Preparation method of anamorelin key intermediate
The key intermediates of anamorelin are prepared through an asymmetric synthesis strategy, avoiding chiral splitting, and achieving the preparation of anamorelin intermediates with high yield and high purity, solving the problems of complicated operation and low yield in the existing technology, and being suitable for industrial production.
Patent Information
- Application Number
- CN202510298679.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-13
- Publication Date
- 2025-10-10
AI Technical Summary
The existing methods for preparing key intermediates of anamorelin are complicated, have low yields, and are difficult to meet high purity requirements.
An asymmetric synthesis strategy is adopted, wherein the compound of formula I-2 reacts with a Bn-X reagent and is subsequently converted into a compound of formula I-4 in the presence of an acid and a reducing agent, thereby avoiding the chiral resolution step, simplifying the operation and improving the yield.
The preparation of key anamorelin intermediates with high yield and high chiral purity was achieved, the operation process was simplified, and it is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the field of drug synthesis, and in particular relates to a method for preparing a key intermediate of anamorelin. Background Art
[0002] On December 11, 2020, anamorelin received the world's first approval for the treatment of cancer cachexia. An application for manufacturing and marketing authorization for anamorelin was submitted in Japan for the treatment of cancer cachexia in four cancer types: non-small cell lung cancer, pancreatic cancer, and colorectal cancer. Currently, it is the only drug in the world that effectively improves cancer cachexia.
[0003] The compound shown in formula I is a key intermediate in the synthesis of anamorelin.
[0004]
[0005] The synthesis of anamorelin is currently mainly carried out by a splitting method. Patent CN 115960080 utilizes the carboxyl group in the structure and uses R-configured phenylethylamine for splitting. The operation is relatively cumbersome. According to the patented process, three recrystallizations are required after splitting to achieve the required optical purity, and the overall yield is relatively low.
[0006]
[0007] The paper J.Med.Chem.1998,41,2439-2441 and patent CN110402245 are based on the alkalinity of piperidine in the intermediate structure and use chiral acid for separation. However, they also require multiple recrystallization operations and have low overall yields.
[0008]
[0009] Therefore, there is an urgent need in the art to develop a method for preparing a key intermediate of anamorelin with simple operation, mild reaction conditions, high yield and good chiral purity. Summary of the Invention
[0010] The object of the present invention is to provide a novel method for preparing a key intermediate of anamorelin, which adopts an asymmetric synthesis strategy and does not require chiral resolution, and can prepare a chiral compound of formula I in high yield.
[0011] In a first aspect of the present invention, a method for preparing a key intermediate of anamorelin is provided, the method comprising the following steps:
[0012]
[0013] (a) reacting a compound of formula I-2 with a Bn-X reagent in an inert reagent in the presence of a base to prepare a compound of formula I-3;
[0014] (b) preparing a compound of formula I-4 from a compound of formula I-3 in an inert solvent in the presence of an acid and a reducing agent;
[0015] Wherein, X is selected from the following group: Br, Cl, I,
[0016] R3 is C1-6 alkyl.
[0017] In another preferred embodiment, X is Br.
[0018] In another preferred embodiment, the step (b) comprises the following steps:
[0019]
[0020] (b-1) reacting the compound of formula I-3 with a reagent R4-NHNH2 in an inert solvent to prepare a compound of formula C;
[0021] (b-2) preparing a compound of formula D from a compound of formula C in an inert solvent in the presence of an acid and a reducing agent;
[0022] (b-3) hydrolyzing the compound of formula D in an inert solvent to obtain a compound of formula I-4;
[0023] Among them, the structure of R4 is
[0024] R2 is each independently selected from the group consisting of -NO2, C1-C6 alkyl.
[0025] In another preferred embodiment, the method further comprises the following steps before step (a):
[0026]
[0027] (a-1) In an inert solvent, in the presence of a catalyst, the compound of formula I-1 reacts with the compound of formula B to prepare the compound of formula I-2.
