CN112939841A - Synthesis method of (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) butyric acid - Google Patents
Synthesis method of (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) butyric acid Download PDFInfo
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- CN112939841A CN112939841A CN202110259111.4A CN202110259111A CN112939841A CN 112939841 A CN112939841 A CN 112939841A CN 202110259111 A CN202110259111 A CN 202110259111A CN 112939841 A CN112939841 A CN 112939841A
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- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000003786 synthesis reaction 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
- UOQTXZICFVMERR-UHFFFAOYSA-N diethyl 2-ethenylcyclopropane-1,1-dicarboxylate Chemical compound CCOC(=O)C1(C(=O)OCC)CC1C=C UOQTXZICFVMERR-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 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 9
- 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
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 150000001413 amino acids Chemical class 0.000 abstract description 3
- 238000000746 purification Methods 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
- 229910052763 palladium Inorganic materials 0.000 abstract description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 2
- 229910052751 metal Inorganic materials 0.000 abstract 2
- 239000002184 metal Substances 0.000 abstract 2
- 230000008878 coupling Effects 0.000 abstract 1
- 238000010168 coupling process Methods 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- 239000000047 product Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 4
- 230000035484 reaction time Effects 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
- 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
- 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
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000001035 drying Methods 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
- 150000003839 salts Chemical class 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
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 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
- -1 metal compounds palladium acetate Chemical class 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 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
- 238000009987 spinning Methods 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-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) butyric acid. The invention solves the technical problems that the regioselective coupling synthesis of amino acid is catalyzed and protected by metal palladium, the metal catalyst palladium acetate and silver acetate reagents are expensive, most synthesis routes reported by literatures are suitable for gram-grade production, kilogram-grade production cannot be realized, and the like, and the cost is high. The synthesis method comprises the following steps: (1) 3-chloro phenethyl iodide and diphenylmethylene glycine methyl ester. (2) And (4) hydrolyzing. (3) Resolution with (+) -diacetyl-D-tartaric acid. (4) And (4) hydrolyzing the lithium hydroxide. (5) And Fmoc-OSu reaction. In the whole synthesis process, the intermediate and the target product do not need to be separated by a chromatographic column, the raw materials are cheap, and the purification is simple. The method is suitable for synthesizing the (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) butyric acid with low cost and high efficiency.
Description
Technical Field
The invention relates to synthesis of (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) butyric acid.
Background
The resistance research of protease in bioactive polypeptide drugs is very popular at present, and the introduction of phenyl halogen substituted amino acid greatly increases the drug activity, so that the amino acid is increasingly applied to polypeptide drugs. The (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) 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 arene is directly synthesized at home and abroad by a palladium-catalyzed 2-aminobutyric acid method. In the literature reported in the synthesis route of 'palladium catalytic synthesis of 2-aminobutyric acid derivatives' disclosed in Germany applied chemistry (2013, vol.125, 12374-12377), palladium acetate (10 mol%) and silver acetate (1.5 equivalent) are used as catalysts in a large amount, high temperature (100 ℃) is required, a tube sealing reaction is performed, the reaction conditions are severe, and the method is very unfavorable for kilogram-level production and industrial large-scale synthesis of the compounds; the synthetic route is as follows:
disclosure of Invention
The invention aims to provide a synthesis method of (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) butyric acid, which mainly solves the technical problems that the existing synthesis method has harsh reaction conditions and can not produce in kilogram level.
The technical scheme of the invention is as follows: a method for synthesizing (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) butyric acid comprises the following steps: step one, performing condensation reaction on 3-chloro phenethyl iodine and diphenylmethylene glycine methyl ester in N, N-dimethylformamide and potassium tert-butoxide at room temperature to obtain a compound 1, wherein the product is directly used for the next reaction without purification; secondly, adding hydrochloric acid into the compound 1 and dichloromethane, stirring at room temperature to react to obtain a compound 2, and directly using the product in the next reaction without purification; thirdly, dissolving the compound 2 in methanol, adding (+) -diacetyl-D-tartaric acid, and performing salt forming treatment to obtain a compound 3; fourthly, adding lithium hydroxide into the compound 3 and methanol for hydrolysis to obtain a compound 4; and fifthly, reacting the compound 4 in acetone and sodium hydroxide, adding Fmoc-OSu, reacting at room temperature, and acidifying by hydrochloric acid to obtain a target compound 5.
