A method for synthesizing s-2,6-dimethyl tyrosine derivatives using a novel chiral phase transfer catalyst

Abstract

The application belongs to the field of preparing chiral amino acids, and particularly relates to a method for catalytically synthesizing S-2,6-dimethyl tyrosine derivatives by using a chiral phase transfer catalyst. A compound of formula S11 is prepared by a nucleophilic substitution reaction of a compound of formula S10 and a compound of formula S5, and then a deprotection reaction is performed to prepare S-2,6-dimethyl tyrosine derivatives. In the nucleophilic substitution reaction, a novel chiral phase transfer catalyst with high efficiency is used, and the structural formula is as follows:

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of preparing chiral amino acids, and particularly relates to a method for catalytically synthesizing S-2,6-dimethyl tyrosine derivatives by using a chiral phase transfer catalyst. BACKGROUND

[0002] S-2,6-dimethyl tyrosine derivatives are a class of unnatural chiral amino acids, which are widely used in the production of many bioactive peptides and pharmaceutical opioid receptor antagonists, such as SUPER-DALDA, Bendavia, Eluxadoline and H-Dmt-Tic-OH, etc., all of which contain fragments of S-2,6-dimethyl tyrosine derivatives. In recent years, with the rise of polypeptide-related drugs, the demand for S-2,6-dimethyl tyrosine derivatives is also increasing. There are numerous patent literatures on the synthesis of such compounds, such as the method for directly synthesizing racemates (Synthetic Communications 2019, 49, 925-932., CN104987302A, CN108383744A), which needs to use chiral resolution to obtain optically pure S-2,6-dimethyl tyrosine derivatives; the method for synthesizing S-2,6-dimethyl tyrosine derivatives by using chiral nickel complex, which is complicated and needs chiral column separation and purification (Tetrahedron: Asymmetry. 2000, 11, 2917-2925, CN109608352A); the method for synthesizing S-2,6-dimethyl tyrosine derivatives by using chiral auxiliary, which is expensive in reagent price and high in production cost (Tetrahedron: Asymmetry 2009, 20, 1398-1401., Organic Preparations and Procedures International 2020, 52, 510-516., CN110903205A); and the method for preparing S-2,6-dimethyl tyrosine derivatives by using precious metal catalytic coupling or reduction, which is not suitable for industrial production due to the involvement of precious metal or chiral precious metal catalyst (ACS Med. Chem. Lett. 2015, 6, 1199-1203., CN104193638A, WO2019195634A1, Synthesis, 1992, 8, 741-743, Org. Letter., 2017, 19, 246-249). SUMMARY

[0003] In summary, the prior art production cost is high, and is not suitable for industrial production. It is necessary to develop a simple, inexpensive, and efficient route for synthesizing S-2, 6-dimethyl tyrosine derivatives.

[0004] The present application first provides an intermediate compound of chiral amino acid, specifically:

[0005]

[0006] R1 or R2 is the same or different, and is an aryl group. More preferably, it is a phenyl group.

[0007] Specifically, it can be a compound of formula S11, with the structural formula:

[0008]

[0009] Secondly, a novel chiral phase transfer catalyst is provided, with the structural formula:

[0010]

[0011] More preferably, the structural formula of Cat. 1-4 is

[0012]

[0013] Secondly, a novel chiral phase transfer catalyst is provided, with the structural formula:

[0014]

[0015] R1 and R2 are the same as defined above. 1， R2 is the same as defined above.

[0016] More preferably, the reaction is as follows:

[0017]

[0018] The catalyst is a chiral phase transfer catalyst, with the structural formula:

[0019] More preferably, the structural formula of the chiral phase transfer catalyst is:

[0020]

[0021] Most preferably, the structural formula of the chiral phase transfer catalyst is:

[0022]

[0023] The above reaction is carried out in the presence of a base, which is an organic base or an inorganic base, more preferably an inorganic base, and most preferably potassium hydroxide.

[0024] The reaction temperature can be 0-25℃.

[0025] The present application provides a preparation method of a compound of formula S12, which is prepared from a compound of formula S11 by removing a protecting group through imine hydrolysis,

[0026]

[0027] More preferably, the reaction is as follows:

[0028]

[0029] In the imine hydrolysis reaction, the hydrolysis reagent is an acid, which can be an organic acid or an inorganic acid, more preferably an inorganic acid, and most preferably hydrochloric acid.

[0030] The present application provides a preparation method of a compound of formula S13, which is prepared from a compound of formula S12 by further removing a protecting group through hydrolysis,

[0031]

[0032] In the hydrolysis reaction, the hydrolysis reagent is a base, such as an organic base or an inorganic base, and specifically LiOH.

