METHOD FOR SYNTHESIZING DOPA OLIGOPEPTIDE INTERMEDIATE AND USE, COMPOSITION AND PREPARATION THEREOF

Abstract

In the technical field of lithium ion batteries, disclosed is a wet synthesis method of a high-nickel NCMA quaternary precursor. The method includes synthesizing solid tiny crystal nuclei of the NCMA quaternary precursor in a first reactor, and prompting the crystal nuclei of the quaternary precursor to grow to a certain particle size in a second reactor, wherein in the first reactor, an upper feeding mode is used to continuously produce the solid tiny crystal nuclei of the NCMA quaternary precursor. In the second reactor, an upper-and-lower dual feeding mode is used to prompt the continuous growth of the solid tiny crystal nuclei of the NCMA quaternary precursor. During a washing process, the NCMA quaternary precursor is washed with a mixed alkali solution of sodium carbonate and sodium hydroxide at certain concentration, so that Na can be reduced below 50 ppm and sulfur can be reduced below 800 ppm.

Claims

1. A wet synthesis method of a high-nickel NCMA quaternary precursor, characterized by comprising: synthesizing solid tiny crystal nuclei of the NCMA quaternary precursor in a first reactor, and prompting the solid tiny crystal nuclei of the quaternary precursor to continuously grow to a certain particle size in a second reactor; wherein in the first reactor, an upper feeding mode is used to continuously produce the solid tiny crystal nuclei of the NCMA quaternary precursor, and in the second reactor, an upper-and-lower dual feeding mode is used to prompt the continuous growth of the solid tiny crystal nuclei of the NCMA quaternary precursor.

2. The wet synthesis method of the high-nickel NCMA quaternary precursor of claim 1, characterized by comprising the steps of: (1) formulation of solution: formulating a solution A of a complexing agent and a solution B of a precipitant; formulating a solution C of nickel, cobalt, manganese salt; formulating a solution D of sodium meta-aluminate; (2) preparation of the tiny crystal nuclei of the NCMA quaternary precursor: in the first reactor, adding distilled water, the solution A and the solution B to formulate a reactor bottom liquid E; regulating the initial pH, temperature, stirring speed, and concentration of the complexing agent of the reactor bottom liquid E, and passing an inert gas to regulate the reaction atmosphere within the reactor; continuously adding the solution A, the solution B, the solution C, and the solution D through the respective liquid feed pipes to the first reactor under stirring in the upper feeding mode, controlling the stirring speed of the reaction system, temperature, pH value, concentration of the complexing agent, solid content, reaction time, supernatant color of the slurry, and concentration of free Ni during the reaction process, detecting the particle size in the reaction slurry in real time, and stopping the reaction until D.sub.50 reaches 2-10 μm, to give a slurry F of the tiny crystal nuclei of the NCMA quaternary precursor; (3) continuous growth of the tiny crystal nuclei of the NCMA quaternary precursor: in the second reactor, adding distilled water, the solution A and the solution B to formulate a reactor bottom liquid G with a certain pH and a certain concentration of the complexing agent, and regulating the temperature, stirring speed, and gas atmosphere in the second reactor; adding the tiny crystal nuclei of the NCMA quaternary precursor prepared in Step (2) into the reactor bottom liquid G in the second reactor, and stirring uniformly; adding the solution A, the solution C and the solution D through their respective upper and lower liquid feed pipes into the second reactor in the upper-and-lower dual feeding mode, adding the solution B through the upper liquid feed pipes into the second reactor in the upper feeding mode; regulating the stirring speed, reaction temperature, reaction pH value, concentration of the complexing agent, solid content, reaction time, supernatant color of the slurry, concentration of free Ni, and color of the slurry, detecting the particle size of the reaction slurry in real time, and stopping the reaction until D.sub.50 reaches to 3-16 μm, to give a slurry H of the high-nickel NCMA quaternary precursor; (4) filtering the slurry H of the high-nickel NCMA quaternary precursor, washing, drying, screening and removing iron from materials on the sieve, to give the high-nickel NCMA quaternary precursor.

3. The wet synthesis method of the high-nickel NCMA quaternary precursor of claim 2, characterized by that, in Step (1), the concentration of the complexing agent in the solution A is 4-11 mol/L; and the complexing agent is at least one of ammonium hydroxide, ammonium hydrocarbonate, ethylenediamine, and ethylenediamine tetraacetic acid; the concentration of the precipitant in the solution B is 1-11 mol/L; and the precipitant is at least one of NaOH, KOH, Ba(OH).sub.2, Na.sub.2CO.sub.3 or LiOH; the total concentration of the nickel, cobalt, and manganese metal ion(s) in the solution C is 0.8-5.0 mol/L; and the nickel, cobalt, manganese salt is at least one of sulfate, acetate, halide, or nitrate; the concentration of the sodium meta-aluminate in the solution D is 0.01-5.0 mol/L; and the aluminum of the sodium meta-aluminate is derived from at least one of aluminum nitrate, aluminum carbonate, and aluminum sulfate.

