A preparation method of gliclazide intermediate 1,2-cyclopentanediethanol

Abstract

The present invention discloses a method for preparing 1,2-cyclopentane dimethanol, an intermediate of gliclazide. The method uses dicyclopentadiene as a raw material and sequentially undergoes depolymerization, [2+2] cycloaddition, ring opening, hydrolysis, reduction, hydrogenation, or re-reduction reactions to obtain a product. The raw materials used in the present invention are inexpensive and widely available, and the reaction conditions in each step are mild, the process is simple, production costs are reduced, and the product has high application value.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a method for preparing a gliclazide intermediate. Background Art

[0002] Gliclazide, as a second-generation sulfonylurea drug, regulates ion channels on the surface of pancreatic cells, thereby promoting the synthesis and secretion of insulin, and ultimately achieving the effect of lowering blood sugar.

[0003] However, the original production process is expensive and produces toxic impurities, so improving the process has become a new direction for research on this type of subject.

[0004] The existing process for preparing the gliclazide intermediate 1,2-cyclopentyl dimethanol generally adopts esterification followed by reduction of 1,2-cyclopentanedicarboxylic acid. Patent (CN 102993080 A) and literature (China Journal of Pharmaceutical Industry. 2017;48(2):154-156) all adopt this method. However, the raw material 1,2-cyclopentanedicarboxylic acid in this method is expensive and difficult to obtain, and the reducing agent lithium aluminum tetrahydride is expensive and sensitive to water, making it impossible to achieve industrial production. Summary of the Invention

[0005] In view of the existing defects and problems, the present invention provides a method for preparing 1,2-cyclopentanedimethanol with simple process, low cost and easy operation.

[0006] The technical solution adopted in the present invention is as follows:

[0007] The present invention provides a method for preparing a gliclazide intermediate compound of formula A-1 or formula A-2, which is prepared by a reduction reaction of a compound of formula VI. The reaction equation is:

[0008] .

[0009] Furthermore, the reducing agent for the reduction reaction is a boron reducing agent, which can be selected from sodium borohydride, lithium borohydride, potassium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.

[0010] Wherein, the reduction reaction solvent is an organic solvent, preferably tetrahydrofuran.

[0011] Wherein, the mass ratio of the raw material compound VI to the solvent in the reduction reaction for preparing compound A-1 is in the range of 1:8 to 9.9.

[0012] The present invention provides a method for preparing a compound of formula I-1 or a compound of formula I-2, which is further prepared by hydrogenating a compound of formula A-1 or A-2, respectively. The reaction equation is as follows:

[0013] .

[0014] Furthermore, in the preparation method of the compound of formula I-1, the catalyst used in the hydrogenation reaction is one or more of Pd / C and skeleton nickel, preferably Pd / C; the hydrogen source used is hydrogen, formic acid or ammonium formate.

[0015] Wherein, the hydrogenation reaction solvent is an ether solvent or an ester solvent, and ethyl acetate is more preferred.

[0016] The mass ratio of the raw material compound of formula A-1 to the solvent in the hydrogenation reaction is in the range of 1:5-15, preferably 1:8-9.

[0017] Furthermore, the hydrogenation reaction step in the preparation method of the compound of formula I-2 includes reacting the compound of formula A-2, formic acid, and 10% Pd / C to prepare the compound of formula I-2.

[0018] Wherein, the reaction time of the hydrogenation reaction is 15 to 25 hours.

[0019] The present invention also provides a method for preparing 1,2-cyclopentane dimethanol, an intermediate of gliclazide. The method uses a compound of formula II as a starting material, undergoes depolymerization reaction, [2+2] cycloaddition, ring opening, and hydrolysis reaction to obtain a compound of formula VI. The compound of formula VI is further subjected to reduction and hydrogenation reaction or reduction, hydrogenation, and reduction reaction to obtain a compound of formula I-1. The reaction formula is as follows:

[0020] .

[0021] Wherein, the reaction temperature of the depolymerization reaction is 100~200℃.

[0022] Wherein, the reaction reagent of the [2+2] cycloaddition is dichloroacetyl chloride.

[0023] The reaction temperature of the [2+2] cycloaddition is 20-30°C, and the preferred temperature is 25-30°C.

[0024] Among them, the treatment process after the ring-opening reaction is: adding acid dropwise at 0°C to adjust the pH to acidic, keeping warm for 2 hours after the addition is completed, filtering to obtain a light yellow solid, and the solid is recrystallized with petroleum ether and then dried to obtain the fine formula V compound 2-(dichloromethyl)cyclopent-3-ene-1-carboxylic acid.

