CN101250172B - Arginine double-protective preparation technique - Google Patents

Arginine double-protective preparation technique Download PDF

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CN101250172B
CN101250172B CN2008100343909A CN200810034390A CN101250172B CN 101250172 B CN101250172 B CN 101250172B CN 2008100343909 A CN2008100343909 A CN 2008100343909A CN 200810034390 A CN200810034390 A CN 200810034390A CN 101250172 B CN101250172 B CN 101250172B
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arginine
pentamethyl
alkylsulfonyl
dihydrofuran
fluorenylmethyloxycarbonyl
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CN101250172A (en
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马士忠
刘焕书
高仰哲
吴法浩
刘明军
诸斌
许玉东
李竹良
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Shanghai Hanhong Technology Co ltd
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SHANGHAI HANHONG CHEMICAL INDUSTRY Co Ltd
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a dual-protection preparation method of arginine, belonging to the pharmaceutical chemical engineering technical field, in particular to a N<G>-(2, 2, 4, 6, 7-pentamethylbenzene propyl dihydrofuran-5-sulfonyl)-N<alpha>-(9-fluorenylmethoxycarbonyl)-arginine. The invention introduces N<G>-(2, 2, 4, 6, 7-pentamethylbenzenepropyl dihydrofuran-5-sulfonyl) protective group into Boc-Arg-OH, namely N<G>-pbf protective group, to prepare N<alpha>-boc-NG-(2, 2, 4, 6, 7-pentamethylbenzenepropyl dihydrofuran-5-sulfonyl)-arginine and removes alpha protective group in saturated hydrogen chloride ethanol solution, thereby avoiding expensive catalyst as palladium-charcoal and catalytic hydrogenolysis. The removal of alpha protective group is simple, the conditions are easy to control, the operability is strong and the production cost is low, therefore, the invention is suitable for industrial production, in addition, the invention avoids palladium-charcoal and catalytic hydrogenolysis, thereby reducing environment pollution. The total yield of the invention can reach 63.51% (referring to L-arginine) and product content is higher than 99.0%.

Description

Arginine double-protective preparation technique
Technical field
Arginine double-protective preparation technique of the present invention belongs to pharmaceutical chemistry technical field.Be specifically related to a kind of N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-l-arginine is (hereinafter to be referred as the preparation method of Fmoc-Arg (pbf)-OH).
Background technology
The amino acid whose method of the two protections of existing preparation Fmoc-Arg (pbf)-OH, as: (application number: 200410018114.5), this patent proposes by 2 the preparation patented process of being invented by people such as Xu Yunsheng, Pueraria lobota nation wheels; 2; 4,6,7-pentamethyl-benzo dihydrofuran--5-SULPHURYL CHLORIDE and N α-carbobenzoxy-(Cbz) L-l-arginine carries out condensation reaction with pyridine as acid binding agent and obtains N in the non-aqueous solvent system of HMPA α-carbobenzoxy-(Cbz)-N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl) L-l-arginine with 10% palladium-Pd/carbon catalyst catalytic hydrogenolysis, obtains N G(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl) L-l-arginine carries out phase-transfer-catalyzed reactions with N-(9-fluorenylmethyloxycarbonyl oxygen) succinimide again and obtains purpose product Fmoc-Arg (pbf)-OH.The Hu Qiaofei of East China Normal University is in its paper " technical studies of the two protections of several seed amino acids ", by N α-carbobenzoxy-(Cbz) L-l-arginine introduces 2,2,4,6, adopts during 7-pentamethyl-benzo dihydrofuran--5-sulfonyl group to add phase-transfer catalyst tetraethyl-amine bromide (TEBA) and obtain N α-carbobenzoxy-(Cbz)-N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl) L-l-arginine spends the night with logical hydrogen under 10% palladium-50 ℃ of conditions of Pd/carbon catalyst, the elimination catalyzer, and removal of solvent under reduced pressure obtains N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl) L-l-arginine reacts with N-(9-fluorenylmethyloxycarbonyl oxygen) succinimide and obtains purpose product Fmoc-Arg (pbf)-OH.Above-mentioned two kinds of preparing methods have used palladium catalyst-charcoal and hydrogenolysis process when removing alpha-amino group and protect basic carbobenzoxy-(Cbz); Palladium-Pd/carbon catalyst costs an arm and a leg on the one hand; Cause production cost high, complex operation step such as catalytic hydrogenolysis on the other hand, unfavorable industrializing implementation.
Summary of the invention:
The objective of the invention is to overcome above-mentioned shortcoming in the prior art, provide a kind of arginine double-protective new preparation method, reach and reduce production costs, the step that simplifies the operation satisfies the suitability for industrialized production needs.