[0028] In another preferred embodiment, the inert solvent is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, dichloromethane, dichloroethane, toluene, acetonitrile, alcohol solvents, ether solvents, or combinations thereof.
[0029] In another preferred embodiment, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, or a combination thereof.
[0030] In another preferred embodiment, the ether solvent is selected from the group consisting of diethyl ether, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, or a combination thereof.
[0031] In another preferred embodiment, the base in step (a) is selected from the group consisting of LDA, LiHMDS, NaHMDS, or a combination thereof.
[0032] In another preferred embodiment, the acid is selected from the group consisting of CF3COOH, CH3SO3H, H2SO4, or a combination thereof.
[0033] In another preferred embodiment, the reducing agent is selected from the group consisting of NaBH3CN, NaBH4, NaBH(OAc)3, KBH4, BH3.Me2S, or a combination thereof.
[0034] In another preferred embodiment, the compound of formula B is prepared by the following method:
[0035]
[0036] (aa) preparing a compound of formula B from a compound of formula A in the presence of a base in an inert solvent.
[0037] In another preferred embodiment, the base in step (aa) is selected from the group consisting of triethylamine, diisopropylethylamine, or a combination thereof.
[0038] In another preferred embodiment, the catalyst in step (a-1) is selected from the group consisting of TsOH, TfOH, or a combination thereof.
[0039] In another preferred embodiment, the molar ratio of the Bn-X reagent to the compound of formula I-2 is 1:1 to 1:5; preferably 1:2.
[0040] In another preferred embodiment, the reaction temperature in step (a) is -20 to -80 °C; preferably -40 to -80 °C.
[0041] In another preferred embodiment, the reaction time in step (a) is 2 to 48 hours; preferably 12 to 24 hours.
[0042] In another preferred embodiment, the reaction time in step (a-1) is 2 to 24 hours; preferably 6 to 12 hours.
[0043] In another preferred embodiment, the reaction temperature in step (b-1) is 20 to 80 °C; preferably 40 to 70 °C.
[0044] In another preferred embodiment, the reaction time in step (b-1) is 1 to 12 hours; preferably 2 to 6 hours.
[0045] In another preferred embodiment, the reaction time of step (b-2) is 1 to 12 hours, preferably 2 to 6 hours.
[0046] In another preferred embodiment, the reaction temperature of step (b-3) is 20-80°C; preferably 40-70°C.
[0047] In another preferred embodiment, the reaction time of step (b-3) is 1 to 12 hours, preferably 1 to 4 hours.
[0048] In another preferred embodiment, the method is used to prepare an important intermediate of anamorelin, the structure of which is shown in the compound of formula I:
[0049]
[0050] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS
[0051] Figure 1 Proton spectrum data of the compound of formula I-2 is shown.
[0052] Figure 2 Proton spectrum data of the compound of formula I-3 is shown.
[0053] Figure 3 Proton spectrum data for the compound of formula I-4 is shown.
[0054] Figure 4 Proton spectrum data for the compound of formula I is shown. DETAILED DESCRIPTION
[0055] After extensive and in-depth research, the inventors unexpectedly discovered that using a compound of Formula I-2 modified with a chiral auxiliary as a starting material, the compound of Formula I-3 can be directly prepared in high yield to obtain a compound of Formula I with high chiral purity. This method is simple to operate, has high yields, and good chiral purity, and is amenable to industrial production. Based on this, the inventors completed the present invention.
[0056] the term
[0057] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
[0058] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."
[0059] As used herein, the terms "the method of the present invention" and "the preparation method of the present invention" are used interchangeably to refer to the method described in the first aspect of the present invention.
[0060] The "inert solvent" described in the present invention refers to a solvent that does not react with the compounds in the reaction system.
[0061] As used herein, "Toluene" refers to toluene, which has the structure
[0062] As used herein, "TsOH" refers to p-toluenesulfonic acid, which has the structure
[0063] As used herein, "LDA" refers to lithium diisopropylamide, which has the structure
[0064] As used herein, "HMPT" refers to hexamethylphosphoric triamide, which has the structure
[0065] As used herein, "Bn-" refers to a benzyl group, the structure of which is
[0066] Refers to the position where a group is attached to other parts of the structure.
