Preparation method of rifapentine side chain

Abstract

The invention belongs to the technical field of organic synthesis. The invention particularly relates to a preparation method of a rifapentine side chain. The preparation method comprises the following steps: taking diethanol amine and cyclopentanone as starting materials, and carrying out reductive amination reaction to obtain the 2, 4-dichloro-2, 4-dione The preparation method comprises the following steps: reacting 2, 2 '-(cyclopentyl imino) diethanol with methanesulfonyl chloride to obtain (cyclopentyl azane diyl) bis (ethane-2, 1-diyl) dimethyl sulfonate, and carrying out cyclization reaction on the (cyclopentyl azane diyl) bis (ethane-2, 1-diyl) dimethyl sulfonate and 80% hydrazine hydrate in the presence of alkali to obtain the rifapentine side chain 1-amino-4-cyclopentyl piperazine. According to the method disclosed by the invention, the use of an intermediate containing a nitrosamine structure is avoided, and the content of nitrosamine in a rifapentine side chain is greatly reduced. The reaction conditions are mild, high-temperature and low-temperature reactions are avoided, and special equipment is not needed. The raw materials are wide in source and low in price, so that the cost of the raw materials is greatly reduced, and the yield of the 1-amino-4-cyclopentyl piperazine is also increased.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and specifically relates to a method for preparing a rifapentine side chain. Background Art

[0002] Rifapentine is a drug mainly used for anti-tuberculosis, anti-leprosy and acute lung infection, and belongs to the rifamycin antibiotics. Its chemical name is 3-[[(4-cyclopentyl-1-piperazinyl)imino]methyl]-rifamycin, and its molecular weight is 877.04. The mechanism of action and antibacterial spectrum of rifapentine are the same as those of rifampicin, and it has a killing effect on Mycobacterium tuberculosis, non-tuberculous mycobacteria, Mycobacterium leprae, Gram-positive bacteria, Gram-negative bacteria, certain viruses, and Chlamydia. Rifapentine is mainly used for the initial treatment and retreatment of various tuberculosis, but it is not suitable for the treatment of tuberculous meningitis. In addition, it can also be used for the treatment of non-tuberculous mycobacterial infections, and it may be effective in combination with other anti-leprosy drugs for the treatment of leprosy. When using rifapentine, it is usually taken orally on an empty stomach, once a week, with a dose of 0.5g to 0.6g. Rifapentine has relatively few adverse reactions, mainly gastrointestinal reactions, leukopenia, rash, etc. It is contraindicated in patients with severe liver dysfunction, biliary obstruction and pregnant women. Rifapentine also has a strong effect on tuberculosis bacteria that are resistant to anti-tuberculosis drugs other than Rifapentine.

[0003]

[0004] The structure of rifapentine

[0005] Since the detection of nitrosodimethylamine (NDMA) in valsartan API in July 2018, drug regulatory agencies, the medical community, and academia in various countries or regions have begun to pay close attention to the presence of such substances in drugs. On May 8, 2020, the State Drug Administration issued the "Technical Guidelines for the Study of Nitrosamine Impurities in Chemical Drugs (Trial)". The guidelines point out that nitrosamine impurities belong to the "concern queue" substances mentioned in the ICH M7 (R1) guidelines. Even if the intake is lower than the threshold of toxicological concern (TTC) level, there is still a potential significant carcinogenic risk in theory, and it is a highly effective mutagenic carcinogen. The presence of extremely small amounts in drugs can also cause great harm to those who take them, so nitrosamine impurities in drugs should be strictly controlled.

[0006] The existing synthesis methods of 1-amino-4-cyclopentylpiperazine as the side chain of rifapentine mostly use cyclopentylpiperazine as the starting material, and after nitrosamination, use zinc powder as a reducing agent to reduce the nitroso group to the amino group to obtain 4-cyclopentyl-1-aminopiperazine. The intermediate 1-cyclopentyl-4-nitrosopiperazine (CPNP) in this process is a nitrosamine impurity.