4. The wet synthesis method of the high-nickel NCMA quaternary precursor of claim 2, characterized by that, in Step (2), the initial pH of the reactor bottom liquid E is controlled at 11-14, the concentration of the complexing agent is 6-15 g/L; and the volume of the reaction bottom liquid E is ⅙ to 1 of the volume of the first reactor; the stirring speed of the reaction system is regulated to 300-1,200 rpm, the solid content is 150-400 g/L, the temperature is 30-90° C.; at certain intervals, a small amount of slurry is sampled, which stands for observing the color of supernatant, the supernatant of the slurry is kept to be free of blue color, and the concentration of free Ni is kept at 0-600 ppm.

5. The wet synthesis method of the high-nickel NCMA quaternary precursor of claim 2, characterized by that, in Step (3), the volume of the reactor bottom liquid G is ½-1 of the volume of the second reactor, the initial pH is controlled at 10-13, and the concentration of the complexing agent is 6-15 g/L; 20-220 g of the tiny crystal nuclei of the NCMA quaternary precursor are added per liter of the reactor bottom liquid G; the stirring speed of the reaction system is regulated to 300-1200 rpm, the solid content is 300-1000 g/L, and the reaction temperature is 30-90° C.; the supernatant of the slurry is kept to be free of blue color, and the concentration of the free Ni is kept at 0-700 ppm.

6. The wet synthesis method of the high-nickel NCMA quaternary precursor of claim 2, characterized by that, in the second reactor, the stirring paddle is set as an upper stirring paddle and a lower stirring paddle, the upper feed pipes for delivering the solution A, the solution C and the solution D and the liquid feed pipe for delivering the solution B are disposed at the same horizontal position as that of the upper stirring paddle, and the lower feed pipes for delivering the solution A, the solution C and the solution D are disposed at the same horizontal position as that of the lower stirring paddle.

7. The wet synthesis method of the high-nickel NCMA quaternary precursor of claim 6, characterized by that, in Step (2) and Step (3), the flow or the total flow of the solution A is 1-80 mL/min, the flow of the solution B is 20-100 mL/min, the flow or the total flow of the solution C is 10-1000 mL/min; and the flow or the total flow of the solution D is 5-60 mL/min; the flow ratio of the solutions in the upper and lower dual liquid feed pipes of the solution A is 1:(0.1-10), the flow ratio of the solutions in the upper and lower dual liquid feed pipes of the solution C is 1:(0.1-20), and the flow ratio of the solutions in the upper and lower dual liquid feed pipes of the solution D is 1:(0.1-8).

8. The wet synthesis method of the high-nickel NCMA quaternary precursor of claim 2, characterized by that, in Step (4), the tiny crystal nuclei and the mother liquor which are filtered during filtration are recirculated to the first reactor for sequential production of crystal nuclei.

9. The wet synthesis method of the high-nickel NCMA quaternary precursor of claim 1, characterized by that, the volume ratio of the second reactor to the first reactor is 4-12:1.

10. The wet synthesis method of the high-nickel NCMA quaternary precursor of claim 1, characterized by that, in Step (4), a mixed solution of sodium carbonate and sodium hydroxide is used as washing water during the washing, and the molar ratio of the concentrations of the sodium carbonate to the sodium hydroxide is 1-10:1.

Description

FIGURES ATTACHED

[0058] FIG. 1: characteristic diagram of gel formation with FDD-16.

[0059] FIG. 2: the electron microscope (SEM) diagram of the gel formed with FDD-18

[0060] FIG. 3: the electron microscope (SEM) diagram of the gel formed with FDD-14

SPECIFIC EMBODIMENTS

[0061] To verify the feasibility of the technical scheme of this invention, inventors have carried out research on the synthetic methods of key intermediates and the end products as well as the characterization techniques. It should be noted that the synthetic methods and detection techniques of the key intermediates and end products of this invention are only representative, and other synthetic methods, end products and detection techniques included in this invention are not exhausted herein due to space limitations.

