CN111170892A - Synthesis method of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) - Google Patents
Synthesis method of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) Download PDFInfo
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- CN111170892A CN111170892A CN202010069240.2A CN202010069240A CN111170892A CN 111170892 A CN111170892 A CN 111170892A CN 202010069240 A CN202010069240 A CN 202010069240A CN 111170892 A CN111170892 A CN 111170892A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
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Abstract
The invention relates to a synthetic method of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester). Mainly solves the technical problem of racemization of products in the existing synthetic method and the problem of scale-up production. The method comprises four steps of synthesis, wherein in the first step, a raw material A is dissolved in tetrahydrofuran, cesium carbonate is added, and methyl iodide is added to obtain a compound 1, and a product is directly used for the next reaction without purification; secondly, introducing hydrogen into the compound 1 in methanol at room temperature for reaction, and catalyzing by palladium-carbon to obtain a compound 2; thirdly, dissolving the compound 2 in methanol, adding L- (-) -diacetyl tartaric acid, and carrying out salt formation treatment to obtain a compound 3, wherein ee is more than 99%; and fourthly, reacting the compound 3 in acetone and sodium hydroxide, then adding Fmoc-OSu for reaction, and acidifying by hydrochloric acid to obtain a target compound 4.
Description
Technical Field
The invention relates to the synthesis of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) (CAS: 152548-66-8).
Background
N-methyl amino acids are present in a variety of natural peptides and have a variety of biological effects, including antibacterial, anticancer, antiviral, and immunosuppressive effects. The binding of N-methyl amino acids to biologically active peptides alters their chemical and physical properties and can thus provide important information about the conformation of the scaffold. Peptide-containing N-methyl amino acids exhibit potent therapeutic properties and are increasingly recognized as potentially useful therapeutic approaches. At present, the compounds are widely reported, wherein the ratio of a line 1: the synthesis of N-methyl amino acids by this method is used in large amounts in the literature reported in the synthetic route of organic chemistry (48 (1983) 77-81) "Synthesis of Fmoc-protected N-methyl amino acids by reduction of oxazolidinones", and cannot be used for the synthesis of the compounds of the invention.
Synthetic scheme 1 reaction scheme:
line 2: in organic chemistry (70 (2005) 5183-5189) "a convenient N methyl amino acid synthesis method in Fmoc solid phase Synthesis" the amino group is protected by o-nitrobenzenesulfonyl chloride in the literature reported by the synthetic route, and dimethyl sulfate is used as N methyl, and is not suitable for industrial use because the dimethyl sulfate is a highly toxic product.
Synthetic scheme 2 reaction scheme:
disclosure of Invention
The invention aims to provide a synthetic method of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester), which mainly solves the problems of the existing synthetic method that the raw materials are extremely toxic and racemization occurs in the synthetic process of the compound, and adopts simple and easily obtained raw materials and a chemical salt-forming method to obtain an intermediate with high chiral purity.
The technical scheme of the invention is as follows: a synthetic method of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) comprises the following steps: firstly, dissolving a raw material A in tetrahydrofuran, adding cesium carbonate, and then adding methyl iodide to obtain a compound 1, wherein the product is directly used for the next reaction without purification; secondly, introducing hydrogen into the compound 1 in methanol at room temperature for reaction, and catalyzing by palladium-carbon to obtain a compound 2; thirdly, dissolving the compound 2 in methanol, adding L- (-) -diacetyl tartaric acid, and carrying out salt forming treatment to obtain a compound 3; fourthly, reacting the compound 3 in acetone and sodium hydroxide, then adding Fmoc-OSu for reaction, and acidifying by hydrochloric acid to obtain a target compound 4, wherein the synthetic route is as follows:
in the reaction, the reaction temperature in the step 1 is 25-35 ℃, and the preferable reaction temperature is 30 ℃; the reaction time of the step 1 is 12 to 24 hours, and the preferable reaction time is 18 hours; the reaction temperature of the step 3 is 50-70 ℃, and the preferable reaction temperature is 65 ℃; step 4, after adding sodium hydroxide, the pH is controlled to 9.0-10.0, preferably 9.5.
