A preparation method of elastostat and its intermediates

Abstract

The invention provides a method for preparing alacastran and an intermediate thereof, and belongs to the technical field of organic synthesis. The method for preparing the alacastran intermediate comprises the following steps: subjecting a raw material to an N-alkylation reaction, and then subjecting the raw material to a Bouveault aldehyde synthesis reaction or an oxidation reaction, to obtain an alacastran intermediate. In the preparation process of the alacastran intermediate and alacastran, the raw material is simple and easy to obtain, the preparation steps are simple, the yield is high, and it is easy to produce on a large scale.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for preparing elastolide, in particular to a method for preparing elastolide and an intermediate thereof. Background Art

[0002] Elastrogen is a small molecule anti-breast cancer drug developed by Menarini of Italy and Radius Health of the United States. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on January 27, 2023, with the trade name Orserdu. This is also the first non-steroidal oral selective estrogen receptor degrader (SERD) approved by the FDA, which is used for advanced or metastatic breast cancer in postmenopausal women or adult men with estrogen receptor-positive (ER+) / human epidermal growth factor receptor 2-negative (HER2-) who have experienced disease progression after at least one endocrine therapy. In September of the same year, the European Medicines Agency (EMA) also approved the marketing of Elastrogen, which was subsequently approved for marketing in the European Union, the United Kingdom, the United Arab Emirates, Kuwait, etc.

[0003] The patent for the intermediate and its preparation method laid out by the original research enterprise Radius, the disclosed preparation method is as follows:

[0004]

[0005] The above route uses 7-benzyloxy-3-bromo-1,2-dihydronaphthalene and 2-bromo-5-methoxyacetanilide as starting materials and undergoes four-step reactions to obtain the key intermediate A6. The intermediate is chirally resolved and reacts with N-ethyl-2-(4-formylphenyl)acetamide (A8) under acidic conditions to generate a Schiff base. The double bond is then reduced under sodium acetate borohydride hydrogenation and the ethyl group is added to obtain the intermediate A9. The acyl group is then reduced to obtain elastostrat.

[0006] The reductive amination operation of this route is relatively complicated, the reaction is slow, the post-processing is complicated, and a large amount of anhydrous tetrahydrofuran is required. The last step of reduction requires sodium borohydride and elemental iodine, the post-processing is troublesome, and the yield is relatively low (>50%), resulting in a low overall yield and high cost.

[0007] Chengdu Inodabo has developed a new method for synthesizing elastostat, as shown below:

[0008]

[0009] Among them, A8 of the original research route was replaced with B3 to avoid the use of sodium borohydride / iodine to reduce the amide, but it requires two steps of reductive amination, which makes the post-processing complicated. The last step of reductive amination easily generates two ethyl by-products, which makes post-processing purification difficult.

[0010] The invention patent with publication number CN118515576A discloses a method for preparing a key intermediate of elastomeric, comprising the following steps:

[0011]

[0012] The intermediate compound I is obtained through five steps of reaction. However, in the subsequent preparation of elastomeric compound, sodium borohydride / iodine is required to reduce the amide, which is a complicated operation.

[0013] The invention patent with publication number CN118206458A discloses a method for preparing elastomeric, and the specific steps are as follows:

[0014]

[0015] It mainly optimizes the preparation method of intermediate compound A.

[0016] The invention patent with the publication number CN118724758A discloses a method for preparing elastomeric, which comprises the following steps:

[0017] The compound of formula II reacts with the compound of formula III to carry out an amine-aldehyde condensation reaction to generate a compound of formula IV.

[0018]

[0019] Wherein R2 is formyl or Wherein * represents the connection point with the phenyl group; R3 is a nitrogen protecting group, and R3 is selected from Boc, Cbz, Fmoc or Bn.

[0020] Also includes the steps:

[0021] The nitrogen protecting group of the compound of formula IV is removed to obtain elastostat, and the reaction formula is as follows:

[0022]

[0023] However, the invention does not disclose the preparation method of the compound of formula III.