Example 1: Synthesis of Fmoc-DOPA(cyclohexanonide)-OH as Follows

[0062] ##STR00005##

[0063] a. An amount of 14.3 g Na.sub.2B.sub.4O.sub.7.10H.sub.2O (37.5 mmol), 200 ml water and a magnetic stirring bar were added into a 1000 ml three-neck flask. After passing argon for 30 min, 14.8 g L-DOPA (75 mmol) and 8.0 g (75 mmol) Na.sub.2CO.sub.3 were added, followed by addition of Fmoc-OSu (27.8 g, 90 mmol) in 200 ml THF with a dropping funnel. After stirring for 12 hours, the solution was adjusted to pH=3 with 2N HCl solution, followed by addition of 10-20 g Na.sub.2S.sub.2O.sub.3. The mixture was reduced with rotary evaporation, and then extracted with EtOAc. The organic layer was washed with water, dried over anhydrous magnesium sulfate. After filtration, the filtrate was reduced to a small amount with rotary evaporation, followed by addition of petroleum ether to give chemical 5 (white powder, 28.9 g, 91%). HRMS: [M+H].sup.+ Calcd. 420.1442. Found 420.1448.

[0064] To screen the optimal conditions for b-step reaction, probing tests were carried out with a 100 ml two-neck flask, using 2.1 g (5 mmol) chemical 1 as the reactant, CaCl.sub.2 as the adsorbent and HPLC as the detection means. The optimal reaction conditions were screened for: major solvents, co-solvents, acetonide-providing reagents, DMP molar ratios, reaction temperatures, reaction times and catalysts. It found that among the tested solvents of benzene, toluene, acetone, THF and DMF, benzene gave the best result (byproduct impurity 6), followed by toluene (byproduct impurity 7). Using THF or DMF as the major solvents, only tiny amount of Compound I was detected. Due to the low solubility of chemical 5 in benzene, it was found that after addition of acetone as cosolvent, the yield of Compound I was almost doubled, while no such increase was observed when using THF or DMF as the cosolvent. In terms of catalyst screening, it was found that strong acids with low oxidizing abilities performed better: TsOH>camphor sulfonic acid>TFA>HOAc. In terms of acetonide-providing reagent screening: the reactivity of acetone was too low and DMP was quite suitable; 2MT was too reactive and it converted the carboxyl group of L-DOPA into a methyl ester (impurity 8) even at low temperature. In terms of the molar ratio screening of DMP to chemical 5: in case the ratio is less than 2, the reaction cannot complete; in case the ratio was 10 or higher, significant percentages of L-DOPA methyl ester were formed; the best choice of the molar ratio was 2.5.

##STR00006##

[0065] b. To a 100 ml two-neck flask, were added 2.1 g (5 mmol) of chemical 5, 5 ml of anhydrous acetone and 70 ml of anhydrous benzene. After heating and refluxing under argon for 15 minutes, 1.5 ml (12.5 mmol) of DMP and 20 mg TsOH were added. The byproducts H.sub.2O/MeOH generated in the reaction system were removed with anhydrous CaCl.sub.2 (filled in a Soxhlet extractor or a constant-pressure dropping funnel with fritted glass). The reaction process was monitored with ferric chloride test, and it took about 1-2 h to complete. After cooling, the reaction mixture was filtered through a short silica-gel column, which was washed with DCM/EtOAc. The combined filtrate was subjected to rotary evaporation to give a light-yellow solid, which was recrystallized in EtOAc/petroleum ether to produce target chemical 4 (2.0 g, 89%).

[0066] Chemical 6: HRMS [M+H].sup.+ Calcd. 420.1442. Found 420.1448. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 7.89 (s, 1H), 7.87 (s, 1H), 7.66-7.63 (m, 2H), 7.43-7.39 (m, 2H), 7.34-7.28 (m, 2H), 6.67 (d, J=2.1 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.52 (dd, J=8.0, 2.1 Hz, 1H), 4.20 (m, 3H), 4.08 (m, 1H), 2.90 (dd, J=13.8, 4.6 Hz, 1H), 2.70 (dd, J=13.8, 10.2 Hz, 1H). .sup.13CNMR δ 173.56, 155.97, 144.93, 143.82, 143.77, 140.67, 128.71, 127.64, 127.12, 125.37, 125.28, 120.09, 119.86, 116.47, 115.33, 65.67, 55.95, 46.59, 36.04.

