CN102838609B

CN102838609B - Azabicyclo [3.3.0] octane derivative, as well as preparation method and application thereof

Info

Publication number: CN102838609B
Application number: CN201210309254.2A
Authority: CN
Inventors: 姜雪峰; 谭忠飞; 姜卫华
Original assignee: East China Normal University
Current assignee: East China Normal University
Priority date: 2012-08-27
Filing date: 2012-08-27
Publication date: 2014-12-24
Anticipated expiration: 2032-08-27
Also published as: CN102838609A

Abstract

The invention discloses an azabicyclo [3.3.0] octane derivative with a new structure which is shown in a formula (I), wherein R1 in the formula is CH3, CH3CH2, (CH2)2, (CH2CH2CH2) or (CH2C(CH2)2CH2). The invention also discloses a preparation method of the azabicyclo [3.3.0] octane hydrochloride derivative. The preparation method provided by the invention has the advantages of simple operation and high yield and can be widely used in the industrial scale production. The azabicyclo [3.3.0] octane derivative prepared by the method provided by the invention is a potential intermediate for treating diabetes and can be used for preparing drugs for treating diabetes and the intermediate of the drugs for treating diabetes.

Description

azabicyclo [3.3.0] octane derivative and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an azabicyclo [3.3.0] octane derivative, and a preparation method and application thereof.

Background

Diabetes is a series of clinical syndromes caused by absolute or relative insufficiency of insulin in the body. The world health organization 2011 reports that 3.46 million people worldwide have diabetes, and in 2004 it is estimated that 340 million people die as a consequence of hyperglycemia, with over 80% of diabetes deaths occurring in low and medium income countries. At present, type 1 and type 2 diabetes cannot be completely cured. Therefore, research and development of novel drugs for treating diabetes become an important subject of domestic and foreign companies and research institutes.

In the prior art, azabicyclo [3.3.0] octane derivatives (aza-bicyclooctane [3.3.0] derivatives) are a very important chemical intermediate and have very high medical application value, for example, serine protease dipeptidylpeptidase (DDP-4) inhibitor (structure 1) for treating diabetes (Bioorganic and Medicinal Chemistry Letters,2010, 20, 3565-loop 3568) which has an azabicyclo [3.3.0] octane structure.

Azabicyclo [3.3.0] s of the prior art]The synthesis method of the octane derivative mainly comprises the following steps: one method is to use (7S,8R) -1,4-dioxaspiro [4.4 ] spiro as shown in equation (a)]-7.8-dicarboxylic acid methyl ester ((7S,8R) -1,4-dioxaspiro [ 4.4)]nonane-7,8-dicarboxylic acid dimethyl ester) was obtained by a blocked reaction with a secondary amine at 190 ℃ for 16 hours (J.org.chem.1989, 54,5115-5122 and WO 2004/087142). The method has the disadvantages of harsh reaction conditions and difficult realization in industrial scale-up production. Another method is to use Pg protected N, N' -propyne, propylene-amine (N- (prop-2-ynyl) prop-2-en-1-amine) to form a ring by Bauscon-Kande (Pauson-Khand) reaction under metal catalysis, and then to reduce the olefinic bond, as shown in equation (b) (Organic Letters,2002, 4, 3983-₂(CO)₈Is used as a raw material.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides an azabicyclo [3.3.0] octane derivative with a novel structure, which can be used for preparing a medicament for treating diabetes and an intermediate thereof. The preparation method provided by the invention is simple to operate and high in yield.

The invention provides an azabicyclo [3.3.0] octane derivative of a compound shown as a formula (I), which has a structure shown as the formula (I):

wherein R is₁Is CH₃、CH₃CH₂(ii) a Or two R₁Together form (CH)₂)₂Two R₁Together form (CH)₂CH₂CH₂) Or two R₁Together form (CH)₂C(CH₃)₂CH₂)。

The azabicyclo [3.3.0] octane derivatives of the compounds of formula (I) above take the reaction scheme shown below in formula (A):

the invention provides a preparation method of an azabicyclo [3.3.0] octane derivative shown as a formula (I), which is characterized in that 1,2,3, 6-tetrahydrophthalimide shown as a formula (VII) is used as a raw material, and the azabicyclo [3.3.0] octane derivative shown as the formula (I) is obtained through a protecting group reaction on an N atom, an oxidation reaction, a cyclization decarboxylation reaction, a carbonyl ketal protection reaction, a reduction reaction and a substituted benzyl removal reaction in sequence.