The abbreviations used in the present invention have the following meanings: Fmoc-Osu: fluorenylmethoxycarbonyl succinimide.
The invention has the beneficial effects that: the synthetic route adopted by the invention has the advantages of solving the problems that the conventional method reported in the literature cannot synthesize the product and the raw materials for scale-up production are limited. In the research, racemization of a reaction intermediate is found, and an optically pure chiral intermediate is obtained by screening salifying reaction of various chiral raw materials. The route solves the problem of kilogram-level production of the product, and provides an effective solution for the synthesis of similar compounds, and the synthesis method is environment-friendly. And the product in the third step is subjected to salt forming treatment to achieve ee of more than 99%, the used reagent is cheap, the reaction conditions are simple, and the target product and the intermediate are not required to be purified by a chromatographic column.
Detailed Description
Example 1: the synthetic route is as follows:
step 1:
a three-necked flask was charged with raw material A (1.1 kg, 2.66 mol), tetrahydrofuran (5L); cooled to 0 ℃ with ice water, cesium carbonate (1.3 kg, 3.99 mol) was added. The reaction mixture was stirred at 0 ℃ for 30 minutes. Methyl iodide (332 mL,5.33 mol) was then added and the mixture was stirred at 30 ℃ for 18 hours. Ethyl acetate (3L) was added, filtered, the organic phase was added with saturated sodium thiosulfate (5L), stirred for 30 minutes, and the organic phase was washed with saturated sodium chloride (1L x 2). The organic phase was dried over sodium sulfate and filtered. The filtrate was spin-dried to give a yellow liquid, Compound 1 (1.21 kg, 2.83 mol, Yield: 106%) which was used directly in the next reaction;
step 2:
into a three-necked flask, Compound 1 (0.9 kg, 2.11 mol) and methanol (2.5L) were charged and then target carbon (containing 10% by weight of palladium, 90 g) was added, and hydrogen gas was introduced and the mixture was stirred at 30 ℃ for 6 hours. Filtration and spin-drying of the filtrate gave compound 2 as a white solid (0.4 kg, 1.97 mol, ee:87%, Yield: 93%). Directly used for the next reaction;
and step 3:
compound 2 (0.728 kg, 3.58 mol) and methanol (3.5L) were added to a three-necked flask, heated to 65 ℃ and stirred at 60 ℃ for 3 hours with the addition of L- (-) -diacetyltartaric acid (0.626 kg, 3.22 mol). Cooled to 25 ℃ and filtered to give a white solid. Water (5L), dichloromethane (10L) was added to the solid, pH =2 was adjusted with 6N hydrochloric acid, and the organic phase was washed with saturated sodium chloride (1 Lx 2). The organic phase was dried over sodium sulfate and filtered. The filtrate was spin-dried to give Compound 3 as a white solid (0.507 kg, 2.49mol, ee:99.7%, Yield: 69%).
And 4, step 4:
compound 3 (1.19 kg, 5.86 mol), acetone (5L), water (5L) and then sodium hydroxide (0.281 kg, 7.03 mol) and Fmoc-OSu (1.974 kg, 5.86 mol) were added to a three-necked flask, and the reaction solution was stirred with 4N sodium hydroxide at pH 9.5 at 30 ℃ for 12 hours. Petroleum ether extraction (0.5L x 3); the aqueous phase is acidified to pH 2 with 1N hydrochloric acid, extracted with ethyl acetate (0.5L x 3), the organic phases are combined, washed with saturated brine (1L), dried over sodium sulfate and filtered. The filtrate was spin-dried to give the objective compound 4 (2.23 kg, 5.24 mol, Yield: 89.5%, Pu:99%, ee: 99.5%).1H NMR (400 MHz, DMSO, ppm) 1.35-1.39, (m,9 H), 2.49, (m, 1 H), 2.50(s,3 H) ,2.78 (m, 1 H), 4.24-4.36 (m, 3H), 4.74-4.88(m, 1 H), 7.30-7.34(m, 2H) ,7.40-7.42(m, 2 H) ,7.62-7.65(m, 2 H), 7.89-7.91(m, 2 H), 13.00(s, 1 H)。
Example 2, the reaction temperature of step 1 is 25 ℃, the stirring reaction is carried out for 24 hours, and the reaction temperature of step 3 is 55 ℃; step 4 the pH was controlled to 9.0 after the addition of sodium hydroxide, as in example 1.
