Preparation method of dehydronandrolone acetate

Abstract

The invention provides a preparation method of dehydronandrolone acetate, and relates to the technical field of medicine synthesis. The dehydronandrolone acetate is prepared by carrying out oxidation reaction on etherates; wherein the preparation of the etherate comprises the following steps: step 1, carrying out esterification reaction on nandrolone to obtain an ester; and 2, carrying out an etherification reaction on the esterified product obtained in the step 1 to obtain an etherified product. According to the method for preparing the dehydronandrolone acetate, the dehydrogenation reaction can be completed at normal temperature, and compared with the prior art, the energy consumption and the operation complexity are remarkably reduced. The method disclosed by the invention is safe and environment-friendly, is convenient for recycling, reduces the recycling cost, avoids the problem of generating high-risk nitrosamine genotoxic impurities, and meanwhile, the chloranil is used as the dehydrogenating agent, and the reduction product is easy to recycle and reuse, so that the production cost is further reduced, and the generation of wastes is reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing dehydronandrolone acetate. Background Art

[0002] Dehydronandrolone acetate is primarily used in the synthesis of two steroidal drugs, fulvestrant and tibolone. Dehydronandrolone acetate is a key intermediate in the synthesis of fulvestrant, used to treat breast cancer, and tibolone, used to treat menopause and postmenopausal syndrome.

[0003] Jie Tang et al. reported a method for synthesizing dehydronandrolone acetate in Steroids 75 (2010) 859–869. Dehydronandrolone acetate was prepared from nandrolone via a double esterification reaction followed by a debromination reaction.

[0004]

[0005] Patent CN118290508 discloses a process for preparing dehydronandrolone acetate using estradiol-4-ene-3,17-dione as a raw material via two routes. Route 1: Dehydronandrolone acetate is prepared via reduction, double esterification, and upper debromination. Route 2: Dehydronandrolone acetate is prepared via 3-position esterification, upper debromination, enzymatic transreduction, and esterification.

[0006]

[0007] Patent CN113045616 discloses that dehydronandrolone acetate is prepared from estradiol-4-ene-3,17-dione as a raw material through 3-position esterification reaction, reduction reaction, bromination / debromination reaction and esterification reaction.

[0008]

[0009] In the above-disclosed synthetic route, the 3-keto-4,6-diene structure in the molecular structure of dehydronandrolone acetate is formed by esterification of the 3-keto-4-ene structure, followed by bromination and debromination with NBS.

[0010]

[0011] In the bromination and debromination steps, DMF is usually used as the reaction solvent. The debromination reaction temperature is generally above 100°C, and the production energy consumption is high. Moreover, due to the high reaction temperature, there is also the risk of increased production of other by-products. In addition, DMF has a high boiling point (153°C), which makes it difficult to recycle. Moreover, during the recycling process, care must be taken to avoid explosions caused by the decomposition of DMF. Furthermore, due to the use of DMF, nitrosamine impurities (nitrosodimethylamine NDMA, nitrosodiethylamine NDEA) may be produced during the process. Nitrosamine impurities are genotoxic impurities, which will increase the content of drug quality research and also increase drug safety risks.

[0012] Therefore, there is an urgent need to develop a new method for preparing dehydronandrolone acetate to simplify the synthesis process, reduce production costs and improve product quality. Summary of the Invention

[0013] In view of this, the present invention provides a method for preparing dehydronandrolone acetate with mild reaction conditions, low production cost, environmentally friendly process and excellent quality. The technical solution of the present invention is achieved as follows:

[0014] The present invention provides a method for preparing dehydronandrolone acetate, wherein the dehydronandrolone acetate has a structure as shown in formula (I):

[0015]

[0016] The dehydronandrolone acetate is prepared by oxidation reaction of an etherified product;

[0017] The preparation of the etherified product comprises the following steps:

[0018] Step 1, nandrolone is subjected to an esterification reaction to obtain an esterified product;

[0019] Step 2: The esterified product of step 1 is subjected to etherification reaction to obtain an etherified product.

[0020] In one or some possible embodiments, the etherified product is oxidized with acetone and water as solvents under the action of chloranil to obtain dehydronandrolone acetate.

[0021] In one or some possible embodiments, the mass ratio of the etherified compound to the chloranil is 1:(0.85-1.35).

[0022] In one or some possible embodiments, in step 1, the nandrolone is subjected to an esterification reaction with acetic anhydride using pyridine as a solvent to obtain an esterified product.

[0023] In one or some possible embodiments, in step 1, the molar ratio of the nandrolone to the acetic anhydride is 1:(1.15-1.75).

