CN102718695A - Method for synthesizing aza-bicyclo octane [3.3.0] derivatives - Google Patents

Abstract

The invention discloses a method for synthesizing aza-bicyclo octane [3.3.0] derivatives shown as a formula (I). 1,2,3,6-tetrahydrophthalimide (V) is used as an initial raw material; and the aza-bicyclo octane [3.3.0] derivatives shown as the formula (I) are obtained by protective group addition, reduction reaction, protective group removing reaction, oxidation reaction and cyclization decarboxylation reaction sequentially. The method is mild in reaction conditions, readily available and cheap in raw materials, simple in synthetic route and high in yield; and the aza-bicyclo octane [3.3.0] derivatives serving as important medicinal intermediates are widely applied to industrialized large-scale production.

Description

A kind of synthetic method of azabicyclo[3.3.0]octane derivative

technical field

The invention belongs to the technical field of organic compound technology application, and specifically relates to a synthesis method of azabicyclo[3.3.0]octane derivatives.

Background technique

Aza-bicyclo octane [3.3.0] derivatives (aza-bicyclo octane [3.3.0] derivatives) is a very important class of chemical intermediates, with very high pharmaceutical application value. In some new drugs reported in recent years, such as serine protease dipeptidase peptidase (DDP-4) inhibitors for the treatment of diabetes (Bioorganic and Medicinal Chemistry Letters, 2010, 20, 3565-3568), are azabicyclic [3.3.0] Octane structure. The synthetic methods of azabicyclo[3.3.0]octane derivatives in the prior art mainly include: one of the methods, as shown in equation (a), is to combine (7S,8R)-1,4-dioxaspiro[4.4] Nonane-7,8-dicarboxylic acid dimethyl ester reacted with a secondary amine at 190°C for 16 hours with locking (J.Org.Chem.1989, 54, 5115-5122 and WO 2004/087142). The method has harsh conditions and is difficult to realize in industrial scale-up production. Another method is to obtain dimethyl 2-allyl-2-(prop-2-ynyl)malonate through the Pauson-Khand reaction under metal catalysis, and then reduce the olefinic bond, as shown in equation (b) (OrganicLetters, 2002 , 4,3983-3988, J.Org.Chem.2002,67, 1233-246 and US 2004/44029), the method is to be a catalyst with highly toxic metal reagent Co ₂ (CO) ₈ , which is potentially dangerous .

Contents of the invention

The present invention overcomes the above-mentioned defects of the prior art, proposes a compound azabicyclo [3.3.0] octane derivative (aza-bicyclo octane [3.3. 0] derivatives) synthetic method.

A kind of synthetic method of azabicyclo[3.3.0]octane derivatives proposed by the present invention is to use the compound 1,2,3,6-tetrahydrophthalimide of formula (V) as raw material, through Protecting group, reduction reaction, deprotection group reaction, oxidation reaction, cyclodecarboxylation reaction to obtain the azabicyclo[3.3.0]octane derivative as described in formula (I);

Its reaction route is:

in,

When A is O, R is an alkyl substituent of C ₁ to C ₈ or an aryl group;

When A is N, R is hydrogen, C ₁ -C ₈ alkyl, or aryl;

其中，X是H、F、Cl、Br、I、NO₂、CH₃、CH₃CH₂、OCH₃、或OCH₃CH₂。PG is Ph ₃ C, tert-butyl, MOM, BOM, TMS, naphthylmethyl,

Wherein, X is H, F, Cl, Br, I, NO ₂ , CH ₃ , CH ₃ CH ₂ , OCH ₃ , or OCH ₃ CH ₂ .

Wherein, the protecting group reaction is based on formula (V) compound 1,2,3,6-tetrahydrophthalimide as a raw material, and the halogenated protecting group reaction under alkaline conditions generates the formula ( IV) Compounds.

The base used in the protecting group reaction is K ₂ CO ₃ , KHCO ₃ , KOH, KOMe, KOEt, KO ^t Bu, KOPr, KO ⁱ Pr, Na ₂ CO ₃ , NaHCO ₃ , NaOH, NaOMe, NaOEt, NaOPr , NaO ⁱ Pr, NaH, KH, CaH ₂ , pyridine, triethylamine or diisopropylethylamine.