[0024] The preparation methods of elastostat disclosed in the prior art have the disadvantages of low yield, dangerous reagents, difficult to obtain raw materials, difficult to control product quality, and unsuitability for industrialization, and it is urgent to develop a method for industrial large-scale production of elastostat and its intermediates with easy-to-obtain raw materials, high yield, mild reaction conditions. Therefore, the present invention provides a preparation method of elastostat and its intermediates, which has simple and easy-to-obtain raw materials, simple preparation steps, high yield, and is easy to mass produce. Summary of the invention

[0025] The present invention aims to solve the problems existing in the prior art and provides a method for preparing elastostat and its intermediates. The present invention adopts simple and readily available raw materials to prepare elastostat intermediates and elastostat, has simple preparation steps, high yield, and is easy for large-scale production.

[0026] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0027] In a first aspect, the present invention provides a method for preparing an elastomeric intermediate comprising the following steps:

[0028] The raw material is subjected to N-alkylation reaction, and then subjected to Bouveault aldehyde synthesis reaction or oxidation reaction to obtain an elastolide intermediate; the elastolide intermediate is compound 3:

[0029]

[0030] The raw material is selected from compound 1 or compound 7:

[0031]

[0032] wherein R is selected from Boc, Cbz, Fmoc, Bn, Teoc or Tfa.

[0033] Preferably, the N-alkylation reaction uses ethyl bromide and NaH. R is preferably Boc.

[0034] In one embodiment, the preparation method of compound 3 comprises the following steps:

[0035] Compound 1 was subjected to N-alkylation reaction and Bouveault aldehyde synthesis reaction in sequence to obtain compound 3:

[0036]

[0037] Preferably, the N-alkylation reaction uses ethyl bromide and NaH, and specifically comprises the following steps: dissolving compound 1 in an aprotic solvent, adding NaH under low temperature conditions for reaction for 0.5-1h, wherein the low temperature conditions are 0-5°C, then adding ethyl bromide, reacting at room temperature, and extracting to obtain compound 2.

[0038] The aprotic solvent is a commonly used type, including but not limited to: N, N-dimethylformamide (DMF), acetonitrile, dimethyl sulfoxide, acetone, etc., preferably N, N-dimethylformamide. The extraction is preferably carried out using ethyl acetate.

[0039] The molar ratio of the compound 1, ethyl bromide and NaH is 1:1-2:1-2, preferably 1:1-1.5:1-1.5, and more preferably 1:1.2:1.2.

[0040] The Bouveault aldehyde synthesis reaction uses a catalyst of n-butyl lithium, N,N-dimethylformamide and a solvent of tetrahydrofuran, and specifically comprises the following steps:

[0041] Compound 2 is dissolved in tetrahydrofuran solvent, and n-butyl lithium is added as a catalyst at -75 to -85°C for reaction for 15 to 30 minutes, and then N,N-dimethylformamide is added for reaction for 20 to 40 minutes, and an aqueous solution of ammonium chloride is added for extraction to obtain compound 3. The extraction is preferably performed using dichloromethane.

[0042] The molar ratio of the compound 2 to n-butyl lithium is 1:1-2, preferably 1:1.5, more preferably 1:1.2. The ratio of the compound 2 to N,N-dimethylformamide is 5-7 mmol:1 mL, preferably 5.5-6.5 mmol:1 mL.

[0043] In one embodiment, the preparation method of compound 3 comprises the following steps:

[0044] Compound 7 is subjected to N-alkylation reaction and oxidation reaction in sequence to obtain compound 3:

[0045]

[0046] The compound 7 is preferably obtained by protecting the amino group of compound 6:

[0047]

[0048] Preferably, the N-alkylation reaction uses ethyl bromide and NaH, and specifically comprises the following steps: dissolving compound 7 in an aprotic solvent, adding NaH at low temperature (0-5°C) for reaction for 0.5-1h, then adding ethyl bromide, reacting at room temperature, and extracting to obtain compound 2. Compound 2 is directly used in the next reaction without purification.

[0049] The aprotic solvent is a commonly used type, including but not limited to: N, N-dimethylformamide (DMF), acetonitrile, dimethyl sulfoxide, acetone, etc., preferably N, N-dimethylformamide. The extraction is preferably carried out using ethyl acetate.

[0050] The molar ratio of compound 7, ethyl bromide and NaH is 1:1-2:1-2, preferably 1:1-1.5:1-1.5, and more preferably 1:1.2:1.2.

[0051] The oxidation reaction uses SnO2, and specifically includes the following steps: dissolving compound 8 in 1,4-dioxane, adding SnO2, heating under reflux (100-160°C) until the reaction is complete, adsorbing with diatomaceous earth, and extracting to obtain compound 3. The extraction is preferably performed by multiple extractions.