The preparation method of the azabicyclo [3.3.0] octane derivative specifically comprises the following steps:

the first step is as follows: reacting 1,2,3, 6-tetrahydrophthalimide with benzyl chloride in a polar solvent under an alkaline condition at 30-60 ℃, and separating and purifying to obtain the compound shown in the formula (VI).

The second step is that: a compound of formula (VI) with KMnO₄Carrying out oxidation reaction in a mixed solvent of acetone and water at room temperature, and separating and purifying to obtain the compound shown in the formula (V).

The third step: a compound of formula (V) with NaOA_cReacting in an acidic solvent at 100-130 ℃, and separating and purifying to obtain the compound shown in the formula (IV).

The fourth step: a compound of formula (1V) with R₁OH or HOR₁R₁OH dihydric alcohol reacts under the conditions of acid catalysis and reflux in benzene or toluene, and the compound shown in the formula (III) is obtained after separation and purification.

The fifth step: a compound represented by the formula (III) and LiAlH₄The reaction is carried out under the condition of refluxing in an aprotic solvent, and the compound shown in the formula (11) is obtained after separation and purification.

And a sixth step: separating and purifying to obtain the compound shown in the formula (III) and hydrogen, carrying out reduction reaction in an alcohol solvent under the condition of metal catalysis, and separating and purifying to obtain the compound shown in the formula (I).

Wherein,

the base is K₂CO₃，Na₂CO₃NaH, pyridine, triethylamine or diisopropylethylamine.

The acid is HCl, HBr, H₂SO₄，H₃PO₄，AcOH，CH₃COOH，CF₃COOH, TsOH or oxalic acid.

The acidic solvent is acetic acid, acetic anhydride or propionic acid.

The polar solvent is methanol, ethanol or N, N-Dimethylformamide (DMF).

The aprotic solvent is tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, benzene, toluene or ethylbenzene.

In the metal catalysis, the adopted catalyst is Pd/C or Pd (OH)₂/C。

The KMnO described above₄In an amount of three times the molar amount of the compound of formula (VI).

The above LiAlH₄The amount of the compound (B) is twice of the molar amount of the compound (III).

The invention innovatively provides an azabicyclo [3.3.0] octane derivative with a novel structure. The preparation method provided by the invention has the advantages of mild conditions, easily obtained and cheap raw materials, no toxic and harmful hazardous article reagent, simple reaction route, high yield and suitability for large-scale industrial production. The azabicyclo [3.3.0] octane derivative prepared by the invention is a potential intermediate for treating diabetes, and can be used for preparing a medicament for treating diabetes and the intermediate thereof.

Detailed Description

The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited thereto. The data given in the examples below include specific operating and reaction conditions and products. The purity of the product was identified by nuclear magnetism.

Example 1

Weighing 1,2,3, 6-tetrahydrophthalimide VII (4540.0)mg，30.0mmo1)，K₂CO₃(12440.0mg, 90.0mmo1), tetrabutylammonium bromide (TBAB) (970.0mg, 3.0mmo1) in a 250mL round bottom flask, was dissolved by adding 50.0mL of DMF. Benzyl chloride (4940.0mg, 39.0mmo1) was weighed and added dropwise slowly to the flask with stirring. After the reaction was completed at 30 ℃ for 5 hours, 50.0mL of water was added to quench the reaction. Then, 100.0mL of ethyl acetate was added for extraction, and after separation, the organic phase was washed with saturated brine (40.0 mL. times.5) and dried over anhydrous sodium sulfate overnight. The sodium sulfate was removed by filtration and the ethyl acetate was removed by rotary evaporation to give a crude white solid. Recrystallization from ethyl acetate/n-hexane gave 5740.0mg of the title compound (VI) in 79.3% yield. Mass Spectrometry MS (ESI, m/s): 241.

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.30～7.27(m，5H)，5.88～5.87(t，2H)，4.62(s，2H)，3.10～3.08(t，2H)，2.63～2.58(m，2H)，2.25～2.19(m，2H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)179.8，135.8，128.5，128.3，127.8，127.7，42.5，39.1，23.5。

the base used in this example was K₂CO₃Other suitable bases may also be Na₂CO₃NaH, pyridine, triethylamine or diisopropylethylamine. In this embodiment, DMF is used as the polar solvent, and other suitable polar solvents can be methanol or ethanol.