[0025] Wherein, the acid used for adjusting pH in the treatment process after the ring-opening reaction is concentrated hydrochloric acid.

[0026] Wherein, the reaction temperature of the hydrolysis reaction is 50~120℃.

[0027] The raw materials used in the present invention are cheap and widely available, and the reaction conditions in each step are mild, the process is simple, the production cost is reduced, and the invention has high application value. It avoids the use of expensive and highly toxic reaction reagents in the original process route and is more suitable for large-scale industrial production. DETAILED DESCRIPTION

[0028] To further understand the present invention, the following detailed description of the preparation method of 1,2-cyclopentane dimethanol, a gliclazide intermediate provided by the present invention, is provided in conjunction with the following examples. It should be understood that these examples are only provided to further illustrate the features of the present invention and are not intended to limit the scope of the present invention or the scope of the claims.

[0029] Example 1

[0030] A. Preparation of Cyclopentadiene(III)

[0031] Dicyclopentadiene (30 g, 0.2 mol) was added to a reactor equipped with a stirring and heating device. A distillation apparatus was set up and the temperature was raised to 180°C for distillation and depolymerization for 10-15 hours. A colorless liquid, about 27 g of cyclopentadiene (III), was obtained in the receiving flask, with a yield of about 90.1%.

[0032] B. Preparation of 7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one (IV)

[0033] Cyclopentadiene (III) (20 g, 0.3 mol) and 200 ml of n-hexane were added to the reactor, stirred evenly, and then 30.6 g of triethylamine was added. The mixture was then cooled to 0°C in an ice bath, and then 44.6 g of dichloroacetyl chloride was slowly added dropwise. The temperature was kept below 5°C during the addition process, and then the temperature was raised to 25-30°C and the reaction was continued with stirring for 8 hours. After the reaction was completed, the insoluble matter was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain about 45.6 g of brown-red liquid 7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one (IV) with a yield of about 86.6%. 1 HNMR (400 MHz, CDCl3) d (ppm): 6.04 (dq, J = 6.0, 2.1 Hz,1H), 5.80 (dq, J = 4.9, 2.3 Hz, 1H), 4.26 (ddd, J = 8.8, 7.4, 1.2 Hz, 1H), 4.07(dp, J = 7.2, 2.1 Hz, 1H), 2.81 (ddt, J= 17.3, 3.9, 2.0 Hz, 1H), 2.64 – 2.51(m, 1H). EI-MS:m / z[M] + 175.9806, [M+4] + 179.9732

[0034] C. Preparation of 2-(dichloromethyl)cyclopent-3-ene-1-carboxylic acid (V)

[0035] Add 200 ml of 20% aqueous sodium hydroxide solution to the reactor, stir thoroughly, and cool to 0°C in an ice bath. Then, slowly add 7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one (IV) (20 g, 0.1 mol) dropwise over 1 hour, maintaining the temperature above 3°C. After the addition is complete, react at 0°C for 0.5 hour. Then, add concentrated hydrochloric acid (38 ml) dropwise at 0°C to adjust the pH to acidic. After the addition is complete, incubate for 2 hours to allow crystallization. Filter to obtain a pale yellow solid. Recrystallize the solid from petroleum ether and dry to obtain approximately 19.36 g of the fine product 2-(dichloromethyl)cyclopent-3-ene-1-carboxylic acid (V) in an approximately 87.9% yield. Melting point: 90.0–91.9°C. 1 H NMR (400 MHz, CDCl3) d (ppm): 11.11 (s, 1H), 6.35 (d, J = 5.0Hz, 1H), 6.08 (dq, J = 6.3, 2.2 Hz, 1H), 5.88 (dq, J = 6.3, 2.2 Hz, 1H), 3.71(ddt, J = 9.1, 5.0, 2.5 Hz, 1H), 3.40 (td, J = 9.1, 7.6 Hz, 1H), 2.86 (ddq, J =16.9, 7.6, 2.5 Hz, 1H), 2.70 – 2.59 (m, 1H). EI-MS:m / z[M] + 193.9898, [M+4] + 197.9843

[0036] D. Preparation of 2-Formylcyclopent-2-ene-1-carboxylic acid (VI)