For realizing above-mentioned purpose, the present invention implements like this: a kind of N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-arginine double-protective preparation technique, its reaction formula is:
Figure GSB00000664922600021
Figure GSB00000664922600031
Wherein:
In the step 1, l-arginine or its salt are dissolved in the solvent, are cooled to-50 ℃～50 ℃, add t-butoxycarbonyl protecting group, obtain material I:N after the reaction α-tertbutyloxycarbonyl-l-arginine or N α-tertbutyloxycarbonyl-arginic acid salt;
In the step 2, material I is dissolved in the solvent, is cooled to-15～15 ℃; Regulate pH value 5～13 with 5%～25% sodium hydroxide solution, in addition, with 2; 2,4,6; 7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl blocking group joins in the solvent, adds aforesaid sodium hydroxide solution then, obtains material II:N-tertbutyloxycarbonyl-N after the reaction G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-l-arginine;
Three, with N-tertbutyloxycarbonyl-N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-l-arginine is dissolved in the acidic solution, reacts 1～15 hour down at-20～20 ℃, removes t-butoxycarbonyl protecting group, obtains N after the reaction G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-l-arginine;
Four, with N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-l-arginine is dissolved in the solvent, adds the fluorenylmethyloxycarbonyl blocking group under the condition of ice bath, obtains purpose product N after the reaction G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-l-arginine.
On the such scheme basis, described l-arginine and salt thereof are a kind of among L-l-arginine, D-l-arginine, DL-l-arginine, L-arginine monohydrochloride, D-arginine monohydrochloride, DL-arginine monohydrochloride, L-l-arginine vitriol, D-l-arginine vitriol and the DL-l-arginine vitriol.
In above-mentioned second step, described solvent is one or more the mixing in dioxane, dioxane-water, acetone, acetone-water, THF and the THF-water.
Described 2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl blocking group is 2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-SULPHURYL CHLORIDE.
In above-mentioned third step, described acidic solution is a kind of among sulphuric acid soln, hydrogenchloride ethanol, hydrogenchloride propyl alcohol, hydrogenchloride isopropylcarbinol, hydrogenchloride formic acid second fat, hydrogenchloride methyl formate, hydrogenchloride ethyl acetate and the hydrogenchloride methyl acetate of saturated citric acid solution, 0.1～1.0M.
On the such scheme basis, described fluorenylmethyloxycarbonyl blocking group is fluorenes methoxy carbonyl acyl succinimide or fluorenes methoxy dicarbonyl chloride.
Further, the present invention: a kind of N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-arginine double-protective preparation technique is that the arginic mono-hydrochloric salts of L-is added (water: dioxane=1: 1), add (Boc) in 1: 1～1.5 ratios in entry and the dioxane mixed solution according to 1: 1.4～1.6 ratio 2O stirs and constantly to drip the 4N sodium hydroxide solution down, control PH=9-10, and clear and pH value remains unchanged until the solution becomes orange, reacts 2～3 hours again.Pressure reducing and steaming dioxane (50 ℃ of water-baths), add entry dilution after, with cold 3N hydrochloric acid accent PH=4～5, anhydrous diethyl ether extracts (2 * 25mL) removal of impurities under ice bath.Water continues to transfer PH=2～3 with 3N hydrochloric acid, and crystallisation by cooling gets white solid, i.e. N α-tertbutyloxycarbonyl-L-l-arginine. hydrochloride.
Under condition of ice bath (15～15 ℃), with N α-tertbutyloxycarbonyl-L-l-arginine. hydrochloride, promptly Boc-Arg-OH.HCl regulates PH=5～13 according in 1: 6～7 the ratio adding dioxane solution with 5～25% sodium hydroxide solutions.Pbf-Cl is dissolved in the dioxane solution according to 1: 4～5 ratio, is added drop-wise to N under the condition of ice bath then α-tertbutyloxycarbonyl-L-l-arginine. in the hydrochloride dioxane mixed solution.Dropwise and rise to room temperature condition reaction 3～4 hours.Reaction finishes decompression and removes dioxane, and cool to room temperature is transferred PH=3～4 with saturated aqueous citric acid solution, gets yellow oil.Yellow oil adds the ethyl acetate extraction, and standing demix obtains organic phase and water, merges organic phase, and water and saturated brine be washing alternately; Until solution PH=5～6, use anhydrous sodium sulfate drying then, be concentrated into driedly after the filtration, add sherwood oil; Fully stir, filter, oven dry obtains N α-tertbutyloxycarbonyl-N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl) L-l-arginine, i.e. N α-Boc-Arg (pbf)-OH.
