A preparation method of (S)-3,6-diaminohexanoic acid hydrochloride
Synthesis of (S)-3,6-diaminocaproate hydrochloride through three-step reactions, the problems of difficult synthesis and poor stability in the prior art were solved, and efficient, stable and easy to store products were achieved.
Patent Information
- Application Number
- CN202411801175.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-09
- Publication Date
- 2025-04-01
AI Technical Summary
The prior art is difficult to efficiently synthesize (S)-3,6-diaminocaproate hydrochloride with good stability, and its chemical properties are unstable and are not suitable for storage.
Through three steps of reaction: methanesulfonylation reaction of (S)-2,5-tert-butoxycarbonylaminopentan-1 alcohol, cyano-substitution reaction of sulfonate ester, and removal of Boc protecting group under acidic conditions to obtain (S)-3,6-diaminocaproate hydrochloride.
The efficient synthesis of (S)-3,6-diaminocaproate hydrochloride is achieved, ensuring the stability of the product and easy storage and transportation, and simplifying the processing of intermediate products.
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Figure CN119735515A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of biomedicine, and specifically relates to a method for preparing (S)-3,6-diaminohexanoic acid hydrochloride. Background Art
[0002] β-non-natural amino acids are widely used in the fields of medicine and peptide synthesis. Currently, they are mainly synthesized by extending the carbon chain of natural amino acids. However, due to their multifunctional groups and easy racemization, their synthesis is challenging. (S)-3,6-diaminohexanoic acid is one of the β-non-natural amino acids and is widely used in many fields. Currently, there is no literature report on the method of synthesizing (S)-3,6-diaminohexanoic acid. In addition, its chemical properties are unstable and it is not suitable for storage. Therefore, it is urgent to study a new synthesis method that can not only efficiently synthesize (S)-3,6-diaminohexanoic acid hydrochloride, but also meet the purpose of stable performance, easy storage, and direct use as a raw material for other reactions. Summary of the invention
[0003] In view of the above technical problems, the present invention provides a method for preparing (S)-3,6-diaminohexanoic acid, and obtains the target product through three-step reactions, including a methanesulfonylation reaction of (S)-2,5-tert-butoxycarbonylaminopentane-1-ol, a cyano substitution reaction of a sulfonic acid ester, and removal of a Boc protecting group under acidic conditions.
[0004] To achieve this object, the present invention adopts the following technical solutions:
[0005] The present invention provides a method for preparing (S)-3,6-diaminohexanoic acid hydrochloride, and the synthesis route is as follows:
[0006]
[0007] The synthetic route comprises the following steps:
[0008] Step S1, dissolving (S)-2,5-tert-butoxycarbonylaminopentane-1-ol in an organic solvent and cooling to 0° C., adding triethylamine and methanesulfonic anhydride in sequence, and reacting at the temperature to obtain compound 1, wherein the molar ratio of (S)-2,5-tert-butoxycarbonylaminopentane-1-ol, triethylamine, and methanesulfonic anhydride is 1:1:1 to 1:2:2;
[0009] Step S2, dissolving compound 1 and 18-crown-6 in acetonitrile, adding sodium cyanide, and reacting at 50° C. to 100° C. to obtain compound 2; wherein the molar ratio of compound 1, 18-crown-6, and sodium cyanide is 1:0.1:1 to 1:4:4;
[0010] Step S3, compound 2 and hydrochloric acid are placed in an autoclave and stirred at 80° C. to 150° C. to obtain (S)-3,6-diaminohexanoic acid hydrochloride, wherein the molar ratio of compound 2 to hydrochloric acid is 1:10 to 1:100.
[0011] Preferably, in step S1, the molar ratio of (S)-2,5-tert-butoxycarbonylaminopentane-1-ol, triethylamine and methanesulfonic anhydride is 1:2:2.
