and the main reaction product detected by GCMS was the internal product, i.e. methyl exo-8-oxobicyclo[3.2.1]octane-3-carboxylate, and only a small amount of the target external product, when the reaction was 40 h, the reaction product detected by GCMS was the target external product, i.e. exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester.

[0046] The present application is not limited to the above specific embodiments, and various modifications made by those skilled in the art without creative labor, based on the above concept, are all within the scope of protection of the present application.

Claims

1. An exo-8-oxobicyclic [ 3.2.1] A method for preparing methyl octane-3-carboxylate, characterized by comprising the following steps: S1. Under a protective gas, cyclopentanone with the structural formula shown in formula (2) is deprotonated in an aprotic solvent and under the action of a strong base. S2. Methyl 2-(bromomethyl)acrylate and the deprotonated product are subjected to ortho-alkylation reaction to obtain methyl 2-((2-oxocyclopentyl)methyl)acrylate with the structural formula shown in formula (3). S3. The obtained methyl 2-((2-oxocyclopentyl)meth)acrylate was subjected to Michael addition cyclization reaction in a catalyst / organic solvent system to first obtain methyl (1R,5S)-8-oxobicyclospiro[3.2.1]octane-3-carboxylate with the structural formula shown in formula (4). The reaction was continued under the same experimental conditions until the methyl (1R,5S)-8-oxobicyclospiro[3.2.1]octane-3-carboxylate was completely isomerized into the bridged ring compound with the structural formula shown in formula (1), namely exo-8-oxobicyclo[3.2.1]octane-3-carboxylate.

2. The exo-8-oxobicyclo[] according to claim 1 3.2.1] A method for preparing methyl octane-3-carboxylate, characterized in that, In step S1, the temperature of the deprotonation reaction is 0℃ to -78℃, and the reaction time is 0.5 to 2.5 h.

3. The exo-8-oxobicyclo[] according to claim 1 3.2.1] A method for preparing methyl octane-3-carboxylate, characterized in that, The molar ratio of cyclopentanone, strong base and methyl 2-(bromomethyl)acrylate is 1:1 to 2:1 to 1.

8.

4. The method for preparing exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester according to claim 1, characterized in that, In step S1, the strong base is any one or a combination of two or more of lithium diisopropylamino, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium hexamethyldisilazane, lithium 2,2,6,6-tetramethylpiperidine, NaH, and potassium tert-butoxide; the aprotic solvent is any one or a combination of two or more of tetrahydrofuran, diethyl ether, dioxane, and methyltetrahydrofuran.

5. The method for preparing exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester according to claim 1, characterized in that, In step S2, the temperature of the ortho-alkylation reaction is -70℃ to -78℃, and the reaction time is 1 to 3 hours.

6. The method for preparing exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester according to claim 1, characterized in that, In step S3, the Michael addition cyclization reaction is carried out at a temperature of 60–120°C for 20–50 h.

7. The method for preparing exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester according to claim 1, characterized in that, In step S3, the molar ratio of methyl 2-((2-oxocyclopentyl)meth)acrylate to the catalyst is 1:1 to 5.

8. The method for preparing exo-8-oxobicyclo[3.2.1]octane-3-carboxylic acid methyl ester according to claim 1, characterized in that, In step S3, the catalyst is any one or a combination of two or more of TBAB, TBAC, TBAF, DBU, K2CO3, and Na2CO3.

9. The exo-8-oxobicyclo[] according to claim 1 3.2.1] A method for preparing methyl octane-3-carboxylate, characterized in that, In step S3, the organic solvent is any one or a combination of two or more of toluene, chlorobenzene, xylene, diphenyl ether, and THF.

Images