[0007]

[0008] On July 9, 2020, the WHO Prequalification Unit-Medicines Assessment Team (POT / MED) first announced that the nitrosamine impurity 1-cyclopentyl-4-nitrosopiperazine (CPNP) was detected in Sanofi's anti-tuberculosis drug rifapentine. Subsequently, on August 26, 2020, the US FDA issued a statement that the nitrosamine impurities detected in the anti-tuberculosis drug rifapentine exceeded the acceptable daily intake (>0.1ppm), indicating that there are risks to the drug safety of tuberculosis patients. POT / MED subsequently conducted a preliminary risk-benefit assessment and concluded that the risks to patients from treatment interruptions caused by product recalls or suspensions far outweighed the potential carcinogenic risks associated with nitrosamine impurities. Therefore, POT / MED issued an announcement on October 23, 2020, accepting the US FDA's decision not to object to the temporary supply of rifapentine drugs with a CPNP below 14 ppm. On October 30, an updated announcement was issued again, referring to the US FDA's approach. WHO temporarily did not object to the supply of rifapentine drugs with a CPNP below 20 ppm. In May 2022, WHO accepted the temporary release limit of 20 ppm for the CPNP impurity in the first generic isoniazid / rifapentine product.

[0009] At present, CPNP in rifapentine is mainly caused by the residual CPNP intermediates in the side chain of rifapentine. Based on the consideration of safe drug use, it is of great significance to develop a synthetic method for preparing the side chain of rifapentine without using CPNP intermediates.

[0010] In 2005, Japan's Koei Chemical reported in JP2005289988 a method for synthesizing the rifapentine side chain without the CPNP intermediate. The method uses cyclopentylpiperazine as a starting material, reacts with urea to obtain 4-cyclopentylpiperazine-1-carboxamide, and then degrades it in an alkaline solution of sodium hypochlorite to generate the rifapentine side chain.

[0011]

[0012] In 2023, Arene Lifesciences of India reported another method for synthesizing the rifapentine side chain without the CPNP intermediate. The synthetic route of this method is as follows. This method uses cyclopentylpiperazine as the starting material and reacts with chloramine in one step to generate the rifapentine side chain. Compared with the method of Koei Chemical of Japan, this method is simpler, but the yield is not high, and the yield of the same series of products is less than 70%. The above two preparation methods both use cyclopentylpiperazine as the starting material. Since piperazine contains two identical secondary amines, the selectivity of cyclopentanone and piperazine is poor, and a disubstituted product is generated, which brings difficulties to the subsequent separation and purification, and also makes cyclopentylpiperazine expensive.

[0013]

[0014] In 2023, Xuzhou Bokang Information Chemicals Co., Ltd. reported a synthesis method for rifapentine CN117186032A, and the synthesis route is as follows. This method uses cyclopentylamine as the starting material, undergoes an alkylation reaction with ethylene oxide gas to obtain bis(2-hydroxyethyl)-cyclopentylamine, and then reacts with thionyl chloride or oxalyl chloride to generate a chlorinated product bis(2-chloroethyl)-cyclopentylamine, and finally undergoes a cyclization reaction with hydrazine hydrate to generate the rifapentine side chain. This method has the following problems: ethylene oxide is a toxic gas with central nervous system depressant and irritant effects and long-term toxic effects, and gas leakage will have serious consequences; the chlorination reaction of this method will produce a large amount of impurities, and the product is a hydrochloride, which requires the addition of sodium hydroxide, generates more impurities, and requires the use of silica gel for purification.

[0015]

[0016] The prior art synthesis method for preparing rifapentine side chain without CPNP intermediate has the defects of complex preparation process, low yield, difficult purification, etc. Therefore, it is necessary to develop a synthesis method for rifapentine side chain with easy-to-obtain raw materials, simple process, simple post-treatment and high yield. Summary of the invention

[0017] In order to solve one of the above problems existing in the prior art, the present invention provides a method for synthesizing a rifapentine side chain, which has the advantages of low cost, high purity of the final product, less impurities, and can avoid the formation of nitrosamine impurity 1-cyclopentyl-4-nitropiperazine (CPNP), nitrosamine impurities meet the requirements, simple operation, low cost, environmentally friendly process, etc.

[0018] The present invention is achieved through the following technical solutions:

[0019] The invention provides a new synthesis method for preparing rifapentine side chain 1-amino-4-cyclopentylpiperazine by taking cyclopentanone and diethanolamine as raw materials.