Example 2

120.0mL of Compound VI (8542.7mg, 35.4mmo1) in acetone was slowly added dropwise to 200.0mL of KMnO₄(16780.0mg, 106.2mm 1) in water, the reaction was stirred at room temperature for 3 hours, and the crude was monitored by TLCThe material disappeared. Sodium sulfite and concentrated hydrochloric acid were added, and the dichloromethane obtained in the reaction solution was rotary evaporated and extracted with ethyl acetate 4 times. The ethyl acetate were combined and dried over anhydrous sodium sulfate to give 9393.0mg of a crude product, Compound (V), as a white foamy solid. Directly putting into the next reaction.

Sodium acetate (3.788.0mg) was weighed into the above crude compound (V), and 50.0mL of acetic anhydride was added, followed by heating to 120 ℃ for 3 hours to complete the reaction. The acetic anhydride was drained, cooled to room temperature, 50.0mL of water was added, and solid sodium carbonate was added in portions to bring the pH to about 9. Extraction with ethyl acetate, combination of organic layers, drying over anhydrous sodium sulfate, and column chromatography gave 4453.0mg of the title compound. Yield: 51.7% and the product is a white solid, Compound (IV). Mass Spectrometry MS (ESI, m/s): 243(M + H). The acidic solvent used above is acetic anhydride, and the acidic solvent suitable for use herein may also be acetic acid or propionic acid.

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.37～7.31(m，5H)，4.66(s，2H)，3.56～3.52(m，2H)，2.82～2.74(m，2H)，2.59～2.53(m，2H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)212.7，177.7，135.3，128.8，128.7，128.2，42.8，40.7，39.1。

Example 3

Compound IV (973.2mg), ethylene glycol (744.0mg) and p-toluenesulfonic acid (76.1mg) were weighed into a 50.0mL single-neck reaction flask with a water separator, and 30.0mL of benzene was added. The reaction was substantially complete by heating to 60 ℃ for water separation and about 6 hours. The remaining solvent was drained, 30.0mL of ethyl acetate was added for dilution, the organic layer was washed with 10.0mL of saturated aqueous sodium bicarbonate solution,the organic layer was then washed with 10.0mL of saturated saline. Drying over anhydrous sodium sulfate and column chromatography gave 1103.2mg of the title compound III (a). Yield: 96.0% and white solid. Mass Spectrometry MS (ESI, m/s): 287. the acid used above is TsOH, and the acid suitable for use herein may also be HCl, HBr, H₂SO₄，H₃PO₄，AcOH，CH₃COOH，CF₃COOH or oxalic acid.

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.33～7.31(d，2H)，7.24～7.18(m，3H)，4.58(s，2H)，3.78～3.75(t，2H)，3.61～3.58(t，2H)，3.14～3.12(m，2H)，2.10～2.03(m，4H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)179.5，135.6，128.8，128.2，127.6，65.4，64.1，42.7，41.6，37.5。

Example 4

The procedure is as in example 3. Yield 95.0% and product as white solid compound iii (b). Mass Spectrometry MS (ESI, m/s): 288 (M-H).

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.37～7.35(d，2H)，7.28～7.17(m，3H)，4.54(s，2H)，3.11(s，3H)，3.09～3.06(q，2H)，2.54(s，3H)，2.36～2.33(m，2H)，1.89～1.83(m，2H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)179.5，135.7，129.2，128.4，127.7，108.5，50.8，48.1，42.6，41.7.35.8。

Example 5

The procedure is as in example 3. Yield 95.0% and product as white solid compound iii (c). Mass Spectrometry MS (ESI, m/s): 317(M + H).

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.42～7.40(d，2H)，7.32～7.27(m，3H)，4.60(s，2H)，3.51～3.45(q，2H)，3.22～3.12(m，4H)，2.49～2.42(m，2H)，2.03～1.93(m，2H)，1.17～1.14(t，2H)，0.85～0.81(t，2H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)179.7，135.8，129.0，128.6，127.8，106.1，58.7，56.6，42.5，41.9，36.7，15.3，14.9。

Example 6

The procedure is as in example 3. Yield 94.0% and product as white solid compound iii (d). Mass Spectrometry MS (ESI, m/s): 301.