[0037] 2-(Dichloromethyl)cyclopent-3-ene-1-carboxylic acid (V) (20 g, 0.1 mol) and 100 ml of water were added to a stirred reactor, and the temperature was then raised to 100°C for reaction for 8 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The layers were separated, and the organic phase was dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and the solvent was removed by distillation under reduced pressure to obtain approximately 12.2 g of 2-formylcyclopent-2-ene-1-carboxylic acid (VI) in a yield of approximately 87.6%. 1 H NMR (400 MHz, CDCl3) d (ppm):10.05 (d, J = 85.2 Hz, 1H), 9.73 (s, 1H), 7.06 (q, J = 2.4 Hz, 1H), 3.75 (ddt, J = 9.1, 5.3, 1.9 Hz, 1H), 2.87 – 2.56 (m, 2H), 2.47 – 2.16 (m, 2H). ESI-MS (m / z): 139.0 (MH)

[0038] E. Preparation of cyclopent-2-ene-1,2-diyldimethanol (A-1)

[0039] 2-Formylcyclopent-2-ene-1-carboxylic acid (VI) (15 g, 0.1 mol) and 150 ml of tetrahydrofuran were added to the reactor, followed by the addition of 20.7 g of N,N-carbonyldiimidazole. After reacting for 1 hour, 37.5 ml of water was added, and the mixture was cooled to 0°C in an ice bath. Sodium borohydride was added in four batches, 3.1 g in each batch. After the addition was complete, the mixture was heated to room temperature and reacted for 6 hours. 108 ml of 3.6% dilute hydrochloric acid was then added to quench the mixture, and most of the organic solvent was distilled off. The mixture was then extracted with ethyl acetate, separated, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the ethyl acetate was finally distilled off to obtain approximately 10.8 g of cyclopent-2-ene-1,2-diyldimethanol (A-1) in a yield of approximately 85.0%. 1 H NMR (400 MHz, CDCl3) d (ppm): 5.73(t, J = 2.1 Hz, 1H), 4.29 (d, J = 12.4 Hz. 1H). 4.13(dg, J =12.3, 1.2 Hz, 1H),3.72 (dd, J =10.6, 4.4Hz, 1H), 3.50 (dd, J= 10.6, 8.2 Hz, 1H). 3.17(s, 2H),2.92-2.80(m, 1H), 2.41-2.19 (m, 2H), 2.18-2.01 (m, 1H), 1.57 (ddt, J = 12.8,9.0, 6.3 Hz, 1H). ESI-MS (m / z): 151.1 (M+Na)

[0040] F. Preparation Method 1 of 1,2-Cyclopentyldimethanol (I-1)

[0041] Cyclopent-2-ene-1,2-diyldimethanol (A-1) (15 g, 0.1 mol) and 150 ml of ethyl acetate were added to the reactor, followed by the addition of 1.06 g of 5% Pd / C. Hydrogen was introduced at room temperature and atmospheric pressure for 24 hours. After the reaction, the catalyst was filtered out and the solvent was distilled off to obtain approximately 14.5 g of 1,2-cyclopentyldimethanol (I-1) with a yield of approximately 95.1%. 1 H NMR (400 MHz, CDCl3) d (ppm): 4.59 – 3.89 (m, 2H), 3.63 (dd, J = 11.2, 9.1 Hz, 2H),3.56 (dd, J = 11.2, 3.8 Hz, 2H), 2.25 (tt, J = 7.7, 4.2 Hz, 2H), 1.77 – 1.67(m, 2H), 1.60 (dtt, J = 11.8, 7.8, 3.6 Hz, 1H), 1.51 – 1.40 (m, 1H), 1.17 (dq, J = 13.0, 8.1 Hz, 2H). ESI-MS (m / z): 153.1 (M+Na)

[0042] G. Preparation Method 2 of 1,2-Cyclopentyldimethanol (I-1)

[0043] Cyclopent-2-ene-1,2-diyldimethanol (A-1) (15 g, 0.1 mol) and 150 ml of tetrahydrofuran were added to the reactor, followed by the addition of 1.5 g of a skeletal nickel catalyst. Hydrogen was introduced at room temperature and atmospheric pressure for 30 hours. After the reaction, the catalyst was filtered out and the solvent was distilled off to obtain approximately 14.3 g of 1,2-cyclopentyldimethanol (I-1) with a yield of approximately 93.8%. 1 H NMR (400 MHz, CDCl3) d(ppm): 4.59 – 3.89 (m, 2H), 3.63 (dd, J = 11.2, 9.1 Hz, 2H),3.56 (dd, J = 11.2, 3.8 Hz, 2H), 2.25 (tt, J = 7.7, 4.2 Hz, 2H), 1.77 – 1.67(m, 2H), 1.60 (dtt, J = 11.8, 7.8, 3.6 Hz, 1H), 1.51 – 1.40 (m, 1H), 1.17 (dq, J = 13.0, 8.1 Hz, 2H). ESI-MS (m / z): 153.1 (M+Na) Example 2