[0024] In one or some possible embodiments, in step 1, the nandrolone is subjected to an esterification reaction with acetyl chloride using pyridine as a solvent to obtain an esterified product.

[0025] In one or some possible embodiments, in step 1, the molar ratio of the nandrolone to the acetyl chloride is 1:(1.52-2.30).

[0026] In one or some possible embodiments, in step 2, the esterified product undergoes an etherification reaction with an alcohol compound using p-toluenesulfonic acid as a catalyst and triethyl orthoformate as a water scavenger, and is neutralized with triethylamine to obtain an etherified product.

[0027] In one or some possible embodiments, the alcohol compound is selected from C1 to C3 alcohol compounds.

[0028] Furthermore, in the structural formula of the etherified compound, R is selected from one of -CH2CH3, -CH(CH3)2 or -CH3.

[0029] In one or some possible embodiments, the mass volume ratio of the esterified product to the triethyl orthoformate and the alcohol compound is 1 g: (0.8-1.2) mL: (6.4-9.6) mL.

[0030] The preparation method of dehydronandrolone acetate of the present invention has the following beneficial effects compared with the prior art:

[0031] The present method for preparing dehydrogenandrolone acetate utilizes milder dehydrogenation reaction conditions and can be completed at room temperature. Compared to the prior art debromination reaction, which requires high temperatures exceeding 100°C, this method significantly reduces energy consumption and operational complexity. Furthermore, the present invention utilizes acetone / water as the dehydrogenation solvent, which is not only safe and environmentally friendly but also easily recyclable and reusable, avoiding the high recovery costs and high-risk nitrosamine-like genotoxic impurities associated with the use of solvents such as DMF. Furthermore, by using chloroquine as the dehydrogenation agent, the reduced product, chlorohydroquine, is easily recovered and can be reused through reprocessing, further reducing production costs and waste generation, resulting in significant economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0033] Figure 1A reaction flow chart for preparing dehydronandrolone acetate provided by the present invention;

[0034] Figure 2 This is a liquid chromatogram of the esterified product prepared in Example 1 of the present invention;

[0035] Figure 3 This is the hydrogen spectrum of the ester prepared in Example 1 of the present invention;

[0036] Figure 4 This is a liquid chromatogram of the etherified product prepared in Example 1 of the present invention;

[0037] Figure 5 This is the hydrogen spectrum of the etherate prepared in Example 1 of the present invention;

[0038] Figure 6 This is a liquid chromatogram of dehydronandrolone acetate prepared in Example 1 of the present invention;

[0039] Figure 7 This is the hydrogen spectrum of dehydronandrolone acetate prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0040] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0041] The present invention will be further described below with reference to specific examples, but the scope of protection of the present invention is not limited by the following examples. The sources of materials mainly involved in the examples are all conventional commercial products.

[0042] The relevant tests of the following embodiments all refer to the following methods:

[0043] HPLC Method 1:

[0044] Chromatographic column: InfinityLab Poroshell 120EC-C18 (4.6×150 mm, 4-Micron), Agilent.

[0045] Mobile phase: water and acetonitrile gradient

[0046]

[0047]

[0048] Flow rate: 1 mL / min;

[0049] Detector: UV detector (VWD); wavelength: 254 nm; column oven temperature: 35.0°C; injection volume: 10 μL; acquisition time: 30 min, post-run 5 min.

[0050] HPLC Method 2:

[0051] Chromatographic column: LaChrom C18 (5 μm, 250 × 4.6 mm), Hitachi

[0052] Mobile phase: water and acetonitrile gradient

[0053]

[0054] Flow rate: 1 mL / min

[0055] Detector: UV detector (VWD); wavelength: 254 nm; column oven temperature: 40°C; injection volume: 10 μL; acquisition time: 90 min, post-run 5 min.

[0056] In the present invention, the preparation of dehydronandrolone acetate is as follows Figure 1 The reaction scheme shown is implemented.

[0057] Example 1

[0058] This embodiment provides a method for preparing dehydronandrolone acetate, comprising the following steps:

[0059] Step 1, esterification reaction to prepare an esterified product as shown in formula (III);

[0060] Under nitrogen, add 300 mL of pyridine, 100 g of nandrolone, and 50 mL of acetic anhydride to a 3 L reaction flask and stir to dissolve. Incubate the reaction at 60°C for 5 h until complete conversion of the starting material is achieved, as monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 3 / 1, v / v).

[0061] After the reaction was completed, the reaction solution was cooled to room temperature, slowly poured into 2L of water, stirred for 2h, filtered, and dried with air at 50°C to obtain 113g of off-white ester with a molar yield of 98.3% and a purity of 98.63% (HPLC method 1, as Figure 2 、 3 shown).