[0052] In a second aspect, the present invention provides a method for preparing elastostat, comprising the following steps:

[0053] The elastostat intermediate described in the above technical solution is subjected to reductive amination reaction and deprotection reaction to obtain elastostat;

[0054] The reductive amination reaction comprises:

[0055] Compound 3 and compound 4 are subjected to reductive amination reaction to obtain compound 5:

[0056]

[0057] The reductive amination reaction uses an aprotic solvent, an acid, a reducing agent and acetaldehyde, and specifically comprises the following steps:

[0058] Compound 3 and compound 4 are dissolved in a non-protonic solvent, an acid is added as a catalyst, and the reaction is carried out at room temperature for 0.5-1 h. A reducing agent is added to react until the reaction is complete, and then acetaldehyde is added to react until the reaction is complete. The compound 5 is extracted, concentrated, and purified by pulping.

[0059] The aprotic solvent is preferably 1,2-dichloroethane; the acid is preferably acetic acid; the reducing agent is preferably sodium acetate borohydride. The pulping purification preferably uses a mixed solution of n-hexane and tertiary methyl ether.

[0060] The deprotection reaction is a deprotection reaction commonly used by those skilled in the art.

[0061] In one embodiment, compound 5 is subjected to a deprotection reaction to obtain elastostat, wherein R in the compound 5 is Boc, and preferably a mixed solution of HCl and ethyl acetate is used for the deprotection reaction. After the reaction is complete, methanol is used for pulping and purification to obtain elastostat.

[0062] Compared with the prior art, the present invention has the following beneficial effects: the present invention adopts simple and readily available raw materials to prepare elastostat intermediates and elastostat, has simple preparation steps, high yield, and is easy for large-scale production. DETAILED DESCRIPTION

[0063] It is worth noting that, unless otherwise specified, the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0064] Example 1

[0065] The preparation steps of intermediate compound 3 are as follows:

[0066]

[0067] Step 1: Preparation of compound 2 (tert-butyl (4-bromophenethyl) carbamate)

[0068]

[0069] Compound 1 (tert-butyl N-[2-(4-bromophenyl)ethyl]carbamate, 251g, 836mmol, 1.0eq.) was dissolved in 500mL DMF, sodium hydride (24g, 1003mmol, 1.2eq.) was slowly added in batches under an ice bath (0-5°C), and stirred for 30 minutes under an ice bath after the addition was completed. Ethyl bromide (109g, 1003mmol, 1.2eq.) was then slowly added dropwise to the reaction solution, and the temperature was slowly raised to room temperature after the addition was completed. The intermediate was confirmed to be completely reacted by LCMS. 500mL of water was added to the reaction system, and ethyl acetate (500mL) was extracted three times, the organic phases were combined, and saturated brine (200mL) was washed three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated after suction filtration to obtain a crude product of 260g of compound 2 (tert-butyl (4-bromophenylethyl)carbamate), with a yield of 95%, and a light yellow oily liquid.

[0070] Compound 2: 1 H NMR(400MHz, CDCl3) δ7.39(d,J=8.1Hz,2H),7.06(s,2H),3.34(t,J=7.2Hz,2H),3 .17(t,J=18.5Hz,2H),2.76(t,J=7.3Hz,2H),1.43(s,9H),1.06(t,J=7.1Hz,3H).

[0071] Step 2: Preparation of compound 3 (tert-butyl (4-formylphenethyl)carbamate)

[0072]

[0073] tert-Butyl (4-bromophenethyl)carbamate (60 g, 183 mmol, 1.0 eq.) and 300 mL of anhydrous THF were added to a 1000 mL reaction bottle, kept at -78°C for 10 minutes, and then n-butyl lithium (137 mL, 220 mmol, 1.2 eq., 1.6 mol / L) was slowly added dropwise. The reaction solution was reacted at -78°C for 20 minutes, and 30 mL of anhydrous DMF was added, and stirring was continued for 30 minutes. LCMS confirmed that the intermediate was completely reacted. 500 mL of ammonium chloride aqueous solution was added to the reaction system, and the mixture was extracted three times with ethyl acetate (200 mL). The organic phases were combined and washed three times with saturated brine (500 mL). The organic phases were shaken with an excess of saturated sodium bisulfite solution until all the substrate aldehydes were salted. After filtration, sodium carbonate aqueous solution was added and stirred for 30 minutes. After extraction with dichloromethane, the mixture was dried over anhydrous sodium sulfate and concentrated to obtain 40 g of compound 3 (tert-butyl (4-formylphenylethyl)carbamate) as a light yellow oily liquid with a yield of 79%.