[0020] Specifically, the present invention uses diethanolamine and cyclopentanone as starting materials, undergoes a reductive amination reaction to obtain 2,2'-(cyclopentylimino)diethanol (compound 1), then reacts with methanesulfonyl chloride to obtain (cyclopentylazanediyl)bis(ethane-2,1-diyl)dimesylate (compound 2), and finally undergoes a cyclization reaction with 80% hydrazine hydrate in the presence of a base to obtain rifapentine side chain 1-amino-4-cyclopentylpiperazine (compound 3).

[0021]

[0022] Furthermore, the synthesis method of the present invention comprises the following steps:

[0023] Step 1) diethanolamine and cyclopentanone are reacted in a solvent under acidic conditions and with the action of a reducing agent to generate compound 1;

[0024] Step 2) Compound 1 undergoes an esterification reaction with methanesulfonyl chloride in a solvent in the presence of a base to generate compound 2;

[0025] Step 3) Compound 2 is reacted with 80% hydrazine hydrate in a solvent in the presence of a base to generate 1-amino-4-cyclopentylpiperazine (Compound 3).

[0026] In the step 1), the solvent is one or more of acetic acid, water, methanol, anhydrous ethanol, isopropanol, butanol, and tert-butanol, preferably anhydrous ethanol.

[0027] In the step 1), the reducing agent is one or a combination of sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like; preferably sodium triacetoxyborohydride.

[0028] In the step 1), the molar ratio of diethanolamine to cyclopentanone is 1:(0.5-10), preferably 1:(0.5-5), and more preferably 1:(1.2-2.5).

[0029] In the step 1), the reaction temperature is 0 to 90° C., preferably 10 to 40° C.; the reaction time is 0.5 to 10 hours, preferably 2 to 8 hours.

[0030] In the step 1), the pH value of the acidic condition is 5.5-6.0.

[0031] In the step 2), the solvent is one or more of water, methanol, anhydrous ethanol, dichloromethane, chloroform, tetrahydrofuran, ether, methyl tert-butyl ether, isopropyl ether, and dioxane, preferably dichloromethane.

[0032] In the step 2), the base is one or more of triethylamine, pyridine, trimethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably triethylamine.

[0033] In the step 2), the molar ratio of compound 1:methanesulfonyl chloride is 1:(1-10), preferably 1:(2-5).

[0034] In the step 2), the reaction temperature is 0 to 90° C., preferably 10 to 40° C., and the reaction time is 0.5 to 10 hours, preferably 2 to 8 hours.

[0035] In the step 3), the solvent is one or more of water, methanol, anhydrous ethanol, dichloromethane, chloroform, tetrahydrofuran, ether, methyl tert-butyl ether, isopropyl ether, and dioxane, preferably methanol.

[0036] In the step 3), the base is one or more of triethylamine, pyridine, trimethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide.

[0037] In the step 3), the molar ratio of compound 2 to base is 1:(1-10), preferably 1:(1-5), and more preferably 1:(2-5).

[0038] In the step 3), the reaction temperature is 0 to 90° C., preferably 10 to 40° C., and the reaction time is 0.5 to 10 hours, preferably 2 to 8 hours, and more preferably 3 to 5 hours.

[0039] This preparation method has not been reported in the literature so far.

[0040] Compared with the prior art, the present invention has the following advantages:

[0041] Compared with the prior art, the process route of the present invention uses low-priced raw materials, the obtained product has high purity, and the product quality can meet subsequent requirements.

[0042] The technical features and excellent effects of the present invention are as follows:

[0043] 1. The present invention avoids the use of intermediates containing nitrosamine structures, thereby significantly reducing the content of nitrosamines in the side chain of rifapentine.

[0044] 2. The process adopted by the method of the present invention has a high degree of greenness, and avoids the use of zinc powder, a raw material with relatively serious pollution, in the reduction reaction.

[0045] 3. The method of the present invention has mild reaction conditions, avoids high temperature and low temperature reactions, and does not require special equipment.

[0046] 4. The materials used in the method of the present invention, such as cyclopentanone and diethanolamine, have a wide range of sources, are cheap, and have a low total cost. Assuming that 1 mol of 1-cyclopentyl-4-aminopiperazine is required to generate 1 mol of 1-cyclopentylpiperazine, the raw material cost required by the prior art route is at least 7 times the raw material cost of the route of the present invention.