[0012] Preferably, in step S2, the molar ratio of compound 1, 18-crown-6, and sodium cyanide is 1:1.2:3.05 。
[0013] Further preferably, the specific operation of step S1 is:
[0014] 339mmol (S)-2,5-tert-butoxycarbonylaminopentane-1-ol was dissolved in 1L dichloromethane and cooled to 0°C. Then, 678mmol triethylamine and 678mmol methanesulfonic anhydride were added in sequence. After stirring at this temperature for 1 hour, 500mL sodium bicarbonate solution was added to quench the reaction. The mixture was then extracted with dichloromethane. The obtained organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to obtain a crude product A. The crude product A was slurried with MTBE, filtered, and vacuum dried to obtain a white solid, namely compound 1.
[0015] Further preferably, the specific operation of step S2 is:
[0016] 193mmol of compound 1 and 232mmol of 18-crown-6 were dissolved in 760mL of acetonitrile, and then 589mmol of sodium cyanide was added, stirred at 90°C for 2 hours, then cooled to room temperature, and 500mL of sodium bicarbonate was added to the reaction solution to quench the reaction; then, the organic phase was extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product B, which was purified by column chromatography and concentrated to obtain a light yellow oil, which was left for 12 hours to become a light yellow solid, and the light yellow solid was compound 2. During column chromatography purification, the developing solvent was petroleum ether and ethyl acetate in a volume ratio of 2:1.
[0017] Further preferably, the specific operation of step S3 is:
[0018] A mixture of 145 mmol of compound 2 and 500 mL of 36% hydrochloric acid was placed in an autoclave and stirred at 120° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated and dried to obtain a white solid, namely (S)-3,6-diaminohexanoic acid hydrochloride.
[0019] Preferably, in step S1, the organic solvent is any one of dichloromethane, dichloroethane, THF, acetonitrile, DMF or DMSO.
[0020] Compared with the prior art, the present invention has at least the following beneficial effects:
[0021] 1. There are few reaction steps, the raw materials are easily available, and the production can be carried out safely and stably.
[0022] 2. The intermediate product processing process is simple and the final product is easy to store and transport.
[0023] 3. It can be used as (S)-3,6-diaminohexanoic acid without further treatment. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 LC-MS chart of compound 1 in the example of the present invention;
[0025] Figure 2 LC-MS chart of compound 2 in the example of the present invention;
[0026] Figure 3 is the compound 2 in the embodiment of the present invention 1 HNMR spectra;
[0027] Figure 4 LC-MS chart of compound 3 in the example of the present invention;
[0028] Figure 5 is the compound 3 in the embodiment of the present invention 1 HNMR spectrum. DETAILED DESCRIPTION
[0029] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. However, the following examples are only simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.
[0030] Unless otherwise specified, the raw materials used in the present invention are purchased through general commercial channels. The source information of some raw materials, materials and instruments involved in the following examples or comparative examples is as follows:
[0031] (S)-2,5-tert-Butyloxycarbonylaminopentane-1-ol, CAS number: 75178-90-4; purchased from Bid Pharmaceuticals, the model is reagent grade;
[0032] Triethylamine (TEA), CAS No. 121-44-8, purchased from MacLean Company, the model is reagent grade;
[0033] Dichloromethane (DCM), CAS No. 75-09-2, purchased from Sinopharm, reagent grade;
[0034] Methyl tert-butyl ether (MTBE), CAS No. 1634-04-4, purchased from MacLean Company, the model is reagent grade;
[0035] Methanesulfonic anhydride (Ms2O), CAS No. 7143-01-3, was purchased from MacLean Company and was reagent grade.
[0036] LC-MS: LC-MS,ACQUITY-Hclss PLUS+QDA.
[0037] The (S)-3,6-diaminohexanoic acid hydrochloride provided by the present invention has the following preparation route:
[0038]
[0039] The preparation route includes three steps, as follows:
[0040] Step S1, the synthetic route is:
[0041]
[0042] The specific operation of step S1 is: dissolving (S)-2,5-tert-butoxycarbonylaminopentane-1-ol in an organic solvent and cooling to 0°C, adding triethylamine and methanesulfonic anhydride in sequence, and reacting at the temperature to obtain compound 1 (compound 1), wherein the molar ratio of (S)-2,5-tert-butoxycarbonylaminopentane-1-ol, triethylamine, and methanesulfonic anhydride is 1:1:1 to 1:2:2.