Wherein, the reduction reaction is to reduce the carbonyl on the imide of the compound of formula (IV) to methylene with a reducing agent in an aprotic solvent to generate the compound of formula (III).

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

The reducing agent is LiAlH ₄ .

The compound of formula (III) generates the compound of formula (II) through the deprotection reaction, and the high yield of this reaction process is one of the decisive factors of the present invention.

Wherein, when PG is Ph ₃ C, tert-butyl, methyl methyl ether (MOM), benzyl methyl ether (BOM), trimethylsilyl (TMS) or naphthyl methyl, the deprotection group The reaction is to remove the protective group of the compound of formula (III) under acidic or basic conditions to become a secondary amine, and then react with haloformic acid ester or haloformamide under basic conditions to generate formula (II) compound of.

In the compound of formula (III), the N atom of the five-membered ring is connected with a common protecting group (PG), and the protecting group is removed under acidic or basic conditions, and then the N atom is connected with an ester group or amide group. Protecting group, thereby can not destroy this five-membered ring when constructing another five-membered ring.

The base used in the deprotection reaction is NaOH, KOH, Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ or KHCO ₃ .

The acid used in the deprotection reaction is HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ , AcOH, CF ₃ COOH or TsOH.

where, when PG is The deprotecting agent reaction is to react the compound of formula (III) with phosgene or triphosgene under the catalysis of catalyst base, and then react with corresponding alcohol or amine to generate the compound of formula (II); wherein, X is H, F, Cl, Br, I, _NO2 , _CH3 , _CH3CH2 , _OCH3 , _{or OCH3CH2 .}

时，式(III)化合物的结构如式(III')所示。式(III')中，X是H、F、Cl、Br、I、NO₂、CH₃、CH₃CH₂、OCH₃、或OCH₃CH₂。式(III')化合物在催化剂碱的催化下与光气或三光气反应，生成结构如式(III″)所示的酰氯化合物，再与相应的醇或胺反应，得到式(II)化合物。此反应是一锅法合成，不需要分离中间产物，这样可以避免操作带来的损失，提高效率及产率，节省成本。when PG is

, the structure of the compound of formula (III) is shown in formula (III'). In formula (III'), X is H, F, Cl, Br, I, NO ₂ , CH ₃ , CH ₃ CH ₂ , OCH ₃ , or OCH ₃ CH ₂ . The compound of formula (III') reacts with phosgene or triphosgene under the catalysis of the catalyst base to generate an acid chloride compound with the structure shown in formula (III"), and then reacts with the corresponding alcohol or amine to obtain the compound of formula (II). This reaction is a one-pot synthesis without the need to separate intermediate products, which can avoid losses caused by operations, improve efficiency and yield, and save costs.

The catalyst base is any one of triethylamine, trimethylamine, diisopropylethylamine, diethylamine, dipropylamine, dibutylamine, pyridine or DMAP.

Wherein, the oxidation reaction is to oxidize the compound of formula (II) into a dicarboxylic acid structure through an oxidizing agent; preferably, the oxidizing agent is a strong oxidizing agent. Preferably, the oxidizing agent is H ₂ O ₂ , O ₃ , KMnO ₄ or K ₂ Cr ₂ O ₇ .

Wherein, the cyclodecarboxylation reaction is carried out after the oxidation reaction, and the compound of formula (I) is generated by cyclodecarboxylation in an acidic solvent; wherein, the acidic solvent is acetic acid, acetic anhydride or propionic acid.

The reaction scheme of the present invention is as follows:

The synthesis method of the invention has mild conditions, readily available and cheap raw materials, simple synthesis route and high yield, and the compound of the product formula (I), as an important class of pharmaceutical intermediates, is widely applicable to industrial scale production. The synthetic method of the present invention improves the yield of the key reaction (reduction reaction, the highest cost) of the whole route through the protection of the protecting group, and the removal of impurities is simple and the cost is saved. In terms of the yield of the final product, there is no concomitant loss, but an increase.

Detailed ways

In conjunction with the following specific examples, the present invention will be further described in detail, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope. The process, conditions, reagents, experimental methods, etc. for implementing the present invention are general knowledge and common knowledge in the art except for the content specifically mentioned below, and the present invention has no special limitation content. The data given in the following examples include specific operating and reaction conditions and products. The purity of the product was identified by NMR.