[0067] Preparation method of key intermediate of anamorelin
[0068] Typically, the preparation method of the compound of formula I of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
[0069] The present invention provides a method for preparing a key intermediate of anamorelin, comprising the following steps:
[0070]
[0071] (a) reacting a compound of formula I-2 with a Bn-X reagent in an inert reagent in the presence of a base to prepare a compound of formula I-3;
[0072] (b) preparing a compound of formula I-4 from a compound of formula I-3 in an inert solvent in the presence of an acid and a reducing agent;
[0073] Preferably, X is Br;
[0074] Preferably, the inert solvent is selected from the group consisting of dichloromethane, toluene, methanol, ethanol, tetrahydrofuran, or a combination thereof.
[0075] In some embodiments, in another preferred embodiment, the step (b) comprises the following steps:
[0076]
[0077] (b-1) reacting the compound of formula I-3 with a reagent R4-NHNH2 in an inert solvent to prepare a compound of formula C;
[0078] (b-2) preparing a compound of formula D from a compound of formula C in an inert solvent in the presence of an acid and a reducing agent;
[0079] (b-3) hydrolyzing the compound of formula D in an inert solvent to obtain a compound of formula I-4;
[0080] wherein R4 is as defined above.
[0081] In some embodiments, the method further comprises the following steps before step (a):
[0082]
[0083] (a-1) In an inert solvent, in the presence of a catalyst, the compound of formula I-1 reacts with the compound of formula B to prepare the compound of formula I-2.
[0084] In some embodiments, the method is used to prepare an important intermediate of anamorelin (compound of formula I), and the specific steps are as follows:
[0085]
[0086] (c) In an inert solvent, in the presence of a base, the compound of formula I-4 undergoes a hydrolysis reaction to prepare a compound of formula I.
[0087] In some embodiments, the reaction time of step (c) is 1 to 12 hours, preferably 2 to 6 hours.
[0088] In some embodiments, the reaction temperature of step (c) is 20-80°C; preferably 40-70°C.
[0089] Specifically, the method comprises the following steps:
[0090]
[0091] The compound of formula B can be purchased through commercial channels or prepared by the method shown in step aa above.
[0092] The step a-1, step a, step b-1, step b-2, step b-3 and step c are as defined above.
[0093] In some embodiments, the yield of step a is 80-90%; preferably 85-90%.
[0094] Preferably, the yield of step b is 99.0-99.9%.
[0095] Preferably, the yield of step c is 90-95%.
[0096] In some embodiments, the ee value of step c is 99.0-99.9%; preferably 99.5-99.9%.
[0097] Compared with the prior art, the main advantages of the present application are:
[0098] 1. The method of the present application adopts an asymmetric synthesis strategy, and a chiral compound of formula I with high chiral purity can be obtained without chiral resolution.
[0099] 2. The method is simple to operate, and harsh reaction conditions (such as strong acid) are not required, and the reaction conditions are relatively mild.
[0100] 3. The preparation method of the present application has the characteristics of novel route, high yield and good purity, and is easy to industrialize.
[0101] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples without specific conditions are generally carried out under conventional conditions or under the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts.
[0102] Unless otherwise specified, the following examples are carried out under normal pressure, and room temperature refers to 20-30℃.
[0103] Example 1 Preparation of compound of formula B
[0104]
[0105] In a 100ml flask, A (6.3g, mmol) and 20ml dichloromethane were added, stirred for 20min under ice bath condition, then triethylamine (3.87g, 30mmol) was added and stirred for 10min until the solid disappeared and the solution became turbid. Saturated brine was added for liquid-liquid separation, and concentrated to obtain 5.03g of colorless liquid with a yield of 96%.