[0033] A more preferred embodiment of the present application is a preparation method of an S-2,6-dimethyl tyrosine derivative, in which a compound of formula S5 or S10 is subjected to a nucleophilic substitution reaction to prepare a compound of formula S11, and then a deprotection reaction is performed to prepare the S-2,6-dimethyl tyrosine derivative,

[0034]

[0035] In summary, the synthetic route of the present application has the following technical advantages: 1. Two new compounds, a compound of formula S11 and a compound of formula S12, are provided; 2. A highly efficient new chiral phase transfer catalyst (Cat. 1, a new compound) is designed and synthesized; 3. The total yield of the prepared product S-2,6-dimethyl tyrosine derivative reaches 84%; 4. The use of the inexpensive natural compound menthol with chirality as an intermediate compound S-5 as a raw material for the chiral auxiliary makes the next step reaction have chiral induction, further improving the stereoselectivity of the generated product S11; 5. The synthetic route is simple, efficient, green and friendly, which provides a highly competitive synthesis process for the preparation of chiral amino acids, and the synthesis process can be industrialized. DETAILED DESCRIPTION

[0036] For a further understanding of the present application, the application provided by the following examples is described in detail. It should be understood that these examples are only for further detailed description of the features of the present application, but not for the limitation of the scope of the present application or the scope of the claims of the present application.

[0037] Example 1:

[0038] 27℃ (room temperature), quinine (3.24 g, 10 mmol) was added into a 500 mL three-necked round-bottom flask, and stirred under N2 protection after dissolving in 50 mL of acetone; the corresponding aryl benzyl bromide (10.5 mmol) was added, and heated to reflux in a 60℃ oil bath for 4 h; the reaction liquid was filtered under the circulation of a water pump through a 100 mL sand core funnel, and washed with an appropriate amount of acetone for 3 times, to obtain a brown filter cake cat.1 crude product; the filter cake was transferred to a 100 mL single-necked round-bottom flask, and a magnetic sonicator was added, and the slurry was stirred for 3 h, then filtered under the circulation of a water pump through a 100 mL sand core funnel, and washed with an appropriate amount of acetone for 3 times, to obtain a brown powder cat.-1 pure product; which was transferred to a 100 mL single-necked round-bottom flask and dried with a vacuum pump for standby; cat.1: 3.4 g, 55% yield. The NMR data of cat.1 is as follows:1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 9.3 Hz, 1H), 8.49-8.38 (m, 2H), 8.10 (d, J = 9.2 Hz, 1H), 8.07 (d, J = 7.7 Hz, 2H), 7.99-7.95 (m, 2H), 7.87 (d, J = 9.2 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.14-7.05 (m, 2H), 6.87 (s, 1H), 6.45 (d, J = 12.4 Hz, 1H), 6.40-6.26 (m, 1H), 5.62-5.52 (m, 1H), 5.25 (d, J = 17.2 Hz, 1H), 4.99 (dd, J = 10.6, 1.5 Hz, 1H), 4.92-4.84 (m, 1H), 4.56 (t, J = 9.5 Hz, 1H), 4.15 (d, J = 12.5 Hz, 1H), 3.76 (s, 3H), 2.96-2.89 (m, 1H), 2.77 (t, J = 11.9 Hz, 1H), 2.24 (s, 1H), 2.09-1.94 (m, 4H), 1.82 (s, 1H), 1.36-1.31 (m, 1H).

[0039] Example 2:

[0040] 26 °C (room temperature), cat. 1 (10 mol%, 1.6 mmol) was added to a 250 mL three-necked round-bottom flask; under N2protection, S5 (6.0 g, 15.9 mmol) dissolved in 48 mL of toluene, 32 ml of 50% aqueous KOH solution were added in turn, and stirred uniformly; S10 (5.8 g, 19.1 mmol) dissolved in 48 mL of toluene was slowly added dropwise in a constant temperature cold bath at -20 °C and stirred vigorously for 4 h; the sampling point plate was stopped until S5 disappeared, and the reaction was stopped; it was restored to room temperature; it was extracted with EA for 3 times, the organic phase was combined, washed with saturated aqueous sodium chloride solution for 1 time, dried with anhydrous sodium sulfate, and the solvent was rotary evaporated; a yellowish oil liquid S11 crude product was obtained, which was directly used for the next step reaction without silica gel column. 26 °C (room temperature), S11 crude product was added to a 250 mL single-necked round-bottom flask, 300 ml of THF was added and stirred; 2M HCl 150 ml was added in an ice bath at 0 °C and stirred for 2 h; the sampling point plate was stopped until S11 disappeared; under stirring conditions, the system was adjusted to pH = 10 by adding aqueous KOH solution; it was extracted with EA for 3 times, the organic phase was combined, washed with saturated aqueous sodium chloride solution for 1 time, dried with anhydrous sodium sulfate, and the solvent was rotary evaporated; a yellowish oil liquid S12 crude product was obtained, which was then passed through a silica gel column to obtain pure S12, 6.2 g, 89% yield, 99% ee. (Cat. 1 is the best catalyst) The nuclear magnetic resonance data of the compound of formula S12 is as follows:1H NMR (400 MHz, Chloroform-d) δ 7.36-7.21 (m, 5H), 6.59 (s, 2H), 4.93 (s, 2H), 4.66-4.56 (m, 1H), 3.63-3.54 (m, 1H), 3.01-2.89 (m, 1H), 2.79-2.69 (m, 1H), 2.27 (s, 6H), 1.80-1.74 (m, 1H), 1.63-1.57 (m, 2H), 1.52-1.36 (m, 3H), 1.33-1.24 (m, 1H), 1.03-0.92 (m, 1H), 0.84-0.74 (m, 7H), 0.70 (d, J = 7.0 Hz, 2H), 0.63 (d, J = 6.9 Hz, 1H).

[0041] Example 3:

[0042] 26 °C (room temperature), cat. 2 (10 mol%, 1.6 mmol) was added to a 250 mL three-necked round-bottom flask; under N2protection, S5 (6.0 g, 15.9 mmol) dissolved in 48 mL of toluene, 32 ml of 50% KOH aqueous solution were added in turn and stirred uniformly; S10 (5.8 g, 19.1 mmol) dissolved in 48 mL of toluene was slowly added dropwise in a constant temperature cold bath at -20 °C and stirred vigorously for 4 h; the sampling point plate was stopped until S5 disappeared, the reaction was stopped and returned to room temperature; extracted with EA for 3 times, the organic phase was combined and washed with saturated sodium chloride aqueous solution for 1 time, then dried with anhydrous sodium sulfate, and the solvent was rotary evaporated; a light yellow oily liquid S11 crude product was obtained, which was directly used for the next step reaction without silica gel column. 26 °C (room temperature), S11 crude product was added to a 250 mL single-necked round-bottom flask, 300 ml of THF was added for dissolution and stirring; 2M HC1 150 ml was added in an ice bath at 0 °C and stirred for 2 h; the sampling point plate was stopped until S11 disappeared; under stirring conditions, KOH aqueous solution was added to adjust the system to pH = 10; extracted with EA for 3 times, the organic phase was combined and washed with saturated sodium chloride aqueous solution for 1 time, then dried with anhydrous sodium sulfate, the solution was rotary evaporated, and dried with a vacuum pump; a light yellow oily liquid S12 crude product was obtained, which was then passed through a silica gel column to obtain pure S12, 5.2 g, 75% yield, 99% ee.

[0043] Example 4:

[0044] 26 °C (room temperature), cat. 2 (10 mol%, 1.6 mmol) was added to a 250 mL three-necked round-bottom flask; under N2protection, S5 (6.0 g, 15.9 mmol) dissolved in 48 mL of toluene, 32 ml of 50% KOH aqueous solution were added in turn and stirred uniformly; S10 (5.8 g, 19.1 mmol) dissolved in 48 mL of toluene was slowly added dropwise in a constant temperature cold bath at -20 °C and stirred vigorously for 4 h; the sampling point plate was stopped until S5 disappeared, the reaction was stopped and returned to room temperature; extracted with EA for 3 times, the organic phase was combined and washed with saturated sodium chloride aqueous solution for 1 time, then dried with anhydrous sodium sulfate, and the solvent was rotary evaporated; a light yellow oily liquid S11 crude product was obtained, which was directly used for the next step reaction without silica gel column. 26 °C (room temperature), S11 crude product was added to a 250 mL single-necked round-bottom flask, 300 ml of THF was added for dissolution and stirring; 2M HC1 150 ml was added in an ice bath at 0 °C and stirred for 2 h; the sampling point plate was stopped until S11 disappeared; under stirring conditions, KOH aqueous solution was added to adjust the system to pH = 10; extracted with EA for 3 times, the organic phase was combined and washed with saturated sodium chloride aqueous solution for 1 time, then dried with anhydrous sodium sulfate, the solution was rotary evaporated, and dried with a vacuum pump; a light yellow oily liquid S12 crude product was obtained, which was then passed through a silica gel column to obtain pure S12, 5.2 g, 75% yield, 99% ee.