Under-20～20 ℃ of conditions, with N α-Boc-Arg (pbf)-OH according to 1: 5～6 ratio with saturated hydrogenchloride dissolve with ethanol, insulation reaction 1～15 hour.Reaction finishes to regulate PH=3～4 with 5～25% sodium hydroxide, and standing demix gets organic phase and water, and organic phase is repeatedly washed, and merges water, continues adjusting PH=7～8 with 5～25% sodium hydroxide, is cooled to 0～10 ℃, crystallization, filter N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-L-l-arginine, i.e. Arg (pbf)-OH.
Arg (pbf)-OH is added in 10% sodium carbonate solution and the dioxane according to 1: 1～2 ratio, be cooled to-5～0 ℃ then; With N-(9-fluorenylmethyloxycarbonyl oxygen) succinimide, promptly Fmoc-OSu joins in the dioxane according to 1: 8～9 ratio, and is added drop-wise in the previous reaction system; Ice bath reacted 1～2 hour down, and room temperature reaction is 2～3 hours again, and extracted with diethyl ether is removed impurity; Saturated Hydrocerol A is regulated PH=3～4, with the ethyl acetate extraction, tells organic phase and water; Merge the washing of organic phase and water and saturated brine, anhydrous magnesium sulfate drying filters; Most of solvent is removed in underpressure distillation, adds normal hexane and separates out white products N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-L-l-arginine, i.e. Fmoc-Arg (pbf)-OH.
The present invention compares with existing like product working method, and advantage applies exists: because Boc-Arg-OH of the present invention introduces N G-2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl blocking group, i.e. N G-pbf blocking group prepares N α-tertbutyloxycarbonyl-N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-l-arginine removes α position protection base then in the hydrogenchloride alcohol saturated solution, avoid the use of expensive catalyst palladium-charcoal and catalytic hydrogenolysis operating process.The present invention takes off the α position and protects basic process simple, and condition is easy to control, and workable, production cost is low, is convenient to realize suitability for industrialized production; Owing to avoided palladium-charcoal and catalytic hydrogenolysis process, greatly reduce environmental pollution on the other hand.Overall yield of reaction of the present invention reaches 63.51% (in the L-l-arginine), product content >=99.0%.
Embodiment:
Embodiment 1:
(water: dioxane=1: 1) add 250mL and be furnished with in the churned mechanically there-necked flask, in the mixed solution with the arginic mono-hydrochloric salts of 20gL-and 30g water and dioxane then with 26.5g (Boc) 2O adds in the mixed solution, stirs constantly to drip the 4N sodium hydroxide solution down, and control PH=9-10, clear and pH value remains unchanged until the solution becomes orange, reacts 2～3 hours again.Pressure reducing and steaming dioxane (50 ℃ of water-baths) after the dilution of adding 17mL water, is transferred PH=4～5 with cold 3N hydrochloric acid, anhydrous diethyl ether extraction (2 * 25mL) removal of impurities to doing under ice bath.Water continues to transfer PH=2～3 with 3N hydrochloric acid, and crystallisation by cooling gets white solid, i.e. N α-tertbutyloxycarbonyl-L-l-arginine. hydrochloride 26.2g, yield 88.50%.
Get 20g N α-tertbutyloxycarbonyl-L-l-arginine. hydrochloride and 140mL dioxane add 500mL to be furnished with in the churned mechanically there-necked flask, is placed on (5～0 ℃) under the condition of ice bath, and startup mixes.Under the agitation condition, regulate PH=10～12 of mixed solution with 10% sodium hydroxide solution.The dioxane adding 250mL of 34.5gPbf-Cl and 140mL is furnished with in the churned mechanically there-necked flask, is stirred to dissolving fully.Under condition of ice bath, the Pbf-Cl-dioxane solution for preparing is added drop-wise to N α-tertbutyloxycarbonyl-L-l-arginine. in the hydrochloride dioxane mixed solution, in the dropping process with PH=10～12 of 20% sodium hydroxide solution conditioned reaction liquid.Dropwise and rose to room temperature reaction 3.5 hours.Reaction finishes decompression and removes dioxane, and cool to room temperature is transferred PH=3～4 with saturated aqueous citric acid solution, gets yellow oil.Yellow oil add ethyl acetate extraction (5 times * 150mL), standing demix obtains organic phase and water, merges organic phase, water and saturated brine alternately wash, and until solution PH=5～6, use anhydrous sodium sulfate drying then.Dry back is concentrated into dried under vacuum condition with the rotating thin film evaporimeter, add the 200mL sherwood oil, fully stirs, and filters, reduce pressure dry 28.38gN α-tertbutyloxycarbonyl-N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl) L-l-arginine, thin-layer chromatography is a spot, yield is 83.67%.