[0067] Chemical 7: HRMS [M+H].sup.+ Calcd. 460.1755. Found 460.1750. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 7.88 (s, 1H), 7.86 (s, 1H), 7.64 (m, 2H), 7.40 (m, 2H), 7.29 (m, 2H), 6.78 (s, 1H), 6.70 (m, 2H), 6.52 (dd, J=8.0, 2.1 Hz, 1H), 4.20 (m, 4H), 3.00 (dd, J=13.8, 4.4 Hz, 1H), 2.78 (dd, J=13.8, 10.5 Hz, 1H), 1.57 (s, 6H). .sup.13CNMR δ 173.38, 155.96, 146.69, 145.42, 143.75(2C), 140.70, 140.67, 131.04, 127.62(2C), 127.08, 127.05, 125.31, 125.23, 121.66, 120.10(2C), 117.56, 109.29, 107.73, 65.65, 55.76, 46.60, 36.20, 25.51(2C).

[0068] Chemical 8: HRMS [M+H].sup.+ Calcd. 474.1911. Found 474.1912. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 7.89-7.84 (m, 2H), 7.64 (m, 2H), 7.43-7.39 (m, 2H), 7.34-7.27 (m, 2H), 6.765 (d, J=1.7 Hz, 1H), 6.698 (d, J=3.9 Hz, 1H), 6.647 (dd, J=3.9, 1.7 Hz, 1H), 4.242-4.180 (m, 4H), 3.62 (s, 3H), 2.954 (dd, J=13.8, 4.9 Hz, 1H), 2.791 (dd, J=13.8, 10.4 Hz, 1H), 1.577 (s, 6H). .sup.13CNMR δ 172.35, 155.89, 146.71, 145.48, 143.70, 140.70, 140.67, 130.53, 127.61, 127.04, 125.22, 125.16, 121.65, 120.10, 117.60, 109.25, 107.75, 65.63, 55.70, 51.90, 36.11, 25.48.

Example 2: Synthesis of Fmoc-DOPA(cyclohexanonide)-OH as Follows

[0069] a. An amount of 14.3 g Na.sub.2B.sub.4O.sub.7.10H.sub.2O (37.5 mmol), 200 ml water and a magnetic stirring bar were added into a 1000 ml three-neck flask. After passing argon for 30 min, 14.8 g L-DOPA (75 mmol) and 8.0 g (75 mmol) Na.sub.2CO.sub.3 were added, followed by addition of Fmoc-OSu (27.8 g, 90 mmol) in 200 ml THF. After stirring for 12 hours, the solution was adjusted to pH=3 with 2N HCl solution, followed by addition of 10-20 g Na.sub.2S.sub.2O.sub.3. The mixture was reduced with rotary evaporation, and then extracted with EtOAc. The organic layer was washed with water, dried over anhydrous magnesium sulfate. After filtration, the filtrate was reduced to a small amount with rotary evaporation, followed by addition of petroleum ether to give chemical 5 (white powder, 28.9 g, 91%).

[0070] b. To a 100 ml two-neck flask, were added 2.1 g (5 mmol) of chemical 5, 5 ml of anhydrous acetone and 70 ml of anhydrous benzene. After heating and refluxing under argon for 15 minutes, 1.5 ml (12.5 mmol) of DMP and 20 mg TsOH were added. The byproducts H.sub.2O/MeOH generated in the reaction system were removed with anhydrous CaCl.sub.2 (filled in a Soxhlet extractor or a constant-pressure dropping funnel with fritted glass). The reaction process was monitored with ferric chloride test, and it took about 1-2 h to complete. After cooling, the reaction mixture was filtered through a short silica-gel column, which was washed with DCM/EtOAc. The combined filtrate was subjected to rotary evaporation to give a light-yellow solid, which was recrystallized in EtOAc/petroleum ether to produce target chemical 4 with a little amount of 6 (1.5 g, 67%).

Example 3: Synthesis of Fmoc-DOPA(cyclohexanonide)-OH as Follows

[0071] a. An amount of 14.3 g Na.sub.2B.sub.4O.sub.7.10H.sub.2O (37.5 mmol), 200 ml water and a magnetic stirring bar were added into a 1000 ml three-neck flask. After passing argon for 30 min, 14.8 g L-DOPA (75 mmol) and 8.0 g (75 mmol) Na.sub.2CO.sub.3 were added, followed by addition of Fmoc-OSu (27.8 g, 90 mmol) in 200 ml THF. After stirring for 12 hours, the solution was adjusted to pH=3 with 2N HCl solution, followed by addition of 10-20 g Na.sub.2S.sub.2O.sub.3. The mixture was reduced with rotary evaporation, and then extracted with EtOAc. The organic layer was washed with water, dried over anhydrous magnesium sulfate. After filtration, the filtrate was reduced to a small amount with rotary evaporation, followed by addition of petroleum ether to give chemical 5 (white powder, 28.9 g, 91%).