[0044] The other steps are the same as those in Example 1, except that the preparation method of 2-formylcyclopent-2-ene-1-carboxylic acid (VI) in step D is as follows:

[0045] 2-(Dichloromethyl)cyclopent-3-ene-1-carboxylic acid (V) (20 g, 0.1 mol) and 100 ml of water were added to a stirred reactor, followed by the addition of 5.3 g of sodium carbonate. The temperature was then raised to 100°C and the reaction was maintained for 1 hour. After the reaction was completed, the reaction was cooled to room temperature, and 10 ml of concentrated hydrochloric acid was added to adjust the pH to 1. Ethyl acetate was then added for extraction. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was removed by distillation under reduced pressure to obtain approximately 11.9 g of 2-formylcyclopent-2-ene-1-carboxylic acid (VI) in a yield of approximately 85.0%. Example 3

[0046] The other steps are the same as those in Example 1, except that the preparation method of 2-formylcyclopent-2-ene-1-carboxylic acid (VI) in step D is as follows:

[0047] 2-(Dichloromethyl)cyclopent-3-ene-1-carboxylic acid (V) (20 g, 0.1 mol) and 100 ml of water were added to a stirred reactor, followed by the addition of 8.4 g of sodium bicarbonate. The temperature was then raised to 100°C and the reaction was maintained for 1 hour. After completion of the reaction, the reaction was cooled to room temperature, and 10 ml of concentrated hydrochloric acid was added to adjust the pH to 1. Ethyl acetate was added for extraction, and the organic layer was separated. The organic phase was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed by distillation under reduced pressure to obtain approximately 12.3 g of 2-formylcyclopent-2-ene-1-carboxylic acid (VI) in a yield of approximately 87.8%. Example 4

[0048] The other steps are the same as those in Example 1, except that the preparation method of cyclopent-2-ene-1,2-diyldimethanol (A-1) in step E is as follows:

[0049] 2-Formylcyclopent-2-ene-1-carboxylic acid (VI) (15 g, 0.1 mol) and 150 ml of tetrahydrofuran were added to a reactor, followed by 20.7 g of N,N'-carbonyldiimidazole, and the reaction was allowed to proceed for 1 hour. In a separate stirred reactor, 50 ml of tetrahydrofuran and 50 ml of water were added, followed by cooling to 0°C in an ice bath. 12.4 g of sodium borohydride was added, and after dissolution, the reaction solution was added dropwise to the sodium borohydride solution. The temperature was maintained above 5°C during the addition, and the addition time was controlled to be within 3 hours. After the addition was complete, the reaction was maintained at this temperature for 8 hours. After completion of the reaction, 108 ml of 3.6% dilute hydrochloric acid was added to quench the reaction, and most of the organic solvent was distilled off. The mixture was extracted with ethyl acetate, separated, and the organic layer dried over anhydrous magnesium sulfate. The desiccant was filtered, and the ethyl acetate was distilled off to obtain approximately 9.1 g of cyclopent-2-ene-1,2-diyldimethanol (A-1) in a yield of approximately 71.0%. Example 5

[0050] The other steps are the same as those in Example 1, except that the preparation method of cyclopent-2-ene-1,2-diyldimethanol (A-1) in step E is as follows:

[0051] 150 ml of tetrahydrofuran and 7.6 g of lithium aluminum hydride were added to the reactor, which was then cooled to 0°C in an ice bath. 2-Formylcyclopent-2-ene-1-carboxylic acid (VI) (15 g, 0.1 mol) was dissolved in 50 ml of tetrahydrofuran and added dropwise to the above solution. The temperature was maintained below 5°C during the addition process, and the addition time was within 1 hour. After the addition was completed, the reaction was kept warm for 8 hours. After the reaction was completed, 100 ml of water was added at 0°C to quench the reaction. Most of the organic solvent was then distilled off, and then extracted with ethyl acetate. The liquids were separated, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and finally, the ethyl acetate was distilled off to obtain approximately 11.1 g of cyclopent-2-ene-1,2-diyldimethanol (A-1) with a yield of approximately 86.3%. Example 6

[0052] The other steps are the same as those in Example 1, except that the preparation method of 1,2-cyclopentyl dimethanol (I-1) in step F is as follows:

[0053] 150 ml of formic acid was added to the reactor, followed by cyclopent-2-ene-1,2-diyldimethanol (A-1) (15 g, 0.1 mol), and finally 1.06 g of 5% Pd / C. The reaction was carried out at room temperature and normal pressure for 24 hours. After the reaction was completed, the catalyst was filtered out and the solvent was distilled off to obtain about 13.5 g of 1,2-cyclopentyldimethanol (I-1) with a yield of about 90.9%. Example 7

[0054] The other steps are the same as those in Example 1, except that the preparation method of 1,2-cyclopentyl dimethanol (I-1) in step F is as follows:

[0055] 150 ml of methanol was added to the reactor, followed by cyclopent-2-ene-1,2-diyldimethanol (A-1) (15 g, 0.1 mol) and 1.06 g of 5% Pd / C, and finally 31.4 g of ammonium formate. The reaction was carried out at room temperature and normal pressure for 24 hours. After the reaction was completed, the catalyst was filtered out and the solvent was distilled off. The crude product was dissolved in dichloromethane, the precipitated solid was filtered, washed with dichloromethane, and finally distilled off under reduced pressure to obtain about 13.1 g of 1,2-cyclopentyldimethanol (I-1) with a yield of about 86.1%. Example 8

[0056]

[0057] At room temperature, 100 mL of tetrahydrofuran was placed in a 500 mL three-necked flask and compound VI (10.0 g, 71.4 mmol) was added, resulting in a brownish-yellow clear solution. Sodium borohydride (2.7 g, 71.4 mmol) was then added, generating a large amount of bubbles. After completion of the reaction, the reaction solution was filtered and an 18% aqueous solution of HCl (29.0 g, 142.8 mmol) was slowly added dropwise at room temperature at a rate of 10 s / d. After the addition was complete, the solution became a pale yellow clear solution. The solution was heated to 75°C and allowed to react for 3 h, resulting in a brownish-yellow clear solution. The tetrahydrofuran was then removed from the reaction solution by rotary evaporation. 100 mL of water and 75 mL of toluene were added and stirred at 50°C for 20 min until the upper and lower layers became clear. The upper toluene layer was separated and the aqueous layer was extracted once more with 50 mL of toluene. The toluene layers were combined. 75 mL of water was added to the toluene layer, followed by sodium hydroxide (2.0 g, 50.0 mmol). The reaction mixture was heated to 80°C and stirred for 2 h. The toluene layer was removed while hot. The aqueous layer was cooled to 30°C and concentrated hydrochloric acid (7.0 g, 71.4 mmol) was added dropwise to adjust the pH to 0.5. The reaction mixture was heated to 80°C and stirred for 2 h. After TLC monitoring, the reaction mixture was cooled to 50°C and extracted three times with 50 mL of toluene. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered to dryness to obtain 6.0 g of the product in a 67.7% yield. ESI-MS: m / z 124.0 (147.0 [M+Na] + ,100%). Example 9

[0058]

[0059] To a three-necked flask, add 50 mL of formic acid, compound A-2 (5.0 g, 40.29 mmol), and then 10% palladium-on-carbon catalyst (0.46 g, 4.29 mmol). Stir at room temperature for 24 h. After TLC monitoring, the catalyst was removed by filtration. The solvent was removed by rotary evaporation under reduced pressure to obtain 4.8 g of a light yellow oil. The yield was 91.6%. Structural characterization: ESI-MS: m / z 126.0 (149.0 [M+Na]+, 100%).

[0060] Compound I-2: 1H NMR (400 MHz, CDCl3) δ (ppm): 4.44 (dd, J = 9.4, 7.7 Hz, 1H), 3.96 (dd, J = 9.4, 3.2 Hz, 1H), 2.95 (dtd, J = 23.3, 8.8, 3.2 Hz, 2H), 2.13 – 1.98 (m, 1H), 1.95 – 1.79 (m, 2H), 1.69 (ddd, J = 11.2, 6.9, 3.2 Hz, 1H), 1.62 – 1.45 (m, 2H). Example 10

[0061]

[0062] At room temperature, anhydrous zinc chloride (15.7 g, 11.50 mmol) and sodium borohydride (2.3 g, 5.98 mmol) were added to a 50 mL three-necked flask. After replacing nitrogen three times, 50 mL of anhydrous tetrahydrofuran was slowly injected. The solution turned into a white turbid liquid. After the injection, it was stirred at room temperature for 30 min. The solution turned into a gray-black turbid liquid. Compound I-2 (5.8 g, 46.0 mmol) was then added dropwise at a dropwise rate of 1 s / d. Bubbles were generated during the addition. After the addition was complete, the temperature was raised to 60-65°C and the reaction was continued for 6 hours. After TLC analysis, the reaction solution was cooled to room temperature and then cooled to 0°C in an ice bath. 50 mL of water was added dropwise to quench the reaction. After the addition was complete, the solution was stirred at room temperature for 3 hours and filtered. The tetrahydrofuran solvent in the reaction solution was removed by rotary evaporation. The aqueous layer was extracted three times with 50 mL of dichloromethane. The organic layers were combined and dried over anhydrous magnesium sulfate for 30 minutes. The dichloromethane was then removed by rotary evaporation to obtain 5.0 g of the product as a light yellow oil, with a yield of 83.5%. ESI-MS analysis of compound I-1 revealed m / z 130.1 (153.1 [M+Na]+, 100%).

[0063] 1H NMR (400 MHz, CDCl3) δ (ppm): 4.59 – 3.89 (m, 2H), 3.63 (dd, J =11.2, 9.1 Hz, 2H), 3.56 (dd, J = 11.2, 3.8 Hz, 2H), 2.25 (tt, J = 7.7, 4.2Hz, 2H), 1.77 – 1.67 (m, 2H), 1.60 (dtt, J = 11.8, 7.8, 3.6 Hz, 1H), 1.51 –1.40 (m, 1H), 1.17 (dq, J = 13.0, 8.1 Hz, 2H).

Claims

1. A method for preparing a gliclazide intermediate compound of formula I-1 or formula I-2, characterized in that: The compound of formula VI is subjected to a reduction reaction to prepare a compound of formula A-1 or formula A-2, and then the compound of formula A-1 or formula A-2 is further subjected to a hydrogenation reaction to prepare a compound of formula I-1 or a compound of formula I-2, respectively. The reduction of compound VI to prepare compound A-1 is carried out in the presence of N,N'-carbonyldiimidazole using sodium borohydride as a reducing agent; The hydrogenation reaction catalyst is Pd / C or skeleton nickel, and the hydrogen source used is hydrogen gas, formic acid or ammonium formate.

2. A method for preparing a gliclazide intermediate 1,2-cyclopentanedicarbinol compound of formula I-1, characterized in that: The method comprises the steps of preparing a compound of formula A-2 by a reduction reaction of a compound of formula VI, further preparing a compound of formula I-2 by a hydrogenation reaction of the compound of formula A-2, and preparing a compound of formula I-1 by a reduction reaction of the compound of formula I-2. The reaction formula is as follows: The hydrogenation reaction catalyst is Pd / C or skeleton nickel, and the hydrogen source used is hydrogen gas, formic acid or ammonium formate.

3. A method for preparing a gliclazide intermediate compound of formula A-1, characterized in that: in, The preparation of the compound of formula A-1 comprises using the compound of formula II as a starting material, and performing depolymerization reaction, [2+2] cycloaddition, ring opening, hydrolysis, and reduction reaction to prepare the compound of formula A-1. The reduction of compound VI to prepare compound A-1 is carried out in the presence of N,N'-carbonyldiimidazole using sodium borohydride as a reducing agent; the reaction formula is as follows:

4. The preparation method according to claim 1 or 2, characterized in that The hydrogenation reaction step comprises reacting a compound of formula A-2, formic acid or ammonium formate, and a palladium-carbon catalyst / nickel catalyst to prepare a compound of formula I-2.

5. The preparation method according to claim 1, characterized in that The hydrogenation reaction solvent is an ether solvent or an ester solvent.

6. The preparation method according to claim 5, characterized in that The mass ratio of the raw material compound formula A-1 to the solvent in the hydrogenation reaction is in the range of 1:5 to 15.

7. A method for preparing a gliclazide intermediate 1,2-cyclopentanedicarbinol compound of formula I-1, characterized in that: The compound of formula II is used as the starting material to prepare the gliclazide intermediate 1,2-cyclopentane dimethanol. The reaction formula is as follows:

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