[0047] 5. The present invention improves the yield and purity of 1-amino-4-cyclopentylpiperazine of the rifapentine side chain, the purity can reach up to more than 99%, and the yield can reach up to about 90%. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1H NMR spectrum of the side chain of rifapentine;

[0049] Figure 2 Mass spectrum of the rifapentine side chain. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention. Such structures and technologies are also described in many publications.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly used in the art to which this invention belongs.

[0052] The starting materials and solvents used herein are commercially available.

[0053] The following are only some specific embodiments of the present invention, and the present invention is not limited to the following embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by ordinary technicians in this field should be considered as the protection scope of the present invention.

[0054] The content of CPNP in 1-amino-4-cyclopentylpiperazine, the side chain of rifapentine, was detected by ultra-high performance liquid chromatography-mass spectrometry under the following conditions:

[0055] Chromatographic conditions:

[0056]

[0057] Mass spectrometry conditions:

[0058] Q Exactive mass spectrometer (Thermo Fisher Scientific): sheath gas flow rate 55; auxiliary gas flow rate 15; sweep gas flow rate 0; spray voltage 3.5; capillary temperature 300°C; auxiliary gas heater temperature 300°C; scan type: PRM; mode: positive ion; scan time 4.8 min-5.5 min; PRM mass-to-nuclear ratio: 184.1444; collision energy: 30; number of scans: 1

[0059] Solution preparation:

[0060] Mobile phase A: 10 mM ammonium formate aqueous solution at pH = 9.0. Accurately weigh 630 mg of ammonium formate and transfer to a 1 L volumetric flask. Dilute to the required volume with water. Adjust the pH to 9.0 with ammonium hydroxide.

[0061] Mobile phase B: methanol.

[0062] Diluent and blank: methanol.

[0063] Preparation of mixed CPNP intermediate stock standard (100 ng / mL):

[0064] Using the CPNP reference standard, prepare a 100 ng / mL intermediate stock standard solution of CPNP mixture in methanol.

[0065] Preparation of working standard (3 ng / mL): Transfer 0.75 mL aliquot of the mixed intermediate stock standard into a 25 mL volumetric flask and dilute to volume with methanol. Prepare immediately before use.

[0066] Sample preparation: Accurately weigh 150 mg of the API into a 15 mL glass centrifuge tube. Add 5.0 mL of methanol and mix the solution with a vortex mixer until dissolved. Filter the solution using a 0.22 μm filter, discard the first 1 mL, and transfer the filtered sample to an HPLC vial for LC / MS analysis. After extraction, centrifuge the sample at 4000 rpm for 10 minutes. Filter the supernatant using a 0.22 μm filter, discard the first 1 mL, and transfer the filtered sample to an HPLC vial for LC / MS analysis.

[0067] Example 1

[0068] 1-Amino-4-cyclopentylpiperazine was prepared according to the following reaction scheme

[0069] Step 1): Under nitrogen protection, cyclopentanone (4.8 g, 0.057 mol) was added to a 100 mL three-necked flask, anhydrous ethanol (50 mL) was added, and diethanolamine (5 g, 0.047 mol) was added at room temperature. The system was colorless and transparent, and the pH was adjusted to 5.5-6.0 with acetic acid. Sodium triacetoxyborohydride (20.2 g, 0.095 mol) was added in batches. After the addition was completed, the reaction was stirred at room temperature for 4 hours. After the reaction was completed, the insoluble matter was filtered off, the filter cake was washed with ethanol (15 mL), and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain 2,2'-(cyclopentylimino)diethanol (Compound 1), 8.1 g of yellow oil, and the yield was 98.1%.

[0070]

[0071] Step 2): Under an ice-water bath, weigh 2,2'-(cyclopentylimino)diethanol (5.0 g, 0.029 mol) and triethylamine (3.5 g, 0.035 mol) and add them to a 250 mL three-necked flask, add dichloromethane (50 mL), stir at room temperature for 5 min, add a dichloromethane solution of methanesulfonyl chloride (3.6 g, 0.058 mol) dropwise to the reaction system, after the addition is complete, stir at room temperature for 2 h, filter out the insoluble matter, wash the organic layer three times with water (30 mL), dry with anhydrous magnesium sulfate, and evaporate dichloromethane to obtain (cyclopentylazanediyl)bis(ethane-2,1-diyl dimethanesulfonate (Compound 2), 9.27 g of oil, yield 97.5%.