[0074] Compound 3: 1 H NMR (400MHz, CDCl3) δ9.97 (s, 1H), 7.80 (d, J = 7.7Hz, 2H), 7.36 (s, 2H), 3.41 (t, J = 7.4Hz ,2H),3.17(d,J=26.8Hz,2H),2.90(t,J=7.7Hz,2H),1.43(s,9H),1.06(t,J=7.1Hz,3H).

[0075] Example 2

[0076] The preparation steps of elastomeric are as follows:

[0077]

[0078] Step 1: Preparation of compound 5 (tert-butyl (R)-ethyl (4-(ethyl (2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate)

[0079]

[0080] At room temperature, in a 1L three-necked flask, compound 4 ((R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 60 g, 223 mmol, 1.0 eq.), compound 3 (tert-butyl (4-formylphenethyl)carbamate, 74.3 g, 268 mmol, 1.2 eq.) and 1,2-dichloroethane (DCE, 300 mL) were added, followed by a catalytic amount of acetic acid (AcOH, 2.68 g, 44.6 mmol, 0.2 eq.), the atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at room temperature for 30 minutes. Sodium acetic acid borohydride (213 g, 100 mmol, 4.5 eq.) was added to the reaction solution in batches under an ice bath. After the addition was completed, the reaction was continued to stir at room temperature for 1 hour. The reaction was confirmed to be completely reacted by LCMS. Acetaldehyde (54 mL, 5 mol / L in THF, 1.2 eq.) was added to the reaction system, and the reaction was continued to stir at room temperature for 1 hour. The reaction was confirmed to be completely reacted by LCMS. Saturated sodium carbonate aqueous solution was added to the reaction system to quench the reaction, and dichloromethane (200 mL) was extracted three times. The organic phase was combined, and saturated brine (200 mL) was washed three times, and then concentrated after suction filtration to obtain tert-butyl (R)-ethyl (4-(ethyl (2-(6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-yl)-5-methoxyphenyl) amino) methyl) phenethyl) carbamate crude product, and then n-hexane / tert-methyl ether (volume ratio 10 / 1) was used for pulping and purification to obtain compound 5, a white solid, 112 g, with a yield of 90%.

[0081] Compound 5: 1 H NMR (400MHz, CDCl3)δ 1 H NMR (400MHz, CDCl3) δ7.16 (dd, J=10.5, 8.0Hz, 3H), 7.05 (d, J=7.6Hz, 2H), 6.97-6.87 (m, 1H), 6.7 8(d,J=2.6Hz,1H),6.69(dd,J=8.6,2.7Hz,1H),6.64(dd,J=6.1,2.8Hz,2H),5.49(s,1H),3.99(s, 2H),3.79(s,3H),3.75-3.58(m,1H),3.37(d,J=25.2Hz,2H),3.18(s,2H),2.96-2.69(m,8H),1.76 (td,J=10.8,9.8,4.2Hz,2H),1.46(d,J=3.3Hz,9H),1.06(t,J=7.1Hz,3H),0.94(t,J=7.0Hz,3H).

[0082] Step 2: Preparation of elastostat ((R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride)

[0083]

[0084] At room temperature, compound 5 (tert-butyl (R)-ethyl (4-(ethyl (2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl) amino) methyl) phenethyl) carbamate, 60 g, 107 mmol, 1.0 eq.) and anhydrous ethyl acetate (300 mL) were added to a 500 mL three-necked flask, and HCl / ethyl acetate solution (107 mL, 4 mol / L, 4.0 eq.) was added to a constant pressure dropping funnel. The reaction solution was stirred at room temperature for 3 hours, and LCMS confirmed that the raw materials were completely reacted. The product was precipitated as a solid, and after suction filtration, a crude product of elastostat ((R)-6-(2-(ethyl (4-(2-(ethylamino)ethyl) benzyl) amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride) was obtained. After purification by methanol beating, a white solid of 54.2 g was obtained with a yield of 95%.