[0072] b. To a 100 ml two-neck flask, were added 2.1 g (5 mmol) of chemical 5, 5 ml of anhydrous acetone and 70 ml of anhydrous benzene. After heating and refluxing under argon for 15 minutes, 1.5 ml (12.5 mmol) of DMP and 20 mg TsOH were added. The byproducts H.sub.2O/MeOH generated in the reaction system were removed with anhydrous CaCl.sub.2 (filled in a Soxhlet extractor or a constant-pressure dropping funnel with fritted glass). The reaction process was monitored with ferric chloride test, and it took about 1-2 h to complete. After cooling, the reaction mixture was filtered through a short silica-gel column, which was washed with DCM/EtOAc. The combined filtrate was subjected to rotary evaporation to give a light-yellow solid, which was recrystallized in EtOAc/petroleum ether to produce target chemical 4 with a little amount of 6 (1.0 g, 45%).

Example 4: Synthesis of Fmoc-DOPA(cyclohexanonide)-OH as Follows

[0073] a. An amount of 14.3 g Na.sub.2B.sub.4O.sub.7.10H.sub.2O (37.5 mmol), 200 ml water and a magnetic stirring bar were added into a 1000 ml three-neck flask. After passing argon for 30 min, 14.8 g L-DOPA (75 mmol) and 8.0 g (75 mmol) Na.sub.2CO.sub.3 were added, followed by addition of Fmoc-OSu (27.8 g, 90 mmol) in 200 ml THF. After stirring for 12 hours, the solution was adjusted to pH=3 with 2N HCl solution, followed by addition of 10-20 g Na.sub.2S.sub.2O.sub.3. The mixture was reduced with rotary evaporation, and then extracted with EtOAc. The organic layer was washed with water, dried over anhydrous magnesium sulfate. After filtration, the filtrate was reduced to a small amount with rotary evaporation, followed by addition of petroleum ether to give chemical 5 (white powder, 28.9 g, 91%).

[0074] b. To a 100 ml two-neck flask, were added 2.1 g (5 mmol) of chemical 5, 5 ml of anhydrous acetone and 70 ml of anhydrous benzene. After heating and refluxing under argon for 15 minutes, 1.5 ml (12.5 mmol) of DMP and 20 mg TsOH were added. The byproducts H.sub.2O/MeOH generated in the reaction system were removed with anhydrous CaCl.sub.2 (filled in a Soxhlet extractor or a constant-pressure dropping funnel with fritted glass). The reaction process was monitored with ferric chloride test, and it took about 1-2 h to complete. After cooling, the reaction mixture was filtered through a short silica-gel column, which was washed with DCM/EtOAc. The combined filtrate was subjected to rotary evaporation to give a light-yellow solid, which was recrystallized in EtOAc/petroleum ether to produce target chemical 4 with a little amount of 6 (1.9 g, 80%).

Example 5: Synthesis of Fmoc-DOPA(cyclohexanonide)-OH as Follows

[0075] a. An amount of 14.3 g Na.sub.2B.sub.4O.sub.7.10H.sub.2O (37.5 mmol), 200 ml water and a magnetic stirring bar were added into a 1000 ml three-neck flask. After passing argon for 30 min, 14.8 g L-DOPA (75 mmol) and 8.0 g (75 mmol) Na.sub.2CO.sub.3 were added, followed by addition of Fmoc-OSu (27.8 g, 90 mmol) in 200 ml THF. After stirring for 12 hours, the solution was adjusted to pH=3 with 2N HCl solution, followed by addition of 10-20 g Na.sub.2S.sub.2O.sub.3. The mixture was reduced with rotary evaporation, and then extracted with EtOAc. The organic layer was washed with water, dried over anhydrous magnesium sulfate. After filtration, the filtrate was reduced to a small amount with rotary evaporation, followed by addition of petroleum ether to give chemical 5 (white powder, 28.9 g, 91%).

[0076] b. To a 100 ml two-neck flask, were added 2.1 g (5 mmol) of chemical 5, 5 ml of anhydrous acetone and 70 ml of anhydrous benzene. After heating and refluxing under argon for 15 minutes, 1.55 ml (12.5 mmol) of DMP and 20 mg CSA were added. The byproducts H.sub.2O/MeOH generated in the reaction system were removed with anhydrous CaCl.sub.2 (filled in a Soxhlet extractor or a constant-pressure dropping funnel with fritted glass). The reaction process was monitored with ferric chloride test, and it took about 1-2 h to complete. After cooling, the reaction mixture was filtered through a short silica-gel column, which was washed with DCM/EtOAc. The combined filtrate was subjected to rotary evaporation to give a light-yellow solid, which was recrystallized in EtOAc/petroleum ether to produce target chemical 4 with a little amount of 6 (1.8 g, 85%).