[0062] 1H NMR(600MHz, CDCl3)δ5.82(d,J=2.1Hz,1H),4.61(dd,J=9.2,7.9Hz,1H),2.52–2.35(m,2H),2.30–2.20(m,3H),2. 19–2.05(m,2H),2.04(s,3H),1.86–1.74(m,3H),1.66(dddd,J=12.6,9.9,7.1,3.2Hz,1H),1.59–1.47(m,2H),1.41

[0063] –1.30(m,2H),1.29–1.16(m,2H),1.14–1.02(m,2H),0.87(dd,J=10.8,4.0Hz,1H),0.84(s,3H).

[0064] Step 2: etherification reaction to prepare the etherified product shown in formula (IV)

[0065] Under nitrogen protection, 100 g of esterified product, 0.5 g of p-toluenesulfonic acid, 100 mL of triethyl orthoformate and 800 mL of anhydrous ethanol were added to a 3 L reaction flask, and the mixture was stirred at 25 ° C for 4 h until TLC (developing solvent: petroleum ether / ethyl acetate = 2 / 1) showed complete conversion of the raw materials.

[0066] After the reaction was complete, 100 mL of triethylamine was added and stirred for 20 min to quench. After quenching, the reaction solution was slowly poured into 950 mL of ice water, stirred for 1.5 h, and filtered. The mixture was dried with air at 45 ° C to obtain 102 g of off-white etherified product with a molar yield of 93.6% and a purity of 97.18% (HPLC method 1, as shown in FIG. Figure 4 、 5 shown).

[0067] 1 H NMR(600MHz, CDCl3)δ5.28(dt,J=5.2,2.4Hz,1H),5.21–5.17(m,1H),4.62(dd ,J=9.2,7.8Hz,1H),3.84–3.68(m,2H),2.32–2.05(m,6H),2.04(s,3H),1.94– 1.88(m,1H),1.78–1.73(m,1H),1.71–1.60(m,2H),1.54–1.39(m,2H),1.33(d d,J=12.3,5.9Hz,1H),1.29(t,J=7.0Hz,3H),1.25–1.08(m,5H),0.82(s,3H).

[0068] Step 3: Oxidation reaction to prepare dehydronandrolone acetate as shown in formula (V)

[0069] Under nitrogen protection, in a 3 L reaction flask, 100 g of etherified product, 600 mL of acetone and 100 mL of water were added, and 112 g of chloranil was added. The reaction was kept at 30 ° C for 1 h until the raw material conversion was complete as monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 2 / 1).

[0070] After the reaction was completed, 300 mL of water was added to the reaction solution and stirred, and the mixture was filtered. The filter cake was dissolved by stirring with ethyl acetate, and tetrachlorohydroquinone was recovered by filtration. The filtrate was washed twice with a saturated aqueous sodium carbonate solution, and then concentrated under reduced pressure to near dryness. 400 mL of isopropyl ether was added and beaten for 2 h, filtered, and dried with air at 45 ° C to obtain 85 g of off-white dehydronandrolone acetate with a molar yield of 93.4% and a purity of 96.46% (HPLC method 2, as Figure 6 、 7 shown).

[0071] 1 H NMR (600MHz, CDCl3) δ6.18(qd,J=9.6,2.1Hz,2H),5.77(d,J=2.3Hz,1H),4.64(t,J=8.5Hz,1H),2.53(dt,J=16.2,3.2Hz,1H),2.38–2.19(m,4 H),2.19–2.11(m,1H),2.05(s,3H),1.88–1.77(m,3H),1.61–1.42(m,3 H),1.36–1.20(m,3H),1.13(tdd,J=11.9,9.3,3.6Hz,1H),0.87(s,3H).

[0072] Example 2

[0073] This embodiment provides a method for preparing dehydronandrolone acetate, comprising the following steps:

[0074] Step 1, esterification reaction to prepare an esterified product as shown in formula (III);

[0075] Under nitrogen, add 300 mL of pyridine, 100 g of nandrolone, and 40 mL of acetic anhydride to a 3 L reaction flask and stir to dissolve. Incubate the reaction at 65°C for 5.5 h until complete conversion of the starting material is achieved as monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 3 / 1).

[0076] After the reaction was complete, the reaction solution was cooled to room temperature, slowly poured into 2 L of water, stirred for 1 h, filtered, and dried under air at 40°C to obtain 109.6 g of an off-white ester with a molar yield of 95.4% and a purity of 98.54%. (HPLC method 1).