[0106] Example 2 Preparation of compound of formula I-2
[0107]
[0108] B (2.57 g, 10 mmol), I-1 (1.73 g, 10 mmol), TsOH (100 mg), and Toluene (50 ml) were added to a 250 ml flask and stirred under reflux for 6 h. The reaction solution was concentrated and purified by column chromatography to obtain compound I-2 in a yield of 92%. 1 H NMR (400MHz, CDCl3) δ9.22–9.02(m,1H),4.07(s,2H),3.86–3.73(m,1H),3.69(s,3H),3.55–3.42 (m,2H),2.28(q,J=5.6Hz,2H),2.21–2.08(m,1H),1.46(d,J=4.3Hz,18H),1.00(d,J=6.8Hz,6H).
[0109] Example 3 Preparation of the compound of formula I-3
[0110]
[0111] I-2 (412 mg, 1 mmol) and Toluene (8 ml, dried over anhydrous magnesium sulfate) were added to a 50 ml three-necked flask, the atmosphere was replaced with nitrogen, and the mixture was stirred at -78 ° C for 30 min. LDA (1.2 mmol, 0.6 ml / 2N solution) was added and the stirring was continued for 1 h. HMPT (179 mg, 1 mmol) was added and the stirring was continued for 1 h. After adding Bn-Br (342 mg, 2 mmol), the mixture was stirred at -78 ° C for 12 h. A small amount of product was generated. The mixture was subsequently transferred to -40 ° C and stirred for 24 h. The reaction was monitored and the product increased significantly. Methanol and brine were added to quench the mixture. The mixture was extracted with EA, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 323 mg of compound I-3 with a yield of 85% and an ee value of 99.2%. 1H NMR (400MHz, CDCl3) δ7.30–7.10(m,5H),4.58(d,J=13.6Hz,1H),4.11(q,J=7.2Hz,1H),3.61(s,3H),3.25(d,J=13.9Hz ,1H),3.21–3.10(m,1H),3.04(d,J=13.6Hz,2H),2.68(ddd,J=14.6,10.5,6.6Hz,1H),2.49–2.32(m,1H),1.45(s,9H).
[0112] Example 4 Preparation of Compound of Formula C
[0113]
[0114] I-3 (3 mmol, 1041 mg), TsNHNH2 (3 mmol, 558 mg), and MeOH (15 ml) were added to a 100 ml flask and stirred at 70°C for 4 h. The reaction was complete with complete conversion of the starting materials. The mixture was concentrated to afford a white foamy solid in 100% yield with an ee value of 99.1%.
[0115] Example 5 Preparation of Compound of Formula D
[0116]
[0117] THF (25 ml) and MeOH (25 ml) were added to the concentrated solid, and the mixture was stirred at 25°C until the solid completely dissolved. CF3COOH was added, the pH was adjusted to 3, and stirring was continued for 1 hour. NaBH3CN (2 mmol, 126 mg) was added and stirring was continued for 3 hours. HPLC monitoring showed that the starting material C had completely disappeared and was converted to intermediate D. EE value: 99.0%.
[0118] Example 6 Preparation of the compound of formula I-4
[0119]
[0120] The reaction system was concentrated, and ethanol (73 ml) and anhydrous sodium acetate (9.8 g, 120 mmol) were added. The mixture was stirred at 70° C. for 1.5 h. The starting material disappeared after TLC monitoring. The mixture was filtered, concentrated, and subjected to column chromatography to obtain 1.06 g of compound I-4 with a yield of 98%. 1 The structure was confirmed to be correct by HNMR and the ee value was 99.4% by chiral HPLC. 1 H NMR (600MHz, CDCl3) δ7.26–7.23(m,2H),7.21(t,J=7.2Hz,1H),7.07(dd,J=6.9,1.8Hz,2H),3.99(s,1H),3.60(s ,4H),3.13(s,2H),2.93(d,J=13.4Hz,1H),2.75(d,J=13.4Hz,1H),2.02(s,1H),1.69–1.50(m,3H),1.45(s,9H).
[0121] Example 7 Preparation of Compound of Formula I
[0122]
[0123] In a 50 ml flask was added I-4 (1 mmol, 330 mg), NaOH (4 mmol, 160 mg), THF (2 ml), MeOH (4 ml), H2O (4 ml), stirred at 70 °C for 6 h, TLC monitored the disappearance of raw materials, the reaction system was concentrated to remaining water, 15 ml water and 20 ml ethyl acetate were added to the system for extraction, the aqueous phase was collected, a saturated aqueous solution of tartaric acid was added under ice bath conditions, the PH was adjusted to 3-4, 30 ml ethyl acetate was added to the system for extraction, the organic phase was washed with saturated brine twice, dried over anhydrous sodium sulfate, concentrated to obtain compound I 287 mg, yield 90%. ee value: 99.5%. 1 H NMR (400 MHz, CDC13) δ 7.27 (d, J = 6.1 Hz, 1H), 7.26 - 7.20 (m, 2H), 7.17 - 7.11 (m, 2H), 5.30 (s, 1H), 4.01 (d, J = 13.4 Hz, 1H), 3.63 (dt, J = 13.3, 4.6 Hz, 1H), 3.12 (d, J = 13.0 Hz, 2H), 2.95 (d, J = 13.5 Hz, 1H), 2.81 (d, J = 13.4 Hz, 1H), 2.03 (d, J = 10.0 Hz, 1H), 1.73 - 1.55 (m, 2H), 1.44 (s, 9H).
[0124] All documents referred to in this disclosure are incorporated by reference as if each were individually incorporated. In addition, it is to be understood that various alterations and modifications will occur to those skilled in the art upon reading the above description. It is the intention that the application be construed as including all such alterations and modifications as fall within the scope of the appended claims.
Claims
1. A method for preparing a key intermediate of anamorelin, comprising the following steps: (a) reacting a compound of formula I-2 with a Bn-X reagent in an inert reagent in the presence of a base to prepare a compound of formula I-3; (b) preparing a compound of formula I-4 from a compound of formula I-3 in an inert solvent in the presence of an acid and a reducing agent; Wherein, X is selected from the following group: Br, Cl, I, R3 is C1-6 alkyl.
2. The method according to claim 1, wherein The step (b) comprises the following steps: (b-1) reacting the compound of formula I-3 with a reagent R4-NHNH2 in an inert solvent to prepare a compound of formula C; (b-2) in an inert solvent, in the presence of an acid and a reducing agent, the compound of formula C is reacted to obtain a compound of formula D; (b-3) hydrolyzing the compound of formula D in an inert solvent to obtain a compound of formula I-4; Among them, the structure of R4 is R2 is each independently selected from the group consisting of -NO2, C1-C6 alkyl.
3. The method according to claim 1, wherein Before step (a), the method further comprises the following steps: (a-1) In an inert solvent, in the presence of a catalyst, the compound of formula I-1 reacts with the compound of formula B to prepare the compound of formula I-2.
4. The method according to claim 1, wherein The inert solvent is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, dichloromethane, dichloroethane, toluene, acetonitrile, alcohol solvents, ether solvents, or combinations thereof.
5. The method according to claim 1, wherein The base in step (a) is selected from the group consisting of LDA, LiHMDS, NaHMDS, or a combination thereof.
6. The method according to claim 1, wherein The acid is selected from the group consisting of CF3COOH, CH3SO3H, H2SO4, or a combination thereof.
7. The method according to claim 3, wherein The preparation method of the compound of formula B is as follows: (aa) In an inert solvent, in the presence of a base, the compound of formula A is reacted to obtain the compound of formula B.
8. The method according to claim 3, wherein The catalyst in step (a-1) is selected from the group consisting of TsOH, TfOH, or a combination thereof.
9. The method according to claim 1, wherein The molar ratio of the Bn-X reagent to the compound of formula I-2 is 1:1 to 1:5, preferably 1:
2.
10. The method according to claim 1, wherein The reaction temperature of step (a) is -20 to -80°C, preferably -40 to -80°C.