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.43～7.41(d，2H)，7.33～7.24(m，3H)，4.61(s，2H)，3.82～3.79(t，2H)，3.30～3.27(t，2H)，3.21～3.15(m，2H)，2.67～2.64(d，2H)，1.99～1.93(m，2H)，1.60～1.55(m，2H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)179.6，135.7，129.1，128.4，127.6，106.0，62.8，60.0，42.6，41.5，36.3，24.9。

example 7

The procedure is as in example 3. Yield 96.0% and product as white solid compound iii (e). Mass Spectrometry MS (ESI, m/s): 329.

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.41～7.39(d，2H)，7.32～7.24(m，3H)，4.60(s，2H)，3.40(s，2H)，3.20～3.15(m，2H)，2.90(s，2H)，2.66～2.62(d，2H)，0.84(s，6H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)179.7，135.7，129.0，128.3，127.6，105.7，73.2，70.5，42.6，41.5，35.9，29.8，22.3。

example 8

Weighing LiAlH₄(304.0mg) in a 100mL two-necked flask with reflux condenser, the nitrogen was evacuated and 20.0mL of Tetrahydrofuran (THF) was added. Compound III (a) (1149.2mg) was weighed out and dissolved in 20.0mL of THF, and slowly added dropwise to the flask. After the dropwise addition, the mixture was heated under reflux and the starting material was substantially disappeared by TLC detection. After cooling to room temperature, the reaction was quenched with 20% aqueous NaOH solution, and then diluted with additional THF and dried over anhydrous sodium sulfate. The crude product, compound II (a), is obtained as a colorless oil. The yield was 99.0%, the product was pure enough to be directly fed to the next reaction without purification. Mass Spectrometry MS (ESI, m/s): 260(M + H).

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.34～7.29(m，4H)，7.24～7.21(q，1H)，3.91(s，4H)，3.58(s，2H)，2.67～2.58(m，2H)，2.49～2.42(m，4H)，1.98～1.93(m，2H)，1.74～1.69(q，2H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)139.5，128.6，128.1，126.7，118.8，64.7，63.9，60.6，59.6，40.7，39.1。

The aprotic solvent used above is tetrahydrofuran, and suitable aprotic solvents herein may also be methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, benzene, toluene or ethylbenzene.

Example 9

The procedure is as in example 8. Yield 99.0%, product II (b) as colorless oil. Mass Spectrometry MS (ESI, m/s): 262(M + H).

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.27～7.22(m，4H)，7.18～7.13(m，1H)，3.51(s，2H)，3.15(s，3H)，3.10(s，3H)，2.53～2.43(m，2H)，2.41～2.38(m，2H)，2.32～2.28(m，2H)，2.07～2.02(m，2H)，1.54～1.49(q，2H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)139.3，128.6，128.1，126.7，111.9，60.2，59.5，50.2，48.6，39.2，39.0。

Example 10

The procedure is as in example 8. Yield 99.0%, product II (c) as colorless oil. Mass Spectrometry MS (ESI, m/s): 290(M + H).

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.34～7.28(m，4H)，7.25～7.21(m，1H)，3.58(s，2H)，3.54～3.42(m，4H)，2.62～2.54(m，2H)，2.47～2.45(q，2H)，2.39～2.35(m，2H)，2.16～2.11(t，2H)，1.63～1.58(m，2H)，1.21～1.15(q，6H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)139.4，128.6，128.1，126.7，111.4，60.2，59.7，57.9，56.3，40.0，39.3，15.6，15.5。

Example 11

The procedure is as in example 8. Yield 99.0%, product II (d) as colorless oil. Mass Spectrometry MS (ESI, m/s): 273.

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.35～7.30(m，4H)，7.25～7.21(m，1H)，3.90～3.86(q，4H)，3.59(s，2H)，2.63～2.54(m，2H)，2.48～2.39(m，4H)，2.33～2.27(m，2H)，1.74～1.63(m，4H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)139.3，128.6，128.1，126.8，109.9，62.2，60.8，60.3，59.5，39.7，39.0，25.7。

example 12

The procedure is as in example 8. Yield 99.0% and product ii (e) as a white solid. Mass Spectrometry MS (ESI, m/s): 301.

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)7.31～7.21(m，4H)，7.19～7.15(m，1H)，3.53(s，2H)，3.42～3.40(d，4H)，2.58～2.48(m，2H)，2.45～2.36(m，4H)，2.24～2.19(m，2H)，1.61～1.57(m，2H)，0.89(s，6H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)128.7，128.2，126.9，109.7，72.7，71.5，60.3，59.5，39.2，

39.0，30.3，30.1，22.5。

example 13

Pd/C (21.0mg) was added to 5.0mL of a methanol solution containing Compound II (a) (107.7mg), and the mixture was reacted under a hydrogen balloon at 45 ℃ for 24 hours, after which the disappearance of the starting materials was monitored by GC. Filtering to remove Pd/C, and rotary evaporating to remove methanol solvent to obtain target compound I (a). Yield: 97% the product was a colorless liquid. Mass Spectrometry MS (ESI, m/s): 168 (M-H).