[0077] Step 2: etherification reaction to prepare the etherified product shown in formula (IV)

[0078] Under nitrogen protection, 100 g of esterified product, 0.5 g of p-toluenesulfonic acid, 80 mL of triethyl orthoformate and 640 mL of anhydrous ethanol were added to a 3 L reaction flask, and the mixture was stirred at 20 ° C for 5 h until TLC (developing solvent: petroleum ether / ethyl acetate = 2 / 1) showed complete conversion of the raw materials.

[0079] After the reaction was complete, 100 mL of triethylamine was added and the mixture was stirred for 20 minutes to quench the reaction. After quenching, the reaction solution was slowly poured into 950 mL of ice water, stirred for 1 hour, and filtered. Air drying at 40°C afforded 102.3 g of an off-white etherified product with a molar yield of 93.8% and a purity of 97.23% (HPLC method 1).

[0080] Step 3: Oxidation reaction to prepare dehydronandrolone acetate as shown in formula (V)

[0081] Under nitrogen protection, in a 3 L reaction flask, 100 g of etherified product, 600 mL of acetone and 100 mL of water were added, and 85 g of chloranil was added. The reaction was kept at 30° C. for 1.5 h until the conversion of the raw material was complete as monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 2 / 1).

[0082] After the reaction was completed, 300 mL of water was added to the reaction solution and stirred, and the mixture was filtered. The filter cake was dissolved by stirring with ethyl acetate and tetrachlorohydroquinone was recovered by filtration. The filtrate was washed twice with a saturated aqueous sodium carbonate solution and concentrated under reduced pressure to near dryness. 400 mL of isopropyl ether was added and the mixture was beaten for 2 h, filtered, and dried with air at 45 ° C to obtain 82.3 g of off-white dehydronandrolone acetate with a molar yield of 90.2% and a purity of 95.14% (HPLC method 2).

[0083] Example 3

[0084] This embodiment provides a method for preparing dehydronandrolone acetate, comprising the following steps:

[0085] Step 1, esterification reaction to prepare an esterified product as shown in formula (III);

[0086] Under nitrogen, add 300 mL of pyridine, 100 g of nandrolone, and 60 mL of acetic anhydride to a 3 L reaction flask and stir to dissolve. Incubate the reaction at 60°C for 4.5 h until complete conversion of the starting material is achieved as monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 3 / 1).

[0087] After the reaction was completed, the reaction solution was cooled to room temperature, slowly poured into 2 L of water, stirred for 2 h, filtered, and dried under air at 50° C. to obtain 111 g of an off-white ester with a molar yield of 96.2% and a purity of 98.58% (HPLC method 1).

[0088] Step 2: etherification reaction to prepare the etherified product shown in formula (IV)

[0089] Under nitrogen protection, 100 g of esterified product, 0.5 g of p-toluenesulfonic acid, 120 mL of triethyl orthoformate and 960 mL of anhydrous ethanol were added to a 3 L reaction flask, and the mixture was stirred at 25 ° C for 4 h until TLC (developing solvent: petroleum ether / ethyl acetate = 2 / 1) showed complete conversion of the raw materials.

[0090] After the reaction was complete, 100 mL of triethylamine was added and the mixture was stirred for 20 minutes to quench the reaction. After quenching, the reaction solution was slowly poured into 950 mL of ice water, stirred for 2 hours, and filtered. Air-dried at 40°C yielded 100.5 g of an off-white etherified product with a molar yield of 92.3% and a purity of 97.52% (HPLC method 1).

[0091] Step 3: Oxidation reaction to prepare dehydronandrolone acetate as shown in formula (V)

[0092] Under nitrogen protection, in a 3 L reaction flask, 100 g of etherified product, 600 mL of acetone and 100 mL of water were added, and 135 g of chloranil was added. The reaction was kept at 30 ° C for 1 h until the raw material conversion was complete as monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 2 / 1).

[0093] After the reaction was completed, 300 mL of water was added to the reaction solution and stirred, and the mixture was filtered. The filter cake was dissolved by stirring with ethyl acetate, and tetrachlorohydroquinone was recovered by filtration. The filtrate was washed three times with a saturated aqueous sodium carbonate solution, and then concentrated under reduced pressure to near dryness. 400 mL of isopropyl ether was added and beaten for 1 h, filtered, and dried with air at 40 ° C to obtain 84.7 g of off-white dehydronandrolone acetate with a molar yield of 92.8% and a purity of 93.75% (HPLC method 2).

[0094] Example 4

[0095] This embodiment provides a method for preparing dehydronandrolone acetate, comprising the following steps:

[0096] Step 1, esterification reaction to prepare an esterified product as shown in formula (III);

[0097] Under nitrogen, add 300 mL of pyridine, 100 g of nandrolone, and 50 mL of acetyl chloride to a 3 L reaction flask and stir to dissolve. Incubate the reaction at 15°C for 5 h until complete conversion of the starting material is achieved as monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 3 / 1).

[0098] After the reaction was completed, the reaction solution was cooled to room temperature, slowly poured into 2 L of water, stirred for 2 h, filtered, and dried under air at 50° C. to obtain 111.8 g of an off-white ester with a molar yield of 96.9% and a purity of 95.34% (HPLC method 1).

[0099] Step 2: etherification reaction to prepare the etherified product shown in formula (IV)

[0100] Under nitrogen protection, 100 g of esterified product, 0.5 g of p-toluenesulfonic acid, 80 mL of triethyl orthoformate and 640 mL of isopropanol were added to a 3 L reaction flask, and the mixture was stirred at 25 ° C for 4 h until TLC (developing solvent: petroleum ether / ethyl acetate = 2 / 1) showed complete conversion of the raw materials.

[0101] After the reaction was complete, 100 mL of triethylamine was added and the mixture was stirred for 20 minutes to quench the reaction. After quenching, the reaction solution was slowly poured into 950 mL of ice water, stirred for 1 hour, and filtered. Air-dried at 40°C yielded 105.2 g of an off-white etherified product with a molar yield of 92.8% and a purity of 98.04% (HPLC method 1).

[0102] Step 3: Oxidation reaction to prepare dehydronandrolone acetate as shown in formula (V)

[0103] Under nitrogen protection, in a 3 L reaction flask, 100 g of etherified product, 600 mL of acetone and 100 mL of water were added, and 120 g of chloranil was added. The reaction was kept at 35 ° C for 1.5 h until the raw material conversion was complete as monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 2 / 1).

[0104] After the reaction was completed, 300 mL of water was added to the reaction solution and stirred, and the mixture was filtered. The filter cake was dissolved by stirring with ethyl acetate, and tetrachlorohydroquinone was recovered by filtration. The filtrate was washed three times with a saturated aqueous sodium carbonate solution, and then concentrated under reduced pressure to near dryness. 400 mL of isopropyl ether was added and beaten for 2 h, filtered, and dried with air at 45 ° C to obtain 83.5 g of off-white dehydronandrolone acetate with a molar yield of 95.2% and a purity of 96.04% (HPLC method 2).

[0105] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing dehydronandrolone acetate, characterized in that: The structure of the dehydronandrolone acetate is shown in formula (I): The dehydronandrolone acetate is prepared by oxidation reaction of an etherified product; The preparation of the etherified product comprises the following steps: Step 1, nandrolone is subjected to an esterification reaction to obtain an esterified product; Step 2: The esterified product of step 1 is subjected to etherification reaction to obtain an etherified product.

2. The method for preparing dehydronandrolone acetate according to claim 1, wherein The etherified product undergoes an oxidation reaction under the action of chloranil using acetone and water as solvents to obtain dehydronandrolone acetate.

3. The method for preparing dehydronandrolone acetate according to claim 2, wherein The mass ratio of the etherified product to the chloranil is 1:(0.85-1.35).

4. The method for preparing dehydronandrolone acetate according to claim 1, wherein In step 1, the nandrolone is subjected to an esterification reaction with acetic anhydride using pyridine as a solvent to obtain an esterified product; Alternatively, in step 1, the nandrolone undergoes an esterification reaction with acetyl chloride using pyridine as a solvent to obtain an esterified product.

5. The method for preparing dehydronandrolone acetate according to claim 4, wherein In step 1, the molar ratio of the nandrolone to the acetic anhydride is 1:(1.15-1.75).

6. The method for preparing dehydronandrolone acetate according to claim 4, wherein In step 1, the molar ratio of the nandrolone to the acetyl chloride is 1:(1.52-2.30).

7. The method for preparing dehydronandrolone acetate according to claim 1, wherein In step 2, the esterified product undergoes etherification reaction with an alcohol compound using p-toluenesulfonic acid as a catalyst and triethyl orthoformate as a water scavenger, and is neutralized with triethylamine to obtain an etherified product.

8. The method for preparing dehydronandrolone acetate according to claim 7, wherein The alcohol compound is selected from C1 to C3 alcohol compounds.

9. The method for preparing dehydronandrolone acetate according to claim 8, wherein The mass volume ratio of the esterified product to the triethyl orthoformate and the alcohol compound is 1 g: (0.8-1.2) mL: (6.4-9.6) mL.

10. A dehydronandrolone acetate, characterized in that The invention is prepared by the preparation method according to any one of claims 1 to 9.

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