[0043] Step S2, the synthetic route is:
[0044]
[0045] The specific operation of step S2 is: dissolving compound 1 and 18-crown-6 in acetonitrile, adding sodium cyanide, and reacting at 90° C. to obtain compound 2 (compound 2), wherein the molar ratio of compound 1, 18-crown-6, and sodium cyanide is 1:0.1:1 to 1:4:4.
[0046] Step S3, the synthetic route is:
[0047]
[0048] The specific operation of step S3 is: compound 2 and hydrochloric acid are placed in an autoclave and stirred at 120° C. to obtain compound 3, i.e., the target product (target) (S)-3,6-diaminohexanoic acid hydrochloride, wherein the molar ratio of compound 2 to hydrochloric acid is 1:10 to 1:100.
[0049] <Example>
[0050] This example prepares (S)-3,6-diaminohexanoic acid hydrochloride.
[0051] Step S1: (S)-2,5-tert-butyloxycarbonylaminopentane-1 alcohol (108g, 339mmol) was dissolved in dichloromethane (1L) and cooled to 0°C, and then triethylamine (68.6g, 678mmol) and methanesulfonic anhydride (118g, 678mmol) were added in sequence, stirred at 0°C for 1 hour to react, and then sodium bicarbonate solution (500mL) was added to quench the reaction. After the reaction was completed, it was extracted twice with dichloromethane, using 300 ml each time, and the organic phase was combined; the organic phase was washed twice with brine, using 500mL each time. Then it was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product A. The crude product A was slurried with MTBE (500mL), filtered, and vacuum dried to obtain a white solid, namely compound 1 (76.7g, 57.0%). The yield of 57.0% was calculated based on (S)-2,5-tert-butoxycarbonylaminopentane-1-ol.
[0052] Compound 1 was detected by LC-MS ( Figure 1 ), the result is: m / z=419.36[M+Na]+.
[0053] Step S2: Compound 1 (76.7 g, 193 mmol) and 18-crown-6 (61.36 g, 232 mmol) obtained in step S1 were dissolved in acetonitrile (760 mL), sodium cyanide (28.44 g, 589 mmol) was added, stirred at 90 ° C for 2 hours, and cooled to room temperature. Sodium bicarbonate (500 mL) was added to the reaction solution for quenching, and then extracted with ethyl acetate twice, using 500 mL each time, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product B. The crude product B was purified by column chromatography and concentrated to obtain a light yellow oil, which was placed for 12 hours to form a light yellow solid. The light yellow solid was compound 2 (47.4 g, 74.84%). The developing solvent used for column chromatography purification was petroleum ether: ethyl acetate = 2: 1 (volume ratio). The yield was calculated based on compound 1.
[0054] Compound 2 was detected by LC-MS ( Figure 2 ), the result is: m / z = 172.23 [M-Boc- t Bu] + Compound 2 1 HNMR detection ( Figure 3 ), the result is: 1HNMR: (400MHz, CDCl3), δ4.75(s,1H),4.61(s,1H),3.82(s,1H),3.15–3.13(m ,2H),2.74–2.70(m,1H),2.55–2.50(m,1H),1.63–1.51(m,4H),1.43(s,18H).
[0055] Step S3: A mixture of compound 2 (47.4 g, 145 mmol) obtained in step S2 and hydrochloric acid (36%, 500 mL) was placed in an autoclave and stirred at 120°C for 2 hours. The resulting reaction solution was cooled to room temperature and concentrated to dryness to obtain (S)-3,6-diaminohexanoic acid hydrochloride as a white solid (31.72 g, 145 mmol).
[0056] Compound 3 was detected by LC-MS ( Figure 4 ), the result was: m / z = 147.0 [M + H] +. Compound 3 was 1 HNMR detection ( Figure 5 ), the result is: 1 HNMR (400MHz, D2O), δ3.52–3.39(m,1H), 3.01–2.89(m,2H), 2.52–2.49(m,1H), 2.47–2.36(m,1H), 1.81–1.61(m,4H).
[0057] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.