¹H-NMR(CDCl₃/TMS，400MHz)：δ(ppm)3.88(s，4H)，2.91～2.86(m，2H)，2.74～2.68(m，2H)，2.66～2.58(m，2H)，2.04～1.99(m，2H)，1.57～1.53(q，2H)。

¹³C-NMR(CDCl₃，75MHz)：δ(ppm)118.6，64.6，64.2，54.6，41.3，41.0。

The catalyst used in the metal catalysis is Pd/C, and the aprotic solvent suitable for the metal catalysis can also be Pd (OH)₂/C。

Example 14

The prepared compound I (a) can be used as a precursor raw material of a medicament for treating diabetes through the reaction route, and the detailed synthesis steps and the medicament activity data of the medicament for treating diabetes can be referred to documents Bioorganic and medicinal Chemistry Letters,2010, 20, 3565-3568.

The application examples of the azabicyclo [3.3.0] octane derivative in preparing the medicine for treating diabetes are shown in the following table:

Claims

1. The preparation method of the azabicyclo [3.3.0] octane derivative shown in the formula (I) is characterized in that 1,2,3, 6-tetrahydrophthalimide shown in the formula (VII) is used as a raw material, and the azabicyclo [3.3.0] octane derivative is prepared and obtained through reaction according to a route shown in the following formula (A);

wherein R is₁Is CH₃、CH₃CH₂(ii) a Or two R₁Together form (CH)₂)₂Two R₁Together form (CH)₂CH₂CH₂) Or two R₁Together form (CH)₂C(CH₃)₂CH₂)；

Wherein, 1,2,3, 6-tetrahydrophthalimide and benzyl chloride react in a polar solvent at 30-60 ℃ under the alkaline condition of tetrabutylammonium bromide catalysis, and the compound shown in the formula (VI) is obtained after separation and purification

Wherein, the compound shown as the formula (VI) is mixed with KMnO₄In a mixed solvent of acetone/water, carrying out oxidation reaction at room temperature, separating and purifying to obtain the compound shown in the formula (V)

Wherein, the compound shown in the formula (V) and NaOAc react in an acid solvent at the temperature of 100-130 ℃, and the compound shown in the formula (IV) is obtained after separation and purification

Wherein, the compound shown as the formula (IV) and R₁OH or HOR₁R₁OH dihydric alcohol reacts under the conditions of acid catalysis and reflux in benzene or toluene, and the compound shown in the formula (III) is obtained after separation and purification

Wherein R is₁Is CH₃、CH₃CH₂(ii) a Or two R₁Together form (CH)₂)₂Two R₁Together form (CH)₂CH₂CH₂) Or two R₁Together form (CH)₂C(CH₃)₂CH₂)

Wherein the compound shown in the formula (III) and LiAlH₄Reacting in an aprotic solvent under the condition of reflux, separating and purifying to obtain the compound shown in the formula (II)

Wherein, the compound shown in the formula (II) and hydrogen are subjected to reduction reaction in an alcohol solvent under the condition of metal catalysis, and the compound shown in the formula (I) is obtained after separation and purification

2. The method of claim 1, wherein the base is K₂CO₃，Na₂CO₃NaH, pyridine, triethylamine or diisopropylethylamine; the polar solvent is methanol, ethanol or DMF.

3. The method according to claim 1, wherein the acidic solvent is acetic acid, acetic anhydride or propionic acid.

4. The method of claim 1, wherein the acid is HCl, HBr, H₂SO₄，H₃PO₄，AcOH，CH₃COOH，CF₃COOH, TsOH or oxalic acid.

5. The method of claim 1, wherein the aprotic solvent is tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, benzene, toluene, or ethylbenzene.

6. The method of claim 1, wherein the metal catalyst is Pd/C or Pd (OH)₂/C。

7. The method of claim 1, wherein the KMnO is KMnO₄In an amount of three times the molar amount of the compound of formula (VI).

8. The method of claim 1, wherein the LiAlH is₄The amount of the compound (B) is twice of the molar amount of the compound (III).