[0085] Example 3

[0086] The preparation steps of intermediate compound 3 are as follows:

[0087]

[0088] Step 1: Preparation of compound 7 (tert-butyl 4-methylphenethylcarbamate)

[0089]

[0090] Compound 6 (2-(p-tolyl)ethylamine, 50g, 370mmol, 1.0eq.) and triethylamine (Et3N, 37.4g, 370mmol, 1.0eq.) were dissolved in 200mL THF, di-tert-butyl dicarbonate (Boc2O, 80.7g, 370mmol, 1.0eq.) was slowly added dropwise under an ice bath, and the reaction was stirred at room temperature for 2 hours after the addition was completed. The intermediate was confirmed to be completely reacted by LCMS. 500mL of saturated aqueous ammonium chloride solution was added to the reaction system, ethyl acetate (200mL) was extracted three times, the organic phases were combined, and saturated brine (200mL) was washed three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a crude product of compound 7 as a light yellow solid, 80.9g, with a yield of 93%, which was directly used for the next step without purification.

[0091] Compound 7: 1H NMR (400MHz, CDCl3) δ7.02-7.17(m,4H),4.52(br s,1H),3.35(d,J=6.3Hz,2H),2.75(t,J=6.9Hz,2H),2.32(s,3H),1.43(s,9H).

[0092] Step 2: Preparation of compound 8 (tert-butyl ethyl (4-methylphenethyl) carbamate)

[0093]

[0094] Compound 7 (tert-butyl 4-methylbenzeneethyl carbamate, 80g, 340mmol, 1.0eq.) was dissolved in 320mL DMF, sodium hydride (9.8g, 408mmol, 1.2eq.) was slowly added in batches under an ice bath, and the reaction was stirred for 30 minutes under an ice bath after the addition was completed. Ethyl bromide (44.5g, 408mmol, 1.2eq.) was then slowly added dropwise to the reaction solution, and the temperature was slowly raised to room temperature after the addition was completed. The intermediate was confirmed to be completely reacted by LCMS. 500mL of water was added to the reaction system, and ethyl acetate (500mL) was extracted three times, the organic phases were combined, and saturated brine (200mL) was washed three times, and the organic phase was dried over anhydrous sodium sulfate, and concentrated after suction filtration to obtain a crude compound 8 (tert-butyl ethyl (4-methylbenzeneethyl) carbamate), a light yellow oily liquid, 85g, a yield of 95%, which was directly used for the next step of reaction without purification.

[0095] Compound 8: 1 H NMR (400MHz, CDCl3) δ7.11 (s, 4H), 3.36 (s, 2H), 3.20 (d, J = 25.1Hz, 2H), 2.79 (t, J = 7.8Hz, 2H), 2.34 (s, 3H), 1.43 (s, 9H), 1.09 (t, J = 7.2Hz, 3H).

[0096] Step 3: Preparation of compound 3 (tert-butyl (4-formylphenethyl)carbamate)

[0097]

[0098] Compound 8 (tert-butyl ethyl (4-methylphenylethyl) carbamate, 85g, 323mmol, 1.0eq.) was dissolved in 500mL 1,4-dioxane, tin dioxide (SnO2, 147g, 969mmol, 3.0eq.) was added, and the mixture was heated in an oil bath and refluxed for 6 hours after the addition was completed. The intermediate was confirmed to be completely reacted by LCMS. After the reaction solution was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration, 500mL of sodium bicarbonate aqueous solution was added to the filtrate, and ethyl acetate (500mL) was extracted three times, the organic phases were combined, and saturated brine (500mL) was washed three times, and the organic phases were shaken together with an excess of saturated sodium bisulfite solution until the substrate aldehyde was completely salted. After filtration, sodium carbonate aqueous solution was added and stirred for 30 minutes, and after dichloromethane extraction, it was dried over anhydrous sodium sulfate and concentrated to obtain compound 3 (tert-butyl (4-formylphenylethyl) carbamate), a light yellow oily liquid, 76g, with a yield of 85%.