Example 1

Weigh 1,2,3,6-tetrahydrophthalimide V (4540.0mg, 30.0mmol), K ₂ CO ₃ (12440.0mg, 90.0mmol), TBAB (970.0mg, 3.0mmol) in 250mL In the round bottom flask, add 50.0mL DMF to dissolve. Benzyl chloride (4940.0mg, 39.0mmol) was weighed and slowly added dropwise into the reaction flask with stirring. After 5 h, the reaction was completed, and 50.0 mL of water was added to quench the reaction. Then 100.0 mL of ethyl acetate was added for extraction, and after separation, the organic phase was washed with saturated brine (40.0 mL×5), and dried over anhydrous sodium sulfate overnight. Sodium sulfate was removed by filtration, and ethyl acetate was removed by rotary evaporation to obtain the crude product as a white solid. Recrystallization from ethyl acetate/n-hexane gave 5740.0 mg of the target compound, with a yield of 79.3%. Mass spectrometry MS (ESI, m/s): 241.

¹ H-NMR(CDCl ₃ /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).

Example 2

The operation is the same as example 1. Yield: 81.3%, white solid. Mass spectrometry MS (ESI, m/s): 393.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)7.29~7.04(m,15H),5.84~5.83(t,2H),2.96~2.94(m,2H),2.50~2.46(m, 2H), 2.11~2.06(m, 2H).

Example 3

Weigh 60% NaH (96.0mg) into a 50mL round bottom flask and add freshly steamed THF. Weigh 1,2,3,6-tetrahydrophthalimide V (302.3mg) and dissolve it in 5.0mL THF slowly into the reaction flask until no bubbles are generated. After MOMCl (193.0mg) was slowly added dropwise into the above reaction solution, KI (32.2mg) was added, and the reaction was stirred for 3h to complete. Water was added to quench the reaction. Then ethyl acetate was added for extraction, and after liquid separation, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was obtained as a colorless liquid, and 321.3 mg of the target compound was obtained by column chromatography, with a yield of 82.3%. Mass spectrometry MS (ESI, m/s) 196 (M+H).

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)5.92~5.90(t,2H),4.84(s,2H),3.29(s,2H),3.14~3.13(t,2H),2.66 ~2.61(m,2H), 2.27~2.21(m,2H).

Example 4

Weigh LiAlH ₄ (380.0mg) into a 100mL two-necked flask with a reflux condenser, evacuate for nitrogen, and add 20.0mLTHF. Weigh compound IV(a) (1206.5mg) and dissolve it in 15.0mL THF, and slowly drop it into the two-necked bottle. After the dropwise addition was completed, it was heated to reflux, and the raw material basically disappeared as detected by TLC. After cooling to room temperature, the reaction was quenched with water, then diluted with THF, and dried over anhydrous sodium sulfate. The crude product was obtained as a colorless oil. The product was pure enough to be put directly into the next reaction without purification. Mass spectrometry MS (ESI, m/s): 214 (M+H).

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)7.31~7.19(m,5H),5.81~5.80(t,2H),3.60(s,2H),2.93~2.89(m,2H) ,2.38~2.37(m,2H),2.20~2.11(m,4H),1.87~1.83(d,2H).

Example 5

The operation is the same as example 4. Yield: 72.3%, white solid. Mass spectrometry MS (ESI, m/s): 365.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)7.37~7.10(m,15H),5.52~5.46(t,2H),3.46~2.45(m,2H),2.79~2.70(m, 2H), 2.23~2.10(m, 4H), 2.05~1.97(m, 2H), 1.86~1.79(m, 2H).

Example 6

The operation is the same as example 4. Yield: 83.2%, colorless oil. Mass spectrometry MS (ESI, m/s): 138 (M+H).

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)5.81~5.79(t,2H),2.87~2.83(m,2H),2.41~2.37(m,2H),2.31(s,2H) ,2.16~2.10(m,4H),1.86~1.81(m,2H).

Example 7

Weigh triphosgene (98.0 mg) and DMAP (6.1 mg) into a reaction flask, add 3.0 mL of dichloromethane, and place in an ice-salt bath. Then add 4.0 mL of compound III'(a) dichloromethane solution, after the dropwise addition, react at this temperature for 2 h. TLC monitored disappearance of starting material. Flash column chromatography yielded 99.6 mg of the title product. Yield: 54.6%, colorless oily liquid. Mass spectrometry MS (ESI, m/s): 185.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)5.67~5.61(t,2H),3.67~3.53(m,2H),3.37~3.28(m,2H),2.43~2.23(m, 4H), 1.93~1.86 (m, 2H).