Example 3, the reaction temperature of step 1 was 35 ℃ and the reaction was carried out with stirring for 12 hours; step 3, the reaction temperature is 70 ℃; step 4 the pH was controlled to 10 after the addition of sodium hydroxide, as in example 1.
Claims (4)
1. A synthetic method of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) is characterized in that: comprises the following steps: firstly, dissolving a raw material A in tetrahydrofuran, adding cesium carbonate, and then adding methyl iodide to obtain a compound 1, wherein the product is directly used for the next reaction without purification; secondly, introducing hydrogen into the compound 1 in methanol at room temperature for reaction, and catalyzing by palladium-carbon to obtain a compound 2; thirdly, dissolving the compound 2 in methanol, adding L- (-) -diacetyl tartaric acid, and carrying out salt forming treatment to obtain a compound 3; fourthly, reacting the compound 3 in acetone and sodium hydroxide, then adding Fmoc-OSu for reaction, and acidifying by hydrochloric acid to obtain a target compound 4, wherein the synthetic route is as follows:
2. the method for synthesizing N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) as claimed in claim 1, wherein the method comprises the following steps: in the first step, the reaction temperature is controlled to be 25-35 ℃, and the stirring reaction is carried out for 12-24 hours.
3. The method for synthesizing N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) as claimed in claim 1, wherein the method comprises the following steps: and the third step is to control the reaction temperature to be 50-70 ℃.
4. The process for synthesizing N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) according to claim 1, wherein the pH is controlled to 9.0 to 10.0 after the sodium hydroxide is added in the fourth step.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112939841A (en) * | 2021-03-10 | 2021-06-11 | 康化（上海）新药研发有限公司 | Synthesis method of (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) butyric acid |
| CN114920669A (en) * | 2022-06-28 | 2022-08-19 | 吉尔多肽生物制药(大连市)有限公司 | Synthesis method of N-methyl-N-benzyloxycarbonyl-L-aspartic acid (4-tert-butyl ester) dicyclohexylamine salt |
| CN115260060A (en) * | 2022-09-07 | 2022-11-01 | 康化（上海）新药研发有限公司 | Synthesis method of (2S) -2-N-fluorenylmethoxycarbonylamino-5, 5-dimethyl norleucine |
| CN112939841B (en) * | 2021-03-10 | 2024-06-07 | 康化（上海）新药研发有限公司 | Synthesis method of (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid |
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| CN110015978A (en) * | 2019-04-29 | 2019-07-16 | 康化（上海）新药研发有限公司 | O- [2- [[tertbutyloxycarbonyl] amino] ethyl]-N- [fluorenylmethyloxycarbonyl]-l-tyrosine synthetic method |
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| CN110015978A (en) * | 2019-04-29 | 2019-07-16 | 康化（上海）新药研发有限公司 | O- [2- [[tertbutyloxycarbonyl] amino] ethyl]-N- [fluorenylmethyloxycarbonyl]-l-tyrosine synthetic method |
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| LIHU YANG ET AL.: "Solid Phase Synthesis of Fmoc N-Methyl Amino Acids:Application of the Fukuyama Amine Synthesis", 《TETRAHEDRON LETTERS》 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112939841A (en) * | 2021-03-10 | 2021-06-11 | 康化（上海）新药研发有限公司 | Synthesis method of (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) butyric acid |
| CN112939841B (en) * | 2021-03-10 | 2024-06-07 | 康化（上海）新药研发有限公司 | Synthesis method of (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid |
| CN114920669A (en) * | 2022-06-28 | 2022-08-19 | 吉尔多肽生物制药(大连市)有限公司 | Synthesis method of N-methyl-N-benzyloxycarbonyl-L-aspartic acid (4-tert-butyl ester) dicyclohexylamine salt |
| CN115260060A (en) * | 2022-09-07 | 2022-11-01 | 康化（上海）新药研发有限公司 | Synthesis method of (2S) -2-N-fluorenylmethoxycarbonylamino-5, 5-dimethyl norleucine |
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