[0045] Example 5:

[0046] 26°C (room temperature), cat. 4 (10 mol%, 1.6 mmol) was added to a 250 mL three-necked round-bottom flask; N2 protection, S5 (6.0 g, 15.9 mmol) dissolved in 48 mL of toluene, 32 ml of 50% aqueous KOH solution were added in turn, and stirred uniformly; -20°C constant temperature cooling hydrazine, S10 (5.8 g, 19.1 mmol) dissolved in 48 mL of toluene was slowly added dropwise and stirred vigorously for 4 h; the sample point plate to S5 disappeared, the reaction was stopped, and it was restored to room temperature; extracted with EA for 3 times, the organic phase was combined, washed with saturated aqueous sodium chloride solution once, and then dried with anhydrous sodium sulfate, and the solvent was rotary evaporated; a light yellow oily liquid S11 crude product was obtained, which was directly used for the next step reaction without silica gel column. 26°C (room temperature), S11 crude product was added to a 250 mL single-necked round-bottom flask, and 300 ml of THF was added to dissolve and stir; 0°C ice bath, 150 ml of 2M HCl was added and stirred for 2 h; the sample point plate to S11 disappeared, the reaction was stopped; under stirring conditions, the system was adjusted to pH = 10 by adding aqueous KOH solution; extracted with EA for 3 times, the organic phase was combined, washed with saturated aqueous sodium chloride solution once, and then dried with anhydrous sodium sulfate, and the solvent was rotary evaporated; a light yellow oily liquid S12 crude product was obtained, which was then passed through a silica gel column to obtain pure S12, 5.4 g, 77% yield, 99% ee.

[0047] Example 6:

[0048] 33°C, S12 obtained in the above examples 2-5 was added with 100 ml of THF and 100 ml of MeOH respectively (4 parallel experiments); 2 ml of water was added; LiOH (0.77 g, 32 mmol) was slowly added, and stirred for 24 h; the sample point plate detected that S12 disappeared, and the reaction was stopped; under stirring conditions, the reaction liquid pH = 7 was adjusted by adding dilute HCl; filtered with a sand core funnel, the filter cake was washed with EA for 3 times, the filter cake was collected, and dried to obtain pure S13 as a white solid, with a yield of: 4 g of white solid S13 was obtained when Cat. 1 was used as a catalyst, with a yield of 84% (total yield of two steps 89%*94%), a purity of 99%, and 99% ee; 3.3 g of white solid S13 was obtained when Cat. 2 was used as a catalyst, with a yield of 70% (total yield of two steps 75%*93%), a purity of 99%, and 99% ee; 3.8 g of white solid S13 was obtained when Cat. 3 was used as a catalyst, with a yield of 80% (total yield of two steps 85%*94%), a purity of 99%, and 99% ee; 3.4 g of white solid S13 was obtained when Cat. 4 was used as a catalyst, with a yield of 72% (total yield of two steps 77%*94%), a purity of 99%, and 99% ee.

[0049] The nuclear magnetic resonance data of the compound of formula S13 are as follows:1 H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.37 (m, 4H), 7.33 - 7.30 (m, 1H), 6.65 (s, 2H), 5.03 (s, 2H), 3.15 - 3.09 (m, 2H), 2.71 - 2.66 (m, 1H), 2.25 (s, 6H).

Claims

1. A compound of formula S11, ###00001### S11 characterized in that, The structural formula is: wherein R1or R2is the same phenyl.

2. A process for the preparation of a compound of formula S11 characterized in that, The compound of formula S10 is prepared by a nucleophilic substitution reaction in the presence of a chiral phase transfer catalyst, wherein R1and R2have the same definition as in claim 1, The chiral phase transfer catalyst has the structural formula:

3. The production method according to claim 2, characterized by, Further prepared by a one-step deprotection reaction to prepare formula S12 wherein R1and R2have the same definition as in claim 1.

4. A method for producing an S-2, 6-dimethyltyrosine derivative, characterized by, The compound of formula S11 is prepared by a nucleophilic substitution reaction, and then prepared by two-step deprotection reaction to prepare S-2, 6-dimethyl tyrosine derivative, 5. The production method according to claim 2 or 4, characterized by, The nucleophilic substitution reaction is carried out in the presence of a base.

6. The production method according to claim 2 or 4, characterized by, The nucleophilic substitution reaction temperature is 0-25℃.

7. The preparation method according to claim 5, characterized in that, The base is an organic base or an inorganic base.

8. The production method according to claim 3 or 4, characterized by, The deprotection step is carried out in the presence of an acid, and the reaction acid is an organic acid or an inorganic acid.

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