Example 8

Weigh compound III" (18.6mg) and dissolve it in 1.0mL dichloromethane and add it to the test tube reaction tube replaced with nitrogen, slowly add 1.0mL NaOMe methanol solution (concentration is 0.12mol/L) dropwise in the reaction tube, immediately there is A colorless solid was generated. TLC monitored the disappearance of the raw material after 5h, and water was added to quench the reaction. Extracted 3 times with dichloromethane, the combined organic layer was dried with anhydrous sodium sulfate. The crude product was obtained as a colorless oil, and column chromatography gave 17.5 mg target compound. Yield: 96.6%, colorless oily liquid.

The preparation of compound II' (a) can also be prepared by compound III' (a) when the reaction ends when compound III ", without separation, can be obtained by directly adding the methanol solution of sodium methylate to react. Mass spectrometry MS (ESI, m/s ):181.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)5.66~5.61(t,2H),3.68(s,3H),3.49~2.39(m,2H),3.23~3.10(m,2H) ,2.31~2.19(m,4H),1.92~1.88(m,2H).

Example 9

The operation is the same as example 8. Yield: 83.2%, colorless oil. Mass spectrometry MS (ESI, m/s): 195.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)5.63~5.58(t,2H),4.10~4.07(m,2H),3.45~3.37(m,2H),3.19~3.07(m, 2H), 2.32~2.16(m,4H), 1.89~1.84(m,2H), 1.24~1.20(t,3H).

Example 10

The operation is the same as example 8. NaOBn was prepared from BnOH and NaH in THF solution. Yield: 82.3%, colorless oil. Mass spectrometry MS (ESI, m/s): 257.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)7.37~7.29(m,5H),5.64(s,2H),5.16~5.09(m,2H),3.50~3.47(m,2H) ,3.26~3.16(m,2H),2.32~2.20(m,4H),1.93~1.88(m,2H).

Example 11

Weigh compound III "(18.6mg) and dissolve it in 1.0mL dichloromethane and add it to the test tube reaction tube replaced with nitrogen, and slowly add 0.5mL 33% aqueous solution of dimethylamine dropwise to the reaction tube. After 5h, TLC monitors the raw material disappeared, adding 2.0 mL of water to quench the reaction. Extracted 3 times with dichloromethane, combined the organic layers, and dried with anhydrous sodium sulfate to obtain a colorless oily crude product. Column chromatography obtained 14.6 mg of the target compound II (d). Yield: 75.4%, colorless oily liquid.

The preparation of compound II (d) can also be prepared from compound III' (a) when the reaction ends when compound III "is not separated, and can be obtained by directly adding methanol solution of sodium methoxide to react. Mass spectrometry MS (ESI, m/s) :194.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)5.64~5.58(t,2H),3.42~3.38(m,2H),3.16~3.12(m,2H),2.79(s,6H) ,2.25~2.16(m,4H),1.90~1.86(m,2H).

Example 12

Operation is the same as Example 11. Yield: 80.3%, colorless oil. Mass spectrometry MS (ESI, m/s): 223 (M+H).

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)5.67~5.60(t,2H),3.43~3.39(m,2H),3.21~3.11(m,6H),2.29~2.18(m, 4H), 1.91~1.87(m,2H), 1.12~1.09(t,6H).

Example 13

Operation is the same as Example 11. Yield: 79.4%, colorless oil. Mass spectrometry MS (ESI, m/s): 278.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)5.66~5.59(t,2H),3.41~3.37(m,2H),3.15~3.09(m,6H),2.28~2.17(m, 4H), 1.90~1.86(m,2H), 1.50~1.44(m,4H), 1.29~1.24(m,4H), 0.91~0.87(t,6H).

Example 14

Operation is the same as Example 11. Yield: 65.3%, colorless oil. Mass spectrometry MS (ESI, m/s): 255 (M-H).

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)7.33~7.27(m,5H),5.67~5.61(t,2H),4.44(s,2H),3.42~3.41(m,2H) ,3.18~3.17(m,2H),2.37~2.21(m,4H),1.94~1.89(m,2H).