[0072]

[0073] Step 3): Under an ice bath, sodium hydroxide (8.00 g, 0.2 mol) was added in batches to a reaction bottle containing 80% hydrazine hydrate (37.50 g, 0.60 mol) and 100 mL of methanol. After the addition was completed, stirring was continued for 10 minutes, (cyclopentylazanediyl)bis(ethane-2,1-diyl) dimethanesulfonate (32.94 g, 0.10 mol) was dissolved in 50 ml of methanol, the temperature was kept below 20°C, and the mixture was added dropwise to the reaction bottle. The mixture was stirred at room temperature for 3 h, and most of the solvent was evaporated. The oil was added with saturated brine 50 mL, and extracted three times with methyl tert-butyl ether (30 mL). The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a yellow oil. After methyl tert-butyl ether was evaporated, the oil was purified by vacuum distillation to obtain a light yellow oil. After cooling, the light yellow crystals (compound 3) 15.64 g were obtained, with a yield of 92.4%. MS (ESI + )m / z 170.19[M+H]; 1 H NMR (CDCl3) δ2.91 (t, J = 5.0 Hz, 2H), 2.66 (s, 1H), 2.47 (t, J = 8.2 Hz, 3H), 1.90–1.81 (m, 2H), 1.68 (d, J = 7.7 Hz, 2H), 1.55 (dt, J = 8.2, 4.0 Hz, 2H), 1.39 (dd, J = 9.9, 6.1 Hz, 2H); the purity was 99.2% as measured by gas chromatography. The CPNP test result was not detected (less than 0.1 ppm).

[0074]

[0075] Example 2

[0076] The reaction solvent in step 1) was changed, and the other conditions were the same as those in Example 1. The effect of the reaction solvent on the yield of 2,2'-(cyclopentylimino)diethanol (Compound 1) was investigated. The results are shown in Table 1.

[0077] Table 1 Effect of reaction solvent on the yield of compound 1

[0078] Reaction solvent Yield (%) Methanol 97.2％ Anhydrous ethanol 98.1％ Isopropyl alcohol 96.5％ Tert-Butanol 97.8％

[0079] As can be seen from Table 1, when the reaction solvent is methanol, anhydrous ethanol, isopropanol, and tert-butanol, there is no significant difference in the yield of the prepared compound 1. Relatively speaking, the yield of anhydrous ethanol is better, and anhydrous ethanol is easier to remove during the reduced pressure concentration process, so anhydrous ethanol is preferably selected as the reaction solvent.

[0080] Example 3

[0081] The molar ratio of diethanolamine to cyclopentanone in step 1) was changed, and the other conditions were the same as those in Example 1. The effect of the molar ratio of diethanolamine to cyclopentanone on the yield of 2,2'-(cyclopentylimino)diethanol (Compound 1) was investigated. The results are shown in Table 2.

[0082] Table 2 Effect of the molar ratio of diethanolamine to cyclopentanone on the yield of compound 1

[0083] Molar Ratio Yield (%) 1：0.5 48.5％ 1：1.0 80.5％ 1：1.2 98.1％ 1：1.5 98.1％ 1：2.0 98.2％ 1：2.5 98.1％

[0084] As shown in Table 2, when the molar ratio of diethanolamine to cyclopentanone is 1:(0.5-2.5), the yield of compound 1 is above 45%, when the molar ratio of the two is 1:(1.0-2.5), the yield of compound 1 is above 80%, when the molar ratio of the two is 1:(1.2-2.5), the yield of compound 1 is above 98%, and when the molar ratio of diethanolamine to cyclopentanone is 1:1.2, the increase in the amount of cyclopentanone significantly reduces the growth rate of the reaction yield. At this time, the raw materials used are increased, and the yield does not change significantly. Considering the comprehensive reaction cost and product yield, the molar ratio of diethanolamine to cyclopentanone is selected to be 1:(1.2-2.5).

