CN112939841B - Synthesis method of (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid - Google Patents
Synthesis method of (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- DNISEZBAYYIQFB-WDSKDSINSA-N (2s,3s)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-WDSKDSINSA-N 0.000 claims abstract description 5
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 claims abstract description 4
- MSBUMXMENVPWGC-UHFFFAOYSA-N 1-chloro-3-(2-iodoethyl)benzene Chemical compound ClC1=CC=CC(CCI)=C1 MSBUMXMENVPWGC-UHFFFAOYSA-N 0.000 claims abstract description 3
- SRJQBBLGTWTOEB-UHFFFAOYSA-N 2-(benzhydrylazaniumyl)acetate Chemical compound C=1C=CC=CC=1C(NCC(=O)O)C1=CC=CC=C1 SRJQBBLGTWTOEB-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 229940125904 compound 1 Drugs 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 abstract description 3
- 229940071536 silver acetate Drugs 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- -1 methylene diphenylglycine methyl ester Chemical compound 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid. The invention solves the technical problems that the metal catalyst palladium acetate and silver acetate reagent are expensive, most of synthetic routes are suitable for gram-scale production, kilogram-scale production is impossible, and the like, and the cost is high. The synthesis method comprises the following steps: (1) 3-chlorophenethyl iodide and benzhydryl glycine methyl ester. (2) hydrolysis. (3) resolution with (+) -diacetyl-D-tartaric acid. And (4) hydrolyzing lithium hydroxide. (5) and Fmoc-OSu reactions. In the whole synthesis process, the intermediate and the target product are not required to be separated by a chromatographic column, the raw materials are cheap, and the purification is simple. The invention is suitable for synthesizing (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid with low cost and high efficiency.
Description
Technical Field
The invention relates to synthesis of (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid.
Background
The research on the resistance of protease in bioactive polypeptide drugs is very hot at present, and the introduction of phenyl halogen substituted amino acid greatly increases the activity of the drugs, so that the amino acid is increasingly applied to the polypeptide drugs. The (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid is used as an important raw material for synthesizing the polypeptide and is widely applied to medical intermediates. 2-aminobutyric acid of 4-site aromatic hydrocarbon is synthesized by directly using a palladium-catalyzed 2-aminobutyric acid method at home and abroad. Among them, palladium acetate (10. 10 mol%) and silver acetate (1.5 eq.) are used as catalysts in large quantities in the literature reported in the "palladium catalyzed synthesis of 2-aminobutyric acid derivatives" synthetic route disclosed in the German application chemistry (2013, vol.125, 12374-12377), high temperature (100 ℃) is required for tube sealing reaction, and the reaction conditions are severe, which is very unfavorable for kilogram-level production and industrialized large-scale synthesis of such compounds; the synthetic route is as follows:
。
Disclosure of Invention
The invention aims to provide a synthesis method of (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid, which mainly solves the technical problems that the existing synthesis method is harsh in reaction conditions and cannot be used for kilogram-level production. The technical scheme of the invention is as follows: a method for synthesizing (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid, comprising the following steps: the first step, 3-chlorophenethyl iodide and benzhydryl glycine methyl ester are subjected to condensation reaction in N, N-dimethylformamide and potassium tert-butoxide at room temperature to obtain a compound 1, and the product is directly used for the next reaction without purification; secondly, adding hydrochloric acid into dichloromethane in the compound 1, stirring at room temperature, and reacting to obtain a compound 2, wherein the product is directly used for the next reaction without purification; thirdly, dissolving the compound 2 in methanol, adding (+) -diacetyl-D-tartaric acid, and carrying out salification treatment to obtain a compound 3; fourthly, adding lithium hydroxide into methanol for hydrolysis of the compound 3 to obtain a compound 4; and fifthly, reacting the compound 4 in acetone and sodium hydroxide, then adding Fmoc-OSu, reacting at room temperature, and acidifying by hydrochloric acid to obtain the target compound 5. The synthetic route is as follows:
In the above reaction, the reaction temperature in the step 1 is 10-30 ℃, preferably 25 ℃; the reaction time in step 1 is 12 to 24 hours, preferably 16 hours. The fifth step, the pH value of the reaction solution is controlled to be 9.0-10.0 by using 4N sodium hydroxide; the pH is preferably controlled to 9.5. The beneficial effects of the invention are as follows: the synthesis route adopted by the invention has the advantages that a target compound is synthesized by noble metal compounds of palladium acetate and silver acetate, which are reported in the literature, is abandoned, a raceme intermediate is synthesized by adopting a conventional method, and the intermediate with high chiral purity is obtained by adopting (+) -diacetyl-D-tartaric acid resolution. In the research, the optically pure chiral intermediate is obtained by screening salt forming reactions of various chiral raw materials. The route solves the kilogram-level production problem of the product, provides an effective solution for the synthesis of similar compounds, and is environment-friendly. And the third step of salifying to reach ee >99%, the reagent is cheap, the reaction condition is simple, and the target product and the intermediate do not need chromatographic column purification.