Example 6: Synthesis of L-DOPA and Fatty Acid Conjugate (Lauric Acid & L-DOPA)

[0077] The synthesis process is shown in the figure below.

##STR00007##

[0078] a) An amount of 5 g CTC resin was added to a solution of SOCl.sub.2/DCM (33 ml, 1:10) for activation for 5-16 h, and then the resin was washed with DCM for 5 times. Fmoc-DOPA(Acetonide)-OH (4.14 g, 9 mmol) was dissolved in DCM, followed by addition of 6.6 ml DIEA. The CTC resin was transferred into a SPPS tube and the activated amino acid solution was poured in.

[0079] b) The resin was then capped with DIEA/MeOH/DCM (5:15:80), and then the Fmoc was removed with 20% 4-methylpiperidine/DMF. 1.24 ml of lauryl chloride was dissolved in an appropriate amount of DCM, followed by addition of 1.29 ml DIEA. The mixture was poured into the SPPS tube and was shaken for 5-16 h. After the reaction was complete as shown by the ninhydrin test, the resin was eluted with a solution of 2% TFA/DCM to obtain the conjugate of L-DOPA and lauric acid in an protected form.

[0080] c) When in need, acetonide was subjected to deprotection with a solution of TFA/TIS/H.sub.2O (95/2.5/2.5) and conjugate FD-12 was obtained. HRMS [M+H].sup.+, Calc. 380.2431. Found 380.2435.

Example 7: Synthesis of L-DOPA and Fatty Acid Conjugate (Stearic Acid & L-DOPA)

[0081] ##STR00008##

[0082] a) An amount of 5 g CTC resin was added to a solution of SOCl.sub.2/DCM (33 ml, 1:10) for activation for 5-16 h, and then the resin was washed with DCM for 5 times. Fmoc-DOPA(Acetonide)-OH (4.14 g, 9 mmol) was dissolved in DCM, followed by addition of 6.6 ml DIEA. The CTC resin was transferred into a SPPS tube and the activated amino acid solution was poured in.

[0083] b) The resin was then capped with DIEA/MeOH/DCM (5:15:80), and then the Fmoc was removed with 20% 4-methylpiperidine/DMF. 1.24 ml of stearyl chloride was dissolved in an appropriate amount of DCM, followed by addition of 1.29 ml DIEA. The mixture was poured into the SPPS tube and was shaken for 5-16 h. After the reaction was complete as shown by the ninhydrin test, the resin was eluted with a solution of 2% TFA/DCM to obtain the conjugate of L-DOPA and stearic acid in the protected form.

[0084] c) When in need, acetonide was subjected to deprotection with a solution of TFA/TIS/H.sub.2O (95/2.5/2.5) and conjugate FD-18 was obtained. HRMS [M+H].sup.+, Calc. 464.3371. Found 464.3373.

Example 8: Synthesis of L-DOPA and Fatty Acid Conjugate (Lauric Acid & L-DOPA-L-Asp)

[0085] The target product was prepared by Fmoc-based SPPS, and the synthesis process is shown in the figure below.

##STR00009##

[0086] In general, CTC resin was used as a solid-supporting material, Fmoc-DOPA(Acetonide)-OH and Fmoc-Asp(OtBu)-OH as reactants, 4-methylpiperidine as the Fmoc-deprotecting reagent, and lauryl chloride as the activation form of lauric acid. The synthesized conjugate of fatty acid and L-DOPA-containing dipeptide was cut off from the resin with a solution of 2% TFA to give the intermediate conjugate with the side chain protected.

[0087] The target conjugate of fatty acid and L-DOPA-containing dipeptide was obtained by rapidly removing the side chain protection with 95% TFA. FDD-12 was characterized by HRMS [M+H].sup.+, Calcd. 495.2700. Found 495.2701.

Example 9: Synthesis of L-DOPA and Fatty Acid Conjugate (Palmitic Acid & L-DOPA-L-Asp)

[0088] The target product was prepared using the Fmoc-based SPPS protocol, and the synthesis process is shown in the figure below.