[0085] Example 4

[0086] The type of reducing agent in step 1) was changed, and other conditions were the same as in Example 1, to investigate the effect of different reducing agents on the yield of 2,2'-(cyclopentylimino)diethanol (Compound 1). The results are shown in Table 3.

[0087] Table 3 Effect of different reducing agents on the yield of compound 1

[0088] Reducing reagent Yield (%) Sodium borohydride 71.2％ Sodium triacetoxyborohydride 98.1％ Sodium cyanoborohydride 98.0％

[0089] As shown in Table 3, the yields of compound 1 prepared by different reducing agents are different. Among them, the yield of compound 1 prepared by sodium borohydride as a reducing agent is much lower than that of compound 1 prepared by triacetoxy and sodium cyanoborohydride, and is not suitable for a one-pot method because sodium borohydride has a strong reducing property, resulting in the reduction of cyclopentanone in the reactant; the yields of compound 1 prepared by sodium triacetoxyborohydride and sodium cyanoborohydride are not much different, and sodium triacetoxyborohydride has mild reaction conditions, good catalytic reduction performance, and is easy to separate and purify. The catalyst itself and the by-products are non-toxic and do not pollute the environment; therefore, sodium triacetoxyborohydride is finally selected as the best reducing agent.

[0090] Example 5

[0091] The reaction solvent in step 2) was changed, and other conditions were the same as in Example 1. The effect of the reaction solvent on the yield of (cyclopentylazanediyl)bis(ethane-2,1-diyl) dimethanesulfonate (Compound 2) was investigated. The results are shown in Table 4.

[0092] Table 4 Effect of reaction solvent on the yield of compound 2

[0093] Reaction solvent Yield (%) Methanol 96.8％ Anhydrous ethanol 97.0％ Dichloromethane 97.5％ Chloroform 97.5％ Tetrahydrofuran 97.4％

[0094] The results show that: as shown in Table 4, when the reaction solvent is methanol, anhydrous ethanol, dichloromethane, chloroform, tetrahydrofuran, the yield of compound 2 has no obvious change. Considering the safety issue, dichloromethane is selected as the solvent.

[0095] Example 6

[0096] The base used in step 2) was changed, and the other conditions were the same as in Example 1, and the effects of different bases on the yield of (cyclopentylazanediyl)bis(ethane-2,1-diyl)dimesylate (Compound 2) were investigated. The results are shown in Table 5.

[0097] Table 5 Effect of different bases on the yield of compound 2

[0098] The base used Yield (%) Triethylamine 97.5％ Pyridine 97.5％ Sodium hydroxide 97.3％ Potassium hydroxide 97.3％ Trimethylamine 96.8％

[0099] As shown in Table 5, various bases have no significant effect on the yield of compound 2. Pyridine and triethylamine are used as bases, and the yield is relatively high. However, considering that the use of pyridine has certain safety hazards, considering the safety of process synthesis and environmental protection, triethylamine is finally selected as the base.

[0100] Example 7

[0101] The molar ratio of 2,2'-(cyclopentylimino)diethanol to methanesulfonyl chloride in step 2) was changed, and other conditions were the same as in Example 1. The effect of the molar ratio of 2,2'-(cyclopentylimino)diethanol to methanesulfonyl chloride on the yield of (cyclopentylazanediyl)bis(ethane-2,1-diyl) dimethanesulfonate (Compound 2) was investigated. The results are shown in Table 6.

[0102] Table 6 Effect of the molar ratio of 2,2'-(cyclopentylimino)diethanol to methanesulfonyl chloride on the yield of compound 2

[0103] Molar Ratio Yield (%) 1：2.0 97.5％ 1：2.5 97.6％ 1：3.0 97.1％ 1：3.5 97.1％ 1：4.0 97.3％ 1：4.5 97.1％ 1：5.0 97.0％

[0104] As shown in Table 6, when the molar ratio of 2,2'-(cyclopentylimino)diethanol to methanesulfonyl chloride is between 1:1-10, especially between 1:2-5, the yield of compound 2 does not change significantly, that is, the molar ratio of the two has no significant effect on the yield of compound 2. Considering the comprehensive reaction cost and product yield, the molar ratio of 2,2'-(cyclopentylimino)diethanol to sulfonyl chloride is finally selected to be 1:2-2.5.

[0105] Example 8

[0106] The reaction solvent in step 3) was changed, and other conditions were the same as in Example 1. The effect of the reaction solvent on the yield and purity of compound 3 was investigated. The results are shown in Table 7.

[0107] Table 7 Effect of reaction solvent on yield and purity of compound 3

[0108]

[0109]

[0110] As shown in Table 7, there is no significant difference in the yield and purity of compound 3 prepared by different reaction solvents, and the content of CPNP in the prepared product is zero. When methanol or ether is used as the reaction solvent, the yield of compound 3 can reach more than 90%, and the purity can reach more than 99%. Taking all factors into consideration, methanol is preferably the reaction solvent.

[0111] Example 9

[0112] The molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl)dimesylate to hydrazine hydrate in step 3) was changed; other conditions were the same as in Example 1, and the effect of the molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl)dimesylate to hydrazine hydrate on the yield and purity of compound 3 was investigated. The results are shown in Table 8.

[0113] Table 8 Effect of the molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl) dimethanesulfonate to hydrazine hydrate on the yield and purity of compound 3

[0114] Molar Ratio Yield (%) purity(%) CPNP(%) 1：2 61.2％ 94.5％ 0 1：4 78.7％ 95.7％ 0 1：6 92.4％ 99.2％ 0 1：8 91.5％ 99.1％ 0 1：10 91.2％ 99.1％ 0

[0115] It can be seen from Table 8 that when the molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl)dimesylate to hydrazine hydrate is 1:2-10, compound 3 with different yields and purities is obtained. When the molar ratio of the two is 1:6-1:10, the yield of compound 3 is more than 90%, and the purity is more than 99%. Comprehensively considering, the molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl)dimesylate to hydrazine hydrate is 1:6 as the best molar ratio.

[0116] Example 10

[0117] The effect of changing different bases in step 3) on the yield and purity of compound 3; other conditions are the same as in Example 1, and the effect of different bases on the yield and purity of compound 3 is investigated. The results are shown in Table 9.

[0118] Table 9 Effect of different bases on the yield and purity of compound 3

[0119] The base used Yield (%) purity(%) CPNP(%) Triethylamine 89.5％ 97.8％ 0 Pyridine 90.1％ 98.0％ 0 Trimethylamine 90.5％ 97.9％ 0 Sodium hydroxide 92.4％ 99.2％ 0 Potassium hydroxide 92.3％ 99.2％ 0 Sodium carbonate 91.5％ 99.1％ 0

[0120] As shown in Table 9, the purity of compound 3 prepared by different bases is above 95%, the yield is above 85%, and the content of CPNP in the product is zero. When sodium hydroxide, potassium hydroxide or sodium carbonate is used as the base, the yield of compound 3 is above 90% and the purity is above 99%. Considering comprehensively, sodium hydroxide is selected as the base for synthesizing compound 3.

[0121] Embodiment 11

[0122] The molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl)dimesylate to the base in step 3) was changed; other conditions were the same as in Example 1, and the effect of the molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl)dimesylate to the base on the yield and purity of compound 3 was investigated. The results are shown in Table 10.

[0123] Table 10 Effect of the molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl) dimethanesulfonate to base on the yield and purity of compound 3

[0124] Molar Ratio Yield (%) purity(%) CPNP(%) 1：1 81.2％ 97.2％ 0 1：2 92.4％ 99.2％ 0 1：3 92.5％ 99.1％ 0 1：4 91.8％ 99.1％ 0 1：5 89.7％ 99.1％ 0

[0125] As can be seen from Table 10, the molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl)dimesylate to the base has different effects on the yield and purity of compound 3. When the molar ratio of the two is between 1:1-1:10, the yield of compound 3 is above 85% and the purity is above 95%. When the molar ratio of the two is 1:2-1:10, especially 1:2-1:5, the purity of compound 3 is above 99%, and the yield is 90% or above. Taking all factors into consideration, the molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl)dimesylate to the base is finally selected to be 1:2-1:5, preferably 1:2-1:4.

[0126] Example 12

[0127] The reaction time in step 3) was changed; other conditions were the same as in Example 1, and the effect of reaction time on the yield and purity of 1-cyclopentyl-4-aminopiperazine was investigated. The results are shown in Table 11.

[0128] Table 11 Effect of reaction time on yield and purity of compound 3

[0129] Reaction time (h) Yield (%) purity(%) CPNP(%) 2 88.3％ 91.2％ 0 3 92.4％ 99.2％ 0 4 92.4％ 99.2％ 0 5 92.2％ 99.1％ 0

[0130] It can be seen from Table 11 that when the reaction time is 2-10 hours, the purity of compound 3 can reach more than 90%, and the yield can reach more than 85%. When the reaction time is 3-5 hours, the purity of compound 3 can reach more than 99%, and the yield can reach more than 90%. Taking all factors into consideration, the optimal reaction time is 3-5 hours. Considering the industrial production efficiency, the final reaction time is 3h.

Claims

1. A method for preparing a rifapentine side chain, characterized in that: The following steps are involved: Using diethanolamine and cyclopentanone as starting materials, a reductive amination reaction was performed to obtain 1, which was then reacted with methanesulfonyl chloride to obtain (cyclopentylazanediyl)bis(ethane-2,1-diyl) dimethanesulfonate 2, and finally a cyclization reaction was performed with 80% hydrazine hydrate in the presence of a base to obtain rifapentine side chain 1-amino-4-cyclopentylpiperazine 3; 2. The preparation method according to claim 1, characterized in that: The steps include: Step 1) diethanolamine and cyclopentanone are reacted in a solvent under acidic conditions and with the help of a reducing agent to generate 2,2'-(cyclopentylimino)diethanol; Step 2) esterification reaction of 2,2'-(cyclopentylimino)diethanol with methanesulfonyl chloride in a solvent in the presence of a base to generate (cyclopentylazanediyl)bis(ethane-2,1-diyl) dimethanesulfonate; Step 3: (Cyclopentylazanediyl)bis(ethane-2,1-diyl) dimethanesulfonate is reacted with 80% hydrazine hydrate in a solvent in the presence of a base to cyclize to form the rifapentine side chain.

3. The preparation method according to claim 2, characterized in that: In the step 1), the molar ratio of diethanolamine to cyclopentanone is 1:0.5-10, preferably 1:0.5-5, and more preferably 1:1.2-2.

5.

4. The preparation method according to claim 2, characterized in that: In the step 1), the reducing agent is one or a combination of sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like; preferably sodium triacetoxyborohydride.

5. The preparation method according to claim 2, characterized in that: In the step 1), the pH value of the acidic condition is 5.5-6.

0.

6. The preparation method according to claim 2, characterized in that: In the step 2), the molar ratio of 2,2'-(cyclopentylimino)diethanol to methanesulfonyl chloride is 1:1-10, preferably 1:2-5.

7. The preparation method according to claim 2, characterized in that: In the step 2), the base is one or more of triethylamine, pyridine, trimethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably triethylamine; In the step 3), the base is one or more of triethylamine, pyridine, trimethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide; The molar ratio of (cyclopentylazanediyl)bis(ethane-2,1-diyl) dimethanesulfonate to the base is 1:(1 to 10), preferably 1:(1 to 5), and more preferably 1:(2 to 5).

8. The preparation method according to claim 2, characterized in that: In the step 1), the solvent is one or more of acetic acid, water, methanol, anhydrous ethanol, isopropanol, butanol, and tert-butanol, preferably anhydrous ethanol; In the step 2), the solvent is one or more of water, methanol, anhydrous ethanol, dichloromethane, chloroform, tetrahydrofuran, ether, methyl tert-butyl ether, isopropyl ether, and dioxane, preferably dichloromethane; In the step 3), the solvent is one or more of water, methanol, anhydrous ethanol, dichloromethane, chloroform, tetrahydrofuran, ether, methyl tert-butyl ether, isopropyl ether, and dioxane, preferably methanol.

9. The preparation method according to claim 1, characterized in that: In the steps 1), 2) or 3), the reaction temperature is 0 to 90° C., preferably 10 to 40° C.; the reaction time is 0.5 to 10 hours, preferably 2 to 8 hours.

10. Use of the preparation method according to any one of claims 1 to 9 in the preparation of 1-amino-4-cyclopentylpiperazine as a side chain of rifapentine.

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