Detailed Description
Example 1: the synthetic route is as follows:
Step 1: to a three-necked flask was added methylene diphenylglycine methyl ester (0.54 kg, 2.13 mol), N-dimethylformamide (3L); potassium tert-butoxide (0.26 kg, 2.34, mol) was added to the ice bath. The reaction solution was stirred at room temperature for 20 minutes. 3-Chloroethyl iodide (0.62 kg, 2.34: 2.34 mol) was added in ice bath and stirred at 25℃for 16 hours. Adding water (1L), extracting with ethyl acetate (1.5L x 3), mixing organic phases, and spin-drying to obtain colorless liquid compound 1 (0.58 kg,1.49 mol, 70%) which is directly used for the next reaction; step 2: to a three-necked flask, compound 1 (0.58 kg,1.49 mol), water (2L) and methylene chloride (1L) were charged; stirring, acidifying with 1N hydrochloric acid until the pH is equal to 2-3, and spin-drying to obtain compound 2 (0.29 kg, 1.3 mol, 87%) which is directly used for the next reaction; step 3: compound 2 (0.29 kg, 1.3 mol) and methanol (1.0L) were added to a three-necked flask, heated to 65 ℃, and (+) -diacetyl-D-tartaric acid (0.26 kg, 1.1 mol) was added thereto and stirred at 60 ℃ for 3 hours. Cooled to 25 ℃ and filtered to give a white solid. Water (1L), dichloromethane (2L) and ph=5 with 6N hydrochloric acid are added to the solid and the organic phase is washed with saturated sodium chloride (1L x 2). The organic phase was dried over sodium sulfate and filtered. The filtrate was dried by spin to give compound 3 (0.12 kg, 0.54: 0.54 mol, ee:99.1%, yield: 84%) as a white solid. Step 4: compound 3 (0.12 kg, 0.54, mol), water (1L) and methanol (1L) were added to a three-neck flask; dropwise adding an aqueous solution of lithium hydroxide monohydrate (25 g), stirring and reacting for 2 hours, acidifying the aqueous phase with 1N hydrochloric acid until the pH is equal to 5-6, and spin-drying to obtain a compound 4, wherein the compound 4 is directly used for the next reaction; step 5: to a three-necked flask, compound 4 (0.54 mol), acetone (1L), water (1L) and then sodium bicarbonate (54 g,0.65 mol) and Fmoc-OSu (182 g,0.54 mol) were added. The reaction solution was stirred at room temperature for 12 hours while controlling pH 9.5 with 4N sodium hydroxide. Petroleum ether extraction (200 mL x 3); the aqueous phase was acidified with 1N hydrochloric acid to pH 3, extracted with ethyl acetate (200 mL. Times.3), the organic phases combined, washed with saturated brine (150 mL), dried over sodium sulfate and filtered. Spin-drying the filtrate to obtain white solid, wherein the reaction temperature of the target compound 5 （208 g, 0.48 mol, 88 %, Pu:98%, ee:99%）.1H NMR (400 MHz, DMSO-d6) 1.99, (m, 2 H), 2.68, (m, 2 H), 3.89 (m, 1H) , 4.25-4.36 (m, 3H), 7.15-7.44(m, 8H), 7.73-7.76(m, 3 H) ,7.89(m, 2 H) , 12.66(s, 1 H) ppm., example 2, step 1 is 10 ℃; the reaction time of the step 1 is 24 hours; the procedure is as in example 1. Example 3, step 1 reaction temperature was 30 ℃; the reaction time of the step 1 is 12 hours; the procedure is as in example 1.
Claims (3)
1. A method for synthesizing (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid is characterized by comprising the following steps: firstly, carrying out condensation reaction on 3-chlorophenethyl iodide and benzhydryl glycine methyl ester at room temperature to obtain a compound 1; step two, adding hydrochloric acid into dichloromethane to hydrolyze the compound 1 to obtain a compound 2; thirdly, dissolving the compound 2 in methanol, adding (+) -diacetyl-D-tartaric acid, and carrying out salification treatment to obtain a compound 3; fourthly, adding lithium hydroxide into methanol for hydrolysis of the compound 3 to obtain a compound 4; fifthly, adding Fmoc-OSu into acetone and sodium hydroxide to react, and acidifying the compound 4 by hydrochloric acid to obtain a target compound 5; the synthetic route is as follows:
。
2. The method for synthesizing (2S) -2-N-fluorenylmethoxycarbonyl-amino-4- (3-chlorophenyl) butanoic acid according to claim 1, wherein the first step is performed at 10 to 30℃with stirring for 12 to 24 hours.
3. The method for synthesizing (2S) -2-N-fluorenylmethoxycarbonyl-amino-4- (3-chlorophenyl) butanoic acid according to claim 1, wherein the reaction solution in the fifth step is controlled to have a pH of 9.0 to 10.0 with 4N sodium hydroxide.
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| CN114689737B (en) * | 2021-12-31 | 2023-12-08 | 浙江车头制药股份有限公司 | Analysis method of S-o-chlorophenylglycine methyl tartrate related substances |
| 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 |
| CN116606223A (en) * | 2023-05-26 | 2023-08-18 | 康化（上海）新药研发有限公司 | Synthesis method of (2S) -2-N-fluorenylmethoxycarbonyl amino-6, 6-dimethyl N-heptanoic acid |
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