##STR00010##

[0089] CTC resin was used as a solid-supporting material; Fmoc-DOPA(Acetonide)-OH and Fmoc-Asp(OtBu)-OH were used as reactants; 4-methylpiperidine was used as Fmoc deprotecting reagent; and palmitic acid was activated with BOP/HOBt/DIEA. The synthesized fatty acid complex containing L-DOPA dipeptide was cut off from the resin with 2% TFA to give the intermediate conjugate with the side chain protected.

[0090] The target conjugate of fatty acid and L-DOPA dipeptide was obtained by rapidly removing the side chain protection of the intermediate with 95% TFA. The target conjugate FDD-16 was characterized by HRMS, [M+H].sup.+, Calcd. 551.3317. Found 551.3327.

Example 10: Synthesis of L-DOPA-Containing Dipeptide and Fatty Acid Conjugate (Tetradecanoic Acid & L-DOPA-L-Asp)

[0091] The target product was prepared using the Fmoc-based SPPS protocol, and the synthesis process is shown in the figure below.

##STR00011##

[0092] CTC resin was used as a solid-supporting material; Fmoc-DOPA(Acetonide)-OH and Fmoc-Asp(OtBu)-OH were used as reactants; 4-methylpiperidine was used as Fmoc deprotecting reagent; and tetradecanoic acid was activated with BOP/HOBt/DIEA. The synthesized fatty acid complex containing L-DOPA dipeptide was cut off from the resin with 2% TFA to give the intermediate conjugate with the side chain protected.

[0093] The target conjugate of fatty acid and L-DOPA dipeptide was obtained by rapidly removing the side chain protection of the intermediate with 95% TFA. The target conjugate FDD-14 was characterized by HRMS, [M+H].sup.+, Calcd. 523.3014. Found 523.3015.

Example 11: Synthesis of L-DOPA and Fatty Acid Conjugate (Stearic Acid & L-DOPA-L-Asp)

[0094] The target product was prepared using the Fmoc-based SPPS protocol, and the synthesis process is shown in the figure below.

##STR00012##

[0095] CTC resin was used as a solid-supporting material; Fmoc-DOPA(Acetonide)-OH and Fmoc-Asp(OtBu)-OH were used as reactants; 4-methylpiperidine was used as Fmoc deprotecting reagent; and stearyl chloride was used as the activated fatty acid form. The synthesized fatty acid complex containing L-DOPA dipeptide was cut off from the resin with 2% TFA to give the intermediate conjugate with the side chain protected.

[0096] The target conjugate of fatty acid and L-DOPA dipeptide was obtained by rapidly removing the side chain protection of the intermediate with 95% TFA. The target conjugate FDD-18 was characterized by HRMS, [M+H].sup.+, Calcd. 579.3640. Found 579.3635.

Example 12: Synthesis of L-DOPA-Containing Dipeptide and Fatty Acid Conjugate (Oleic Acid & L-DOPA-L-Asp)

[0097] ##STR00013##

[0098] The target product was prepared using the Fmoc-based SPPS protocol, and the synthesis process was like that shown in example 7. In short, CTC resin was used as a solid-supporting material; intermediates Fmoc-DOPA(Acetonide)-OH and Fmoc-Asp(OtBu)-OH were used as reactants; 4-methylpiperidine was used as Fmoc deprotecting reagent; and oleic acid was activated with DCC in the form of anhydride. The synthesized fatty acid complex containing L-DOPA dipeptide was cut off from the resin with 2% TFA to give the intermediate conjugate with the side chain protected.

[0099] The target conjugate of fatty acid and L-DOPA dipeptide was obtained by rapidly removing the side chain protection of the intermediate with 95% TFA. The target conjugate UFDD-18 was characterized by HRMS, [M+H].sup.+, Calcd. 563.3460. Found 563.3435.

Validation Embodiments

[0100] Part I. Gel formation tests of fatty acid conjugates with L-DOPA-containing dipeptides or L-DOPA in organic solvents.

[0101] 1. Gel Formation Tests of L-DOPA-Containing Lipodipeptides

[0102] 1.1 Gel Formation Test of FDD-16 and Searching for Proper Concentrations

[0103] 1) Six samples of 40 mg FDD-16 was added into six 2 ml centrifuge tubes, followed by addition of 1 ml of respective organic solvents. Mother solutions were prepared using MeOH, ethanol, toluene, THF, DMSO, and DMF, respectively.

[0104] 2) Aliquots of 50 μl of the above mother solutions were added, respectively, to nine 2 ml centrifuge tubes, followed by addition of organic solvents (MeOH, ethanol, toluene, THF, DMSO, DMF, respectively). The volume ratios of the organic solvent to distilled water were 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2 and 9:1, respectively. Tests of each solvent ratio were repeated 3 times. Gel formation rates and the corresponding sample concentrations were marked down.