[0099] Example 4

[0100] The preparation steps of elastomeric are as follows:

[0101]

[0102] Step 1: Preparation of compound 5 (tert-butyl (R)-ethyl (4-(ethyl (2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate)

[0103]

[0104] At room temperature, in a 1L three-necked flask, compound 9 (N-(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(methoxyphenyl)ethylamine, 29.7 g, 100 mmol, 1.0 eq.), compound 3 (tert-butyl (4-formylphenylethyl)carbamate, 27.7 g, 100 mmol, 1.0 eq.) and 1,2-dichloroethane (DCE, 150 mL) were added, followed by acetic acid (6 g, 100 mmol, 1.0 eq.), the reaction solution was stirred at room temperature for 30 minutes, and sodium acetate borohydride (42.4 g, 200 mmol, 2.0 eq.) was added to the reaction solution in batches. .), after the addition was completed, the reaction was continued to stir at room temperature for 1 hour, and the raw materials were confirmed to be completely reacted by LCMS. Saturated sodium carbonate aqueous solution was added to the reaction system to quench the reaction, and dichloromethane (200mL) was extracted twice, the organic phase was combined, and saturated brine (200mL) was washed three times, and then concentrated after suction filtration to obtain a crude product of compound 5 (tert-butyl (R)-ethyl (4-(ethyl (2-(6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-yl)-5-methoxyphenyl) amino) methyl) phenethyl) carbamate), and then purified by beating with n-hexane / tert-methyl ether (volume ratio 10 / 1) to obtain compound 5, a white solid, 53g, yield 95%.

[0105] Step 2: Preparation of elastostat ((R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride)

[0106]

[0107] At room temperature, compound 5 (tert-butyl (R)-ethyl (4-(ethyl (2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl) amino) methyl) phenethyl) carbamate, 53 g, 95.0 mmol, 1.0 eq.) and anhydrous ethanol (200 mL) were added to a 500 mL three-necked flask, and HCl / ethyl acetate solution (95 mL, 4 mol / L, 4.0 eq.) was added to a constant pressure dropping funnel. The reaction solution was stirred at room temperature for 3 hours, and LCMS confirmed that the raw materials were completely reacted. The product was precipitated as a solid, and after suction filtration, a crude product of elastostat ((R)-6-(2-(ethyl (4-(2-(ethylamino)ethyl) benzyl) amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride) was obtained. After purification by methanol pulping, a white solid of 49.7 g was obtained with a yield of 98%.

[0108] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing an elastostat intermediate, characterized in that: The following steps are involved: The raw material is subjected to N-alkylation reaction, and then subjected to Bouveault aldehyde synthesis reaction or oxidation reaction to obtain an elastolide intermediate; the elastolide intermediate is compound 3: The raw material is selected from compound 1 or compound 7: wherein R is selected from Boc, Cbz, Fmoc, Bn, Teoc or Tfa.

2. The preparation method according to claim 1, characterized in that: The N-alkylation reaction uses ethyl bromide and NaH; the temperature of the N-alkylation reaction is low temperature, and the low temperature is 0-5°C.

3. The preparation method according to claim 1, characterized in that: The preparation method of the compound 3 comprises the following steps: Compound 1 was subjected to N-alkylation reaction and Bouveault aldehyde synthesis reaction in sequence to obtain compound 3:

4. The preparation method according to claim 3, characterized in that: The Bouveault aldehyde synthesis reaction adopts catalyst n-butyl lithium, N,N-dimethylformamide and solvent tetrahydrofuran; the temperature of the Bouveault aldehyde synthesis reaction is -75 to -85°C.

5. The preparation method according to claim 1, characterized in that: The preparation method of the compound 3 comprises the following steps: Compound 7 is subjected to N-alkylation reaction and oxidation reaction in sequence to obtain compound 3:

6. The preparation method according to claim 5, characterized in that: The oxidation reaction uses SnO2; the temperature of the oxidation reaction is 100-160°C.

7. The preparation method according to claim 5, characterized in that: The compound 7 is obtained by protecting the amino group of compound 6: The protection temperature of the amino group is low temperature 0-5°C.

8. The preparation method according to claim 1, characterized in that: The R is Boc.

9. A method for preparing elastostat, characterized in that: The following steps are involved: Subjecting the elastostat intermediate according to any one of claims 1 to 8 to reductive amination reaction and deprotection reaction to obtain elastostat; The reductive amination reaction comprises: Compound 3 and compound 4 are subjected to reductive amination reaction to obtain compound 5: The reductive amination reaction uses a non-protonic solvent, acid, reducing agent and acetaldehyde; the temperature of the reductive amination reaction is room temperature.

10. The preparation method according to claim 9, characterized in that: The aprotic solvent is 1,2-dichloroethane; the acid is acetic acid; and the reducing agent is sodium acetate borohydride.

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