The synthesis route is as follows:
in the reaction, the reaction temperature in the step 1 is 10-30 ℃, and the preferable reaction temperature is 25 ℃; the reaction time of the step 1 is 12 to 24 hours, and the preferred reaction time is 16 hours. In 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 invention has the beneficial effects that: the synthetic route adopted by the invention has the advantages that the target compound synthesized by noble metal compounds palladium acetate and silver acetate reported in literature is abandoned, the racemate intermediate is synthesized by adopting the conventional method, and the intermediate with high chiral purity is obtained by adopting (+) -diacetyl-D-tartaric acid for resolution. In the research, the salifying reaction of various chiral raw materials is screened to obtain the optically pure chiral intermediate. 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:
to a three-necked flask was added diphenylmethylene glycine methyl ester (0.54 kg, 2.13 mol), N, N-dimethylformamide (3L); potassium tert-butoxide (0.26 kg, 2.34 mol) was added in an ice bath. The reaction solution was stirred at room temperature for 20 minutes. 3-Chloroethyl iodide (0.62 kg, 2.34 mol) was added under ice-bath and stirred at 25 ℃ for 16 hours. Water (1L) was added and extracted with ethyl acetate (1.5L x 3), the organic phases were combined and spin dried to give compound 1 (0.58 kg, 1.49 mol, 70%) as a colourless liquid which was used directly in the next reaction;
step 2:
to a three-necked flask, compound 1 (0.58 kg, 1.49 mol), water (2L) and dichloromethane (1L) were added; stirring, acidifying with 1N hydrochloric acid until pH is 2-3, and spin-drying to obtain compound 2 (0.29 kg, 1.3 mol, 87%) for use in the next reaction;
and step 3:
three-necked flask was charged with Compound 2 (0.29 kg, 1.3 mol) and methanol (1.0L), heated to 65 deg.C, charged with (+) -diacetyl-D-tartaric acid (0.26 kg, 1.1 mol), and stirred at 60 deg.C for 3 hours. Cooled to 25 ℃ and filtered to give a white solid. Water (1L), dichloromethane (2L) was added to the solid, pH =5 was adjusted with 6N hydrochloric acid, 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 Compound 3 as a white solid (0.12 kg, 0.54 mol, ee:99.1%, Yield: 84%).
And 4, step 4:
to a three-necked flask, compound 3 (0.12 kg, 0.54 mol), water (1L) and methanol (1L) were added; dropwise adding an aqueous solution of lithium hydroxide monohydrate (25 g), stirring and reacting for 2 hours, acidifying the aqueous phase by using 1N hydrochloric acid until the pH value is equal to 5-6, and spin-drying to obtain a compound 4 which is directly used for the next reaction;
and 5:
compound 4 (0.54 mol), acetone (1L), water (1L) were added to a three-necked flask, followed by sodium bicarbonate (54 g, 0.65 mol) and Fmoc-OSu (182 g, 0.54 mol). The reaction solution was stirred at room temperature for 12 hours while controlling pH to 9.5 with 4N sodium hydroxide. Petroleum ether extraction (200 mL x 3); the aqueous phase was acidified to pH 3 with 1N hydrochloric acid, extracted with ethyl acetate (200 mL x 3), the organic phases combined, washed with saturated brine (150 mL), dried over sodium sulfate and filtered. The filtrate was dried by spinning to give title compound 5 (208 g, 0.48 mol, 88%, Pu:98%, ee: 99%) as a white solid.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 reaction temperature was 10 ℃; step 1, the reaction time is 24 hours; the rest is the same as example 1.
Example 3, step 1 reaction temperature was 30 ℃; step 1, the reaction time is 12 hours; the rest is the same as example 1.
Claims (3)
1. A method for synthesizing (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorphenyl) butyric acid is characterized by comprising the following steps: step one, performing condensation reaction on 3-chloro phenethyl iodide and diphenylmethylene glycine methyl ester at room temperature to obtain a compound 1; secondly, adding hydrochloric acid into the compound 1 and dichloromethane for hydrolysis to obtain a compound 2; thirdly, resolving the compound 2 and (+) -diacetyl-D-tartaric acid to obtain a compound 3; fourthly, adding lithium hydroxide into the compound 3 and methanol for hydrolysis to obtain a compound 4; fifthly, adding Fmoc-OSu into the compound 4 in acetone and sodium hydroxide for reaction, and acidifying by hydrochloric acid to obtain a target compound 5; the synthesis route is as follows:
2. the method for synthesizing (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorophenyl) butanoic acid as claimed in claim 1, wherein in the first step, the reaction is carried out at 10-30 ℃ for 12-24 hours with stirring.
3. The method for synthesizing (2S) -2-N-fluorenylmethoxycarbonylamino-4- (3-chlorophenyl) butanoic acid according to claim 1, wherein in the fifth step, the pH of the reaction solution is controlled to 9.0 to 10.0 with 4N sodium hydroxide.
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| CN202110259111.4A CN112939841B (en) | 2021-03-10 | 2021-03-10 | Synthesis method of (2S) -2-N-fluorenylmethoxycarbonyl amino-4- (3-chlorophenyl) butyric acid |
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| 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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| 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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