CN107286031B - The preparation method of 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxoheptanoate - Google Patents

Abstract

The present invention provides compound 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxo-heptanoate (1) and its synthesis method, the compound 1 has the following structural formula: In addition, the present invention also provides the use of compound 1 as an impurity reference substance for monitoring the synthesis of rosivirine bulk drug. Using cycloheptanone as the starting material to synthesize compound 1 through four-step reaction, the obtained product is easy to process after each step, the product is convenient and easy to obtain, and is suitable for large-scale synthesis. It provides a reference for related substances or impurities in the quality research of the synthesis of rosivirine raw material drug Taste.

Description

The preparation method of 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxoheptanoate

technical field

The invention belongs to the field of chemical drug synthesis, and in particular relates to a preparation method of 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxo-heptanoate, a related substance of rosiverine.

Background technique

Rociverine, chemical name 2-diethylamino-1-methylethyl-cis-1-hydroxy[dicyclohexyl]-2-carboxylate, molecular formula C ₂₀ H ₃₇ NO ₃ , commercial It's called Liraton. As an antispasmodic analgesic, it has a unique dual mechanism of action. On the one hand, it has a direct smooth muscle relaxation effect, and on the other hand, it also has an anticholinergic effect; it is suitable for antispasmodic, analgesic, and dynamic dystocia in the genitourinary tract and biliary tract. , puerperium uterine contraction pain and dysmenorrhea. Its structural formula is as follows:

The literature mainly reports two synthetic routes of rosiverine.

The synthetic route reported in the patent GB1167386 is: use 2-hydroxymethylcyclohexanone as the starting material to obtain rosiverine through 5-step reaction. First, 2-hydroxymethylcyclohexanone reacts with Grignard reagent phenylmagnesium bromide to obtain the intermediate cis-1-phenyl-2-hydroxymethylcyclohexanol; it is oxidized by alkaline potassium permanganate to obtain cis- 1-phenyl-1-hydroxycyclohexyl-2-formic acid; cis-1-hydroxyl-[1,1'-bis(cyclohexane)]-2-formic acid is obtained through platinum oxide catalyzed hydrogenation reduction of benzene ring, and Condensation of 1,2-dibromopropane to obtain 1-methyl-2-bromo-ethyl-cis-1-hydroxy[dicyclohexyl]-2-carboxylate, and finally condensation with diethylamine to obtain the target product Rosivir Forest.

Synthetic route 1

The synthetic route reported in the patent US4336398 is: take 2-hydroxymethylcyclohexanone as the starting material to obtain rosiverine through 5-step reaction. First, 2-hydroxymethylcyclohexanone reacts with Grignard reagent phenylmagnesium bromide to obtain the intermediate cis-1-phenyl-2-hydroxymethylcyclohexanol; it is oxidized by alkaline potassium permanganate to obtain cis- 1-phenyl-1-hydroxycyclohexyl-2-carboxylic acid; cis-1-hydroxyl-[1,1'-bis(cyclohexane)]-2-carboxylic acid was obtained by hydrogenation of benzene ring catalyzed by platinum oxide; Cis-1-hydroxy-[1,1'-bis(cyclohexane)]-2-carboxylic acid is directly condensed with N,N-diethyl-2-chloro-propylamine to obtain rosivirine.

Synthetic route 2

The present inventor has thoroughly studied the existing two routes of synthesizing rosiverine. The common point of the two routes is that the last step of the reaction operation requires heating operation, and the positional isomers of rosiverine and rosiverine In the last step, the mixture was thermally converted into rosivirin, and besides preparing the target product of rosivirin, an unknown impurity was also found.

Any substances that affect the purity of medicines are collectively called impurities, or related substances, and the research on impurities is an important part of drug research and development. Whether impurities can be reasonably and effectively controlled is directly related to the quality controllability and safety of drugs. The State Food and Drug Administration (SFDA) has established strict quality standards for drugs.

The research on related substances is very important. In the gas chromatography GC analysis of the crude product of rosivirin, it was found that there was an unknown impurity at the position of retention time 44.976min. . Through GC-MS spectrum analysis by gas chromatography, it is known that the molecular weight of the unknown impurity is only 339, and there are no other molecular weight peaks, and the molecular weight of rosiverine is also 339, so it is inferred that the molecular weight of the impurity is consistent with that of rosiverine.

The inventors have studied the reaction mechanism of the relevant steps in depth, and found that the last step of the reaction operation requires heating. It is inferred that in the final preparation of rosivirine, high temperature heating may lead to the hydroxyl position in the obtained rosivirine. The carbon atom and its adjacent carbon atom are ring-opened, and then compound 1 is formed as 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxo-heptanoate (1), structural formula:

Whether impurities can be reasonably and effectively controlled is directly related to the quality controllability and safety of drugs, and the research on related substances is very important. In order to develop a high-quality rosiverine raw material, it is necessary to further study this related substance. To this end, the inventor designed a synthetic route and synthesized the related substance in a directional manner. Through the gas phase comparison, the peak positions were consistent, and the mass spectrum MS comparison peaks were consistent; in addition, through the NMR nuclear magnetic data, it was confirmed that the related substance was inferred by the inventor before. The structural formula 1. The compound 1 has no relevant literature reports and is a brand new compound.

Contents of the invention

On the one hand, the present invention provides compound 1, such as the following structural formula:

The compound of formula 1 may be named as 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxo-heptanoate.

On the other hand, the present invention provides a synthetic method of compound 1, comprising the following steps:

1) Using cycloheptanone 2 as a starting material, oxidize it with an oxidizing agent 3 to obtain cyclic ester 4; 2) react cyclic ester 4 with compound 5 and compound 6 in sequence to generate alcohol 7; 3) oxidize alcohol 7 to obtain carboxylic acid 8; 4) Condensation of carboxylic acid 8 and compound 9 to obtain compound 1, refer to the following synthetic route.

Synthetic route 3

Preferred implementation modes and implementation conditions of the above-mentioned steps in the present invention are further provided below.

In the above route of synthesizing compound 1, the oxidizing agent 3 in the step 1) is a peroxide, such as peroxyacetic acid, peroxytrifluoroacetic acid, peroxybenzoic acid, m-chloroperoxybenzoic acid; preferably m-chloroperoxybenzoic acid Oxybenzoic acid. When chloroperoxybenzoic acid is used as an oxidizing agent, the oxidation reaction in step 1) is also called Baeyer-Villiger oxidation, which is an oxidation reaction in which the carbonyl position of a cyclic ketone is inserted into an oxygen atom to obtain the corresponding ester compound.

In the step 2), the cyclic ester 4 is reacted with the compound 5 to obtain the Weinreb amide intermediate 10, and the Weinreb amide intermediate 10 is reacted with the compound 6 to generate the alcohol 7. The operation of the above step 2) is preferably a "one-pot" operation, that is, there is no need to separate and purify the Weinreb amide obtained by the reaction of the cyclic ester 4 and the compound 5, and the compound 6 is directly added to the obtained reaction solution, and the reaction is further obtained. Alcohol 7.

In the step 3), the terminal hydroxyl group in the structure of the alcohol 7 is subjected to an appropriate oxidation operation to obtain the corresponding carboxylic acid compound; the preferred oxidation operation is: the alcohol 7 undergoes TEMPO oxidation to obtain an intermediate aldehyde, which is then oxidized by Pinnick Carboxylic acid 8 is obtained. More preferred operations: TEMPO oxidation and Pinnick oxidation can be performed in one pot.

TEMPO oxidation refers to the oxidation of alcohol to aldehyde in dichloromethane and water two-phase solvent with sodium hypochlorite as oxidant, TEMPO as catalyst, and sodium bromide as cocatalyst at -10°C to 10°C.

Pinnick oxidation refers to using sodium chlorite as an oxidant, 30% hydrogen peroxide as a hypochlorous acid scavenger, tert-butanol as a homogeneous reaction solvent, and a saturated aqueous solution of sodium dihydrogen phosphate to provide a suitable system pH. At room temperature, the aldehyde is oxidized to acid oxidation reaction.

In the step 4), the carboxylic acid 8 and the compound 9 are condensed to obtain the target product 1.

Therefore, a preferred embodiment, the synthetic method of compound 1 provided by the invention comprises the following steps:

1) Using cycloheptanone 2 as the starting material and m-chloroperoxybenzoic acid as the oxidizing agent 3, compound 4 was obtained by Baeyer-Villiger oxidation; 2) Compound 4 was reacted with compound 5 in a one-pot method to generate Weinreb amide intermediate 10 , and then react with compound 6 to generate alcohol 7; 3) Alcohol 7 is also oxidized by TEMPO to obtain intermediate aldehyde in a one-pot method, and then oxidized by Pinnick to obtain carboxylic acid 8; 4) Finally, through the condensation of carboxylic acid 8 and compound 9 The target product 1 was obtained.

In the preferred embodiment of the synthetic method of compound 1 provided by the above-mentioned invention, those skilled in the art can select specific operating conditions such as reaction temperature according to the type of reaction, and the reaction time can be determined by chromatographic methods such as thin layer chromatography or gas chromatography. and other conventional technical means to track the reaction.

Further, in the synthesis method of compound 1 provided by the present invention, a brand new compound, alcohol 7, which has not been disclosed or reported, is also provided, namely: 1-cyclohexyl-7-hydroxyl-1-heptanone.

In the third aspect, the compound 1 (2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxo-heptanoate) provided by the present invention is used as an impurity reference substance for monitoring the synthesis of rosiverine bulk drug the use of.

The present invention has the advantages of: using cycloheptanone as the starting material to synthesize compound 1 through four-step reactions, the obtained product is easy to process after each step, the product is convenient and easy to obtain, suitable for large-scale synthesis, and is a quality research for the synthesis of rosivirine raw material drug Provide related substances or impurity reference substances.

Detailed ways

The following provides a specific embodiment and an example of a specific and detailed operation process to further clarify the present invention. It should be pointed out that those skilled in the art can make some improvements and modifications without departing from the concept of the present invention, and these improvements and modifications should also be considered within the protection scope of the present invention.

Detailed ways

Step 1), the preparation of cyclic ester 4:

First add m-chloroperoxybenzoic acid into the reaction flask, then add the solvent dichloromethane, stir in an ice bath to cool down, drop to -5°C~5°C, add cycloheptanone dropwise, after the dropwise addition, heat up to 25°C~ 40°C, continue to stir for 5-10 days, after the reaction, add saturated sodium thiosulfate aqueous solution to quench, after quenching, wash with saturated sodium bicarbonate aqueous solution several times, then wash with saturated brine, and dry over anhydrous magnesium sulfate , concentrated to obtain the crude compound 4, which was passed through the column to obtain compound 4. In step 1), the reaction temperature is preferably 25°C (room temperature), and the reaction time is preferably 7 days.

Step 2), the preparation of alcohol 7:

Add compound 4, N,O-dimethylhydroxylamine hydrochloride, and dichloromethane as a solvent to the reaction flask in sequence, cool down in an ice-salt bath to -10°C to 0°C, add 2M tetrahydrofuran solution of isopropylmagnesium chloride dropwise, Continue to stir at low temperature for 1-3 hours. After the reaction is complete, slowly add 1M tetrahydrofuran solution of cyclohexylmagnesium bromide dropwise. After all the drops are completed, raise it to room temperature and stir for 3-5 hours. After conventional post-treatment, the crude product of alcohol 7 was obtained as a yellow oil, and alcohol 7 was obtained by column chromatography. In step 2), the molar ratio of the reaction materials is preferably compound 4:N,O-dimethylhydroxylamine hydrochloride:isopropylmagnesium chloride:cyclohexylmagnesium bromide=1:1:2:8.

Step 3), the preparation of carboxylic acid 8:

Add alcohol 7, dichloromethane, water, sodium bromide, and TEMPO into the reaction flask in sequence, stir and cool down to -5°C, then add dropwise a commercially available 5.2% sodium hypochlorite aqueous solution whose pH has been adjusted with saturated aqueous sodium bicarbonate solution, dropwise Continue to stir for 0.5-1.5 hours after the addition, then adjust the pH of the reaction system to 6-7 with 2M hydrochloric acid aqueous solution, add tert-butanol and 30% hydrogen peroxide in sequence, and then adjust the pH of the reaction system to about 4.3 with saturated aqueous sodium dihydrogen phosphate. Finally, sodium chlorite was added dropwise, reacted for 2 to 4 hours, quenched by adding a small amount of anhydrous sodium sulfite, and concentrated to obtain a concentrated solution that was extracted several times with ethyl acetate, dried, and concentrated to obtain a crude product of carboxylic acid 8, which was then washed with n-hexane. Carboxylic acid 8 was obtained. In step 3), the molar ratio of the reaction materials is alcohol 7: TEMPO: NaBr: NaClO: 30% H ₂ O ₂ : NaClO ₂ = 1: (1-2%): (0.1-0.5): (1.1-1.4) : (1.5～2): (1.1～1.4) ; The pH of the saturated sodium bicarbonate aqueous solution adjusting the sodium hypochlorite aqueous solution is preferably 8.5～9.5; The saturated sodium dihydrogen phosphate aqueous solution adjusting the pH of the reaction system is preferably 4.3.

Step 4), the preparation of 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxo-heptanoate (1):

Dissolve the prepared carboxylic acid 8 in isopropanol, add catalyst potassium carbonate, heat to reflux, dissolve N,N-diethyl-2-chloro-propylamine hydrochloride in isopropanol and slowly add Put it into the above-mentioned refluxed reaction liquid, after dropping, continue to stir for 1-5 hours, after the reaction is completed, filter, concentrate to obtain the crude product, and obtain the target product 1 through column separation. In step 4), the reaction time is preferably 3h.

The following examples are further provided.

For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions. The reagents and raw materials used in the present invention are commercially available or prepared according to known literature methods.

Example

Embodiment one: the preparation of cyclic ester 4

First add 85% m-CPBA (95g, 0.55mol, 1.8eq) and dichloromethane (1000ml) into a 2L reaction flask in turn, cool down in an ice bath and stir, and when the temperature of the reaction system reaches 0°C, start to add cyclic Heptanone (34g, 0.31mol), the temperature of the system remained basically unchanged during the dropwise addition, the ice bath was removed after the dropwise addition, and the stirring was continued at room temperature (25°C), and the reaction was carried out for 7 days, during which the reaction solution changed from transparent to white turbid. Add saturated sodium thiosulfate solution to quench, add 10% sodium bicarbonate aqueous solution to wash several times after quenching, saturated brine, dry the organic layer, filter, concentrate to obtain compound 4 crude product, and then obtain compound 4 through column chromatography ( 19.5g), yield 50.2%. [M+H] ⁺ ＝129

¹ H-NMR (400MHz, CDCl ₃ ) δ4.34(t, 2H), 2.53(t, 2H), 1.90～1.77(m, 4H), 1.64～1.53(m, 4H)

Embodiment two: the preparation of alcohol 7

Add compound 4 (0.64g, 5mmol), N, O-dimethylhydroxylamine hydrochloride (0.4875g, 5mmol, 1eq), dichloromethane (20ml) into the reaction flask in turn, stir and cool down in an ice-salt bath, when the system When the temperature reached -3～-4°C, 2M THF solution of isopropylmagnesium chloride (5.5ml, 11mmol, 2.2eq) was added dropwise. After the dropwise addition, a golden yellow liquid was obtained, and the stirring was continued at low temperature for 1h. After the completion of the reaction was monitored by pointing the plate, slowly add 1M THF solution of cyclohexane magnesium bromide (15ml, 15mmol, 3eq) dropwise. The temperature of the system was kept at -3.5°C. Aqueous solution (10ml) was quenched, washed twice with saturated aqueous sodium bicarbonate solution, washed twice with water, the organic layer was dried, filtered, concentrated to give 1.72g of yellow oil, 0.2g of alcohol 7 was obtained by column chromatography, yield 18.9% . [M+H] ⁺ ＝213

¹ H-NMR (400MHz, CDCl ₃ ) δ3.64(t, 2H), 2.43(t, 2H), 2.40-2.25(m, 1H), 1.84-1.54(m, 9H), 1.41-1.18(m, 10H)

Embodiment three: the preparation of alcohol 7

Add compound 4 (1.92g, 15mmol), N, O-dimethylhydroxylamine hydrochloride (1.46g, 15mmol, 1eq), dichloromethane (60ml) into the reaction flask in turn, stir and cool down in an ice-salt bath, when the system When the temperature reached -3～-4°C, start to dropwise add 2M THF solution of isopropylmagnesium chloride (15ml, 30mmol, 2eq). After the dropwise addition, a golden yellow liquid was obtained, and continue to stir at low temperature for 1h. After the reaction was monitored by spotting the plate, slowly add 1M THF solution of cyclohexanemagnesium bromide (120ml, 120mmol, 8eq) dropwise. The temperature of the system was kept below 0°C. The aqueous solution (90ml) was quenched, washed twice with saturated aqueous sodium bicarbonate solution, washed twice with water, the organic layer was dried, filtered and concentrated to give a yellow oil, which was purified by column chromatography to give 1.35g of alcohol 7 with a yield of 42.5%. [M+H] ⁺ ＝213

Embodiment four: the preparation of carboxylic acid 8

Alcohol 7 (1.06g, 5mmol), dichloromethane (20ml), TEMPO (0.0156g, 0.1mmol, 0.02eq), NaBr (0.05g, 0.5mmol, 0.1eq), water (5ml) were added to the reaction flask in sequence , stirred at low temperature, and when the temperature of the system dropped to -5°C, an aqueous solution of sodium hypochlorite (7.15ml, 5.5mmol, 1.1eq) was added dropwise to adjust the pH to 9.2 with saturated aqueous sodium bicarbonate solution. After the addition was complete, the reaction was monitored by TLC. Continue to Stir for 1 h, then adjust the pH of the system to 6-7 with 2M hydrochloric acid aqueous solution, add tert-butanol (15ml) and 30% hydrogen peroxide (1ml, 10mmol, 2eq) in sequence, then adjust the pH of the system to 4.3 with saturated aqueous sodium dihydrogen phosphate, Finally, a 20ml aqueous solution of sodium chlorite (0.79g, 7mmol, 1.4eq) was added dropwise. After the dropwise addition, the reaction was continued for 2.5h. TLC monitored that the reaction was complete. A small amount of sodium sulfite was added to quench, concentrated, and extracted 3 times with ethyl acetate , 100ml each time, dried, filtered, and concentrated to obtain a yellow oil, which was beaten with n-hexane to obtain a white solid, which was dried to obtain 0.9g, with a yield of 80%. [M+H] ⁺ ＝227，[M+K] ⁺ ＝265

¹ H-NMR (400MHz, CDCl ₃ ) δ2.42(t, 2H), 2.35-2.27(m, 3H), 1.81-1.12(m, 16H)

Embodiment five: the synthesis of compound 1

Carboxylic acid 8 (0.7g, 3.1mmol) was dissolved in isopropanol (15ml) and added to the reaction flask, then potassium carbonate (0.68g, 4.9mmol, 1.5eq) was added, heated and stirred to reflux, and compound 9 (0.56 g, 3mmol, 0.97eq) of isopropanol (15ml) solution was slowly added dropwise into the reaction solution, after the dropwise addition, continued heating under reflux, reacted for 3h, monitored by TLC, the reaction was complete, cooled, filtered, and concentrated to obtain 1g of the target Product 1 crude product, 0.25g target product 1 was obtained by column chromatography, yield 24.6% [M+H] ⁺ =340

Embodiment six: the synthesis of compound 1

Carboxylic acid 8 (1.4g, 6.2mmol) was dissolved in isopropanol (30ml) and added to the reaction flask, then potassium carbonate (1.36g, 9.8mmol, 1.5eq) was added, heated and stirred to reflux, compound 9 (1.12 g, 6mmol, 0.97eq) of isopropanol (30ml) solution was slowly added dropwise into the reaction solution, after the dropwise addition, continued to reflux heating, reacted for 3h, monitored by TLC, the reaction was complete, cooled, filtered, and concentrated to obtain 2.1g The crude product of the target product 1 was obtained by column chromatography 0.6g of the target product 1, and the yield was 29.5% [M+H] ⁺ =340

¹ H-NMR (400MHz, CDCl ₃ ) δ4.98(m, 1H), 2.54-2.49(m, 5H), 2.43-2.24(m, 6H), 1.81-1.52(m, 9H), 1.35-1.15( m, 10H), 0.98(t, 6H)

Gas phase detection conditions for rosivirine API:

Chromatographic column: capillary column with 5%-diphenyl-95% dimethylpolysiloxane as stationary liquid (30m×0.32mm×0.25um, DB-5MS UI), column temperature 180°C, detector is hydrogen flame Ionization detector, the detection temperature is 280°C; the inlet temperature is 240°C; the split ratio is 5:1; the carrier gas flow rate is 2.0ml/min.

According to the corresponding conditions of the patented route, the crude product of rosivirin was synthesized. In the final step of synthesizing rosivirin, the temperature of the oil bath was 180° C. to 200° C., and the reaction was carried out for 6 hours to prepare rosivirine. The inventor carried out GC analysis on rosivirine, and there was an impurity with a peak area greater than 0.1% (0.36%) when the retention time was 44.976 min, and it was judged to be compound 1 according to the reaction.

Self-designed route, the first directional synthesis of compound 1. It was confirmed by GC that the synthesized compound 1 was detected under the aforementioned gas phase conditions, and the retention time was 45.777min. Within the error range, the retention time of the related substances in the crude product of rosivirine prepared above is the same. For this reason, the present invention directionally synthesizes the related substances of rosiverine bulk drug, and the synthetic method used has higher yield, and can prepare sufficient amount of impurities for the quality control research in the synthetic process of rosiveril bulk drug.

Claims (11)

1. Compound 1 as shown in the following formula 1: 2. the synthetic method of compound 1 as claimed in claim 1, comprises the following steps: 1) Cycloheptanone 2 is used as the starting material, and cyclic ester 4 is obtained by oxidation with oxidant 3; 2) Cyclic ester 4 is reacted with compound 5 and compound 6 in sequence to form alcohol 7; 3) Alcohol 7 is oxidized to obtain carboxylic acid 8; 4) The condensation of carboxylic acid 8 and compound 9 obtains compound 1, and the synthetic route is: 3. the compound method of compound 1 as claimed in claim 2 is characterized in that, described step 1) in the oxygenant 3 is selected from peracetic acid, peroxytrifluoroacetic acid, peroxybenzoic acid, m-chloroperoxy Peroxides of benzoic acid. 4. The synthetic method of compound 1 as claimed in claim 3, is characterized in that, the oxidizing agent 3 in described step 1) is m-chloroperoxybenzoic acid. 5. the synthetic method of compound 1 as claimed in claim 2 is characterized in that, in described step 2), cyclic ester 4 reacts with compound 5, compound 6 to generate alcohol 7 successively; Step 2) operation is " one pot method" operation. 6. The synthetic method of compound 1 as claimed in claim 2, it is characterized in that, the oxidation reaction of described step 3) is: alcohol 7 obtains intermediate aldehyde through tetramethylpiperidine nitrogen oxide oxidation, then through Linde Glenn oxidation gave carboxylic acid 8. 7. the compound method of compound 1 as claimed in claim 6 is characterized in that, the oxidation reaction of described step 3) is tetramethylpiperidine nitroxide oxidation and Lindgren oxidation reaction, and these two steps pass " One-pot method" operation. 8. The synthetic method of compound 1 as claimed in claim 6 or 7, is characterized in that, in described step 3), the reaction condition of tetramethylpiperidine nitrogen oxide oxidation is: take sodium hypochlorite as oxidant, tetramethylpiperidine Piperidine nitrogen oxide is used as a catalyst, sodium bromide is used as a cocatalyst, at -10°C to 10°C, dichloromethane and water two-phase solvent are used as reaction solvents, and alcohol is oxidized to aldehyde. 9. The synthetic method of compound 1 as claimed in claim 6 or 7, is characterized in that, in described step 3), the reaction condition of Lindgren oxidation reaction is: take sodium chlorite as oxygenant, 30% hydrogen peroxide As a hypochlorous acid scavenger, tert-butanol is a homogeneous reaction solvent, and saturated sodium dihydrogen phosphate aqueous solution provides a suitable system pH. At room temperature, aldehydes are oxidized into acids. 10. The synthetic method of compound 1 as claimed in claim 2, is characterized in that, comprises the following steps: 1) Using cycloheptanone 2 as the starting material and m-chloroperoxybenzoic acid as the oxidizing agent 3, compound 4 was obtained by oxidation; 2) Compound 4 was reacted with compound 5 and compound 6 in a one-pot method to form alcohol 7; 3) Alcohol 7 was oxidized by tetramethylpiperidine nitroxide to obtain intermediate aldehyde through one-pot method, and then carboxylic acid 8 was obtained through Lindgren oxidation reaction; 4) Finally, the target was obtained by condensation of carboxylic acid 8 and compound 9 Product 1. 11. The use of compound 1 according to claim 1 as an impurity reference substance for monitoring the synthesis of rosivirine bulk drug.