Claims
1. A method for preparing (S)-3,6-diaminohexanoic acid hydrochloride, characterized in that: The synthetic route is as follows: The synthetic route comprises the following steps: Step S1, dissolving (S)-2,5-tert-butoxycarbonylaminopentane-1-ol in an organic solvent and cooling the mixture to 0° C., sequentially adding triethylamine and methanesulfonic anhydride, and reacting the mixture at the same temperature to obtain compound 1; Step S2, dissolving the compound 1 and 18-crown-6 in acetonitrile, adding sodium cyanide, and reacting at 50° C. to 100° C. to obtain compound 2; Step S3, placing the compound 2 and hydrochloric acid in an autoclave, stirring at 80° C. to 150° C., to obtain (S)-3,6-diaminohexanoic acid hydrochloride.
2. The method for preparing (S)-3,6-diaminohexanoic acid hydrochloride according to claim 1, characterized in that: In step S1, the molar ratio of the (S)-2,5-tert-butoxycarbonylaminopentane-1-ol, triethylamine, and methanesulfonic anhydride is 1:1:1 to 1:2:
2.
3. The method for preparing (S)-3,6-diaminohexanoic acid hydrochloride according to claim 2, characterized in that: In step S1, the molar ratio of (S)-2,5-tert-butoxycarbonylaminopentane-1-ol, triethylamine and methanesulfonic anhydride is 1:2:
2.
4. The method for preparing (S)-3,6-diaminohexanoic acid hydrochloride according to claim 1, characterized in that: In step S2, the molar ratio of compound 1, 18-crown-6 and sodium cyanide is 1:0.1:1 to 1:4:
4.
5. The method for preparing (S)-3,6-diaminohexanoic acid hydrochloride according to claim 4, characterized in that: In step S2, the molar ratio of compound 1, 18-crown-6 and sodium cyanide is 1:1.2:3.
05.
6. The method for preparing (S)-3,6-diaminohexanoic acid hydrochloride according to claim 1, characterized in that: In step S3, the molar ratio of the compound 2 to the hydrochloric acid is 1:10 to 1:
100.
7. The method for preparing (S)-3,6-diaminohexanoic acid hydrochloride according to claim 1, characterized in that: The specific operations of step S1 are: 339 mmol of the (S)-2,5-tert-butoxycarbonylaminopentane-1-ol was dissolved in 1 L of dichloromethane and cooled to 0°C, and then 678 mmol of triethylamine and 678 mmol of methanesulfonic anhydride were added in sequence. After stirring at this temperature for 1 hour, 500 mL of sodium bicarbonate solution was added to quench the reaction, and then extracted with dichloromethane. The obtained organic phase was washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product A. The crude product A was slurried with MTBE, filtered and vacuum dried to obtain a white solid, namely the compound 1.
8. The method for preparing (S)-3,6-diaminohexanoic acid hydrochloride according to claim 1, characterized in that: The specific operations of step S2 are: 193 mmol of the compound 1 and 232 mmol of 18-crown-6 were dissolved in 760 mL of acetonitrile, and then 589 mmol of sodium cyanide was added, and the mixture was stirred at 90° C. for 2 hours, and then cooled to room temperature, and 500 mL of sodium bicarbonate was added to the reaction solution to quench the reaction; then, the mixture was extracted with ethyl acetate to obtain an organic phase, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product B, which was purified by column chromatography and concentrated to obtain a light yellow oil, which was left to stand for 12 hours to become a light yellow solid, and the light yellow solid was the compound 2; Wherein, during the column chromatography purification, the developing solvent is petroleum ether and ethyl acetate in a volume ratio of 2:
1.
9. The method for preparing (S)-3,6-diaminohexanoic acid hydrochloride according to claim 1, characterized in that: The specific operations of step S3 are: A mixture of 145 mmol of the compound 2 and 500 mL of 36% hydrochloric acid was placed in an autoclave and stirred at 120° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated and dried to obtain a white solid, namely the (S)-3,6-diaminohexanoic acid hydrochloride.
10. The method for preparing (S)-3,6-diaminohexanoic acid hydrochloride according to claim 1, characterized in that: In step S1, the organic solvent is any one of dichloromethane, dichloroethane, THF, acetonitrile, DMF or DMSO.