In being furnished with churned mechanically 500mL there-necked flask, add the saturated hydrogenchloride ethanol of 130g, be cooled to-5～0 ℃, 25g N α-Boc-Arg (pbf)-OH adds, and reaction is 10 hours under the condition of ice bath.Reaction finishes to regulate PH=3～4 with 10% sodium hydroxide, and standing demix gets organic phase and water, and organic phase is with water washing (4 * 120mL); Merge water; Continue to regulate PH=7～8 with 10% sodium hydroxide then, be cooled to 0～10 ℃, crystallization, mistake filter 18.78g N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-L-l-arginine, i.e. N G-Arg (pbf)-OH, fusing point are 154～157 ℃, and thin-layer chromatography is a spot, and yield is 92.86%.
In being furnished with churned mechanically 500mL there-necked flask, add 18g Arg (pbf)-OH, add 10% sodium carbonate solution 30g and dioxane 32g again, be cooled to-5～0 ℃ then; The mixed solution that adds 15.3g N-(9-fluorenylmethyloxycarbonyl oxygen) succinimide and 125g dioxane while stirring, ice bath reacted 2 hours down, and room temperature reaction is 2.5 hours again; Extracted with diethyl ether is removed impurity (100mL * 3 time), and saturated Hydrocerol A is regulated PH=3～4, with ethyl acetate extraction (150mL * 4 time); Tell organic phase and water; Merge the washing of organic phase and water and saturated brine, anhydrous magnesium sulfate drying filters; Remove most of solvent with the rotary film evaporator underpressure distillation, add normal hexane and separate out white products 25.31g N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-L-l-arginine, i.e. Fmoc-L-Arg (pbf)-OH, the thin plate chromatography shows a spot, specific rotatory power [α] D 25=-5.56 0(c=1DMF), yield 92.36%.
Embodiment 2:
Except that following processing parameter was different with routine 1, other preparation technology parameters and process were all with example 1;
1, dioxane substitutes with equivalent acetone;
2, the pbf-cl consumption is 30g;
3, hydrogenchloride ethanol changes equivalent hydrogenchloride formic acid second fat into;
4, obtain Boc-Arg (pbf)-OH 21.42g, yield is 63.15%;
5, obtain Arg (pbf)-OH 15.37g, yield is 75.99%.
Embodiment 3:
Except that following processing parameter was different with routine 1, other preparation technology parameters and process were all with example 1;
1, dioxane substitutes with the equivalent THF;
2, the pbf-cl consumption is 40g;
3, hydrogenchloride ethanol changes the saturated citric acid solution of equivalent into;
4, obtain Boc-Arg (pbf)-OH15.62g, yield is 46.06%;
5, obtain Arg (pbf)-OH 12.78g, yield is 63.19%.

Claims (6)

1. N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-arginine double-protective preparation technique, its reaction formula is:
Figure FSB00000664922500011
Figure FSB00000664922500021
Wherein, in the step 3, with N-tertbutyloxycarbonyl-N G-(2; 2; 4; 6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-and l-arginine is dissolved in the acidic solution, and described acidic solution is a kind of among sulphuric acid soln, hydrogenchloride ethanol, hydrogenchloride propyl alcohol, hydrogenchloride isopropylcarbinol, hydrogenchloride formic acid second fat, hydrogenchloride methyl formate, hydrogenchloride ethyl acetate and the hydrogenchloride methyl acetate of saturated citric acid solution, 0.1～1.0M.
2. N according to claim 1 G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-arginine double-protective preparation technique is characterized in that:
In the step 1, l-arginine or its salt are dissolved in the solvent, are cooled to-50 ℃～50 ℃, add t-butoxycarbonyl protecting group, obtain material I:N after the reaction α-tertbutyloxycarbonyl-l-arginine or N α-tertbutyloxycarbonyl-arginic acid salt;
In the step 2, material I is dissolved in the solvent, is cooled to-15～15 ℃; Regulate pH value 5～13 with 5%～25% sodium hydroxide solution, in addition, with 2; 2,4,6; 7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl blocking group joins in the solvent, adds aforesaid sodium hydroxide solution then, obtains material II:N-tertbutyloxycarbonyl-N after the reaction G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-l-arginine;
Step 3, with N-tertbutyloxycarbonyl-N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-l-arginine is dissolved in the acidic solution, reacts 1～15 hour down at-20～20 ℃, removes t-butoxycarbonyl protecting group, obtains N after the reaction G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-l-arginine;
Step 4, with N G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-l-arginine is dissolved in the solvent, adds the fluorenylmethyloxycarbonyl blocking group under the condition of ice bath, obtains purpose product N after the reaction G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-l-arginine.
3. a kind of N according to claim 2 G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-arginine double-protective preparation technique is characterized in that: described l-arginine and salt thereof are a kind of among L-l-arginine, D-l-arginine, DL-l-arginine, L-arginine monohydrochloride, D-arginine monohydrochloride, DL-arginine monohydrochloride, L-l-arginine vitriol