Example 15

Weigh compound V (302.3mg) into a 50mL two-necked flask with a reflux condenser, evacuate for nitrogen, and add 8.0mL of triethylamine. TMSCl (434.6 mg) was slowly added dropwise with a syringe, and a large amount of solid was formed immediately. After heating to 90°C and reacting for 4 hours, n-hexane was added and filtered quickly. The filtrate was removed by rotary evaporation to give 450.0 mg of crude product.

Weigh LiAlH ₄ (152.0mg,) into a 50.0mL mouth bottle, add 10.0mL freshly steamed THF, dilute 450.0mg of the crude product from the previous step with 3.0mL THF and add dropwise to the reaction bottle, and heat to make it Reflux for 5 hours. Cool to room temperature, add 10.0 mL THF/H ₂ O (10:1) mixture solution to quench the reaction, and add anhydrous sodium sulfate to dry. K ₂ CO ₃ (276.4 mg) was added to the filtrate, and CbzCl (375.0 mg) was slowly added dropwise, and the reaction was stirred for 2 hours, and the reaction was basically completed. The reaction liquid was sucked dry by rotation, 20.0 mL of water was added, extracted 4 times with ethyl acetate, the organic layers were combined, dried with anhydrous sodium sulfate, and column chromatography obtained 255.0 mg of the target compound II(c). Yield: 49.6%.

Example 16

Weigh compound II(a) (158.7mg) and TBAB (28.0mg) into a 50mL one-necked bottle, add 10.0mL dichloromethane to dissolve, and slowly add 10.0mL KMnO ₄ (415.2mg, 2.63mmol) aqueous solution dropwise. The reaction was stirred at room temperature for 2 hours, and the starting material disappeared as monitored by TLC. Add 1200.0 mg of sodium sulfite and 1.0 mL of concentrated hydrochloric acid, rotate the dichloromethane obtained from the reaction liquid to evaporate, and extract 4 times with ethyl acetate. The ethyl acetates were combined and dried over anhydrous sodium sulfate to obtain 199.2 mg of the crude product as a white foamy solid. directly into the next reaction.

Weigh sodium acetate (107.8 mg) into the above crude product, add 4.0 mL of acetic anhydride, and then heat to 120° C. for 2 hours to complete the reaction. Cool to room temperature, add 10.0 mL of water, and add solid sodium carbonate several times. Extract with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, and obtain 108.5 mg of the target product by column chromatography. Yield: 67.7%, colorless oily liquid. Mass spectrometry MS (ESI, m/s): 183.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)3.63~3.58(m,5H),3.25~3.14(m,2H),2.89~2.85(m,2H),2.46~2.39(m, 2H), 2.20~2.06(m,2H).

Example 17

Operation is the same as example 16. Yield 72.7%, colorless oily liquid. Mass spectrometry MS (ESI, m/s): 198 (M+H).

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)4.14~4.08(q,2H),3.72~3.64(m,2H),3.30~3.18(m,2H),2.93~2.92(m, 2H), 2.51~2.44(m,2H), 2.17~2.11(m,2H), 1.26~1.22(t,3H).

Example 18

Operation is the same as in Example 16. Yield 70.0%, light-colored solid. Mass spectrometry MS (ESI, m/s): 259.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)7.37~7.30(m,5H),5.13(s,2H),3.77~3.71(m,2H),3.35~3.25(m,2H) ,2.96.~2.94(m,2H),2.53~2.47(m,2H),2.19~2.13(m,2H).

Example 19

Operation is the same as in Example 16. Yield 56.3%, colorless liquid. Mass spectrometry MS (ESI, m/s): 196.

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)3.71~3.66(m,2H),3.28~3.23(m,2H),3.06~2.88(m,4H),2.83(s,6H) ,2.51~2.44(m,2H),2.19~2.13(m,2H).

Example 20

Operation is the same as in Example 16. Yield 59.0%, colorless liquid. Mass spectrometry MS (ESI, m/s): 225 (M+H).

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)3.68~3.64(d,2H),3.23~3.15(m,6H),2.94~2.85(m,2H),2.50~2.44(m, 2H), 2.17~2.11(m,2H), 1.12~1.09(t,6H).

Example 21

Operation is the same as in Example 16. Yield 61.6%, colorless liquid. Mass spectrometry MS (ESI, m/s): 281 (M+H).

¹ H-NMR(CDCl ₃ /TMS,400MHz):δ(ppm)3.67~3.63(d,2H),3.23~3.20(m,2H),3.14~3.10(t,4H),2.94~2.85(m, 2H), 2.51~2.44(m,2H), 2.17~2.11(m,2H), 1.52~1.45(m,4H), 1.32~1.22(m,4H), 0.92~0.88(t,6H).

Claims (12)

1. a synthetic method of azabicyclo[3.3.0]octane derivatives, characterized in that, with formula (V) compound 1,2,3,6-tetrahydrophthalimide as raw material, After successively going through protective group, reduction reaction, deprotection reaction, oxidation reaction and cyclodecarboxylation reaction, the azabicyclo[3.3.0]octane derivative as shown in formula (I) is obtained;

Its reaction route is:

in, When A is O, R is an alkyl substituent of C ₁ to C ₈ or an aryl group; When A is N, R is hydrogen, C ₁ -C ₈ alkyl, or aryl; PG is Ph ₃ C, tert-butyl, MOM, BOM, TMS, naphthylmethyl,

Wherein, X is H, F, Cl, Br, I, NO ₂ , CH ₃ , CH ₃ CH ₂ , OCH ₃ , or OCH ₃ CH ₂ . 2. synthetic reaction as claimed in claim 1, is characterized in that, described upper protecting group reaction is that described formula (V) compound is through reacting with halogenated protecting group under alkaline condition, generates formula (IV) compound . 3. synthetic reaction as claimed in claim 2, it is characterized in that, the base used in the described upper protecting group reaction is K ₂ CO ₃ , KHCO ₃ , KOH, KOMe, KOEt, KO ^t Bu, KOPr, KO ⁱ Pr , _Na2CO3 , _NaHCO3 , NaOH, NaOMe, NaOEt, NaOPr, ^NaOiPr , NaH, KH, _CaH2 , _pyridine , triethylamine or diisopropylethylamine. 4. synthetic reaction as claimed in claim 1, it is characterized in that, described reduction reaction is to obtain carbonyl reduction on the imide of formula (IV) compound with reducing agent to methylene in aprotic solvent, generate formula (III) Compounds. 5. synthetic reaction as claimed in claim 4, is characterized in that, described aprotic solvent is tetrahydrofuran, methyl tetrahydrofuran, ether, methyl tert-butyl ether, benzene, toluene or ethylbenzene; Described reducing agent is LiAlH . 6. synthetic reaction as claimed in claim 1, it is characterized in that, when PG is Ph ₃ C, tert-butyl, MOM, BOM, TMS or naphthyl methyl, described deprotection reaction is that formula (III ) compound is deprotected under acidic or basic conditions to become a secondary amine, and then reacted with haloformate or haloformamide under basic conditions to generate a compound of formula (II). 7. The synthesis reaction according to claim 6, wherein the base used in the deprotection reaction is NaOH, KOH, Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ or KHCO ₃ . 8 . The synthesis reaction according to claim 6 , wherein the acid used in the deprotection reaction is HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ , AcOH, CF ₃ COOH or TsOH. 9. synthetic reaction as claimed in claim 1, is characterized in that, when PG is

The deprotection reaction is to react the compound of formula (III) with phosgene or triphosgene under the catalysis of the base, and then react with the corresponding alcohol or amine to obtain the compound of general structure formula (II); wherein, X is wherein X is H, F, Cl, Br, I, NO ₂ , CH ₃ , CH ₃ CH ₂ , OCH ₃ , or OCH ₃ CH ₂ . 10. synthetic reaction as claimed in claim 9, is characterized in that, described catalyst base is triethylamine, trimethylamine, diisopropyl ethylamine, diethylamine, dipropylamine, dibutylamine, pyridine or DMAP any of these. 11. The synthesis reaction as claimed in claim 9, characterized in that, the oxidation reaction is that the compound of formula (II) is oxidized to dicarboxylic acid through an oxidizing agent; wherein, the oxidizing agent is H ₂ O ₂ , O ₃ , KMnO ₄ or K ₂ Cr ₂ O ₇ . 12. synthetic reaction as claimed in claim 1, is characterized in that, described cyclodecarboxylation reaction is cyclodecarboxylation generation formula (I) compound in acidic solvent; Wherein, described acidic solvent is acetic acid, acetic anhydride or propionic acid .