[0105] 1.2 Gel Formation Tests for Other Lipodipeptides and Searching for Proper Concentrations

[0106] The experiments were performed like those of FDD-16.

[0107] 1.3 Experimental Results

[0108] The results showed that FDD-12 could not form gels, and it could be deduced that fatty acids with less than 12 C could not form gels under the above conditions; conjugates FDD-16, FDD-18 and FDD-14 could form stable gels. FDD-16 and FDD-14 had a wide range of gelation concentrations. The details are as follows:

TABLE-US-00002 TABLE 1 Gelation tests of L-DOPA-containing lipodipeptides (I) MeOH Ethanol Toluene Gelation Volume ratio Gelation Volume ratio Gelation Volume ratio concentration to water concentration to water concentration to water Samples (g/mL) (V:V) (g/mL) (V:V) (g/mL) (V:V)   FDD-12 — — — — — —   FDD-16  6~26 15/85~65/35  6~24 15/85~60/40 — —   FDD-18 10~16 25/75~40/60 12~26 30/70~65/35 — —   FDD-14  8~22 20/80~55/45  8~20 20/80~50/50 — — UFDD-18 — — — — — — U2FDD18  — — — — — —

TABLE-US-00003 TABLE 2 Gelation tests of L-DOPA-containing lipodipeptides (II) THF DMSO DMF Gelation Volume ratio Gelation Volume ratio Gelation Volume ratio concentration to water concentration to water concentration to water Samples (g/mL) (V:V) (g/mL) (V:V) (g/mL) (V:V)   FDD-12 — — — — — —   FDD-16  8~12 20/80~30/70  6~28 15/85~70/30  6~22 15/85~55/45   FDD-18 — — 16~30 40/60~75/25 14~26 35/65~65/35   FDD-14 6~8 15/85~20/80  8~22 20/80~55/45  6~20 15/85~50/50 UFDD-18 — — — — — — U2FDD18  — — — — — —

[0109] The results from Table 2 and 3 demonstrated that UFDD-18 and U2FDD18 could not form gels in organic solvents (MeOH, ethanol, toluene, THF, DMSO, DMF), but it did not exclude the possibility of gelling in other organic solvents in subsequent development. FDD-16 and FDD-14 formed gels in MeOH, ethanol, THF, DMSO and DMF, and FDD-18 formed gels in MeOH, ethanol, DMSO and DMF. In terms of the organic solvents selected in this invention, the range of gelling concentrations of FDD-18 is narrower than those of FDD-16 and FDD-14.

[0110] 2. Gelation tests of conjugates of fatty acid and L-DOPA

[0111] Gel formation experiments on FD-12 and FD-12

[0112] Tests were performed according to the tests done for FDD-16.

TABLE-US-00004 TABLE 3 Gelation tests of L-DOPA-containing lipodipeptides (II) MeOH Ethanol Toluene Gelation Volume ratio Gelation Volume ratio Gelation Volume ratio concentration to water concentration to water concentration to water Samples (g/mL) (V:V) (g/mL) (V:V) (g/mL) (V:V) FD-12 — — — — — — FD-18 10~15 25/85~55/25- 10~14 35/75~60/40 — —

TABLE-US-00005 TABLE 4 Gelation tests of L-DOPA-containing lipodipeptides (II) THF DMSO DMF Gelation Volume ratio Gelation Volume ratio Gelation Volume ratio concentration to water concentration to water concentration to water Samples (g/mL) (V:V) (g/mL) (V:V) (g/mL) (V:V) FDD-12 — — — — — — U2FDD18 10~16 26/50~40/60 16~28 45/85~70/50 16~24 45/85~55/35

[0113] Part 2. Characterization of Gels Formed from FDD-16

[0114] The appearance and stability of gels formed from FDD-16 was studied by turning the tubes upside down and. The results showed that the gel formed from FDD-16 was in good condition and remained at the bottom while standing for long time. This shed lights on future druggability study of FDD-16 using MeOH, ethanol, THF, DMSO and DMF as solvents. See FIG. 1 for gel formation experiments.

[0115] Part 3. Scanning Electron Microscopy (SEM) images of gels formed from FDD-18 or FDD-14

[0116] Through the gelling experiments, it was found that FDD-18 and FDD-14 exhibited higher possibilities to form gels. The images of electron microscope observation on gels formed from FDD-18 or FDD-14 were shown in FIG. 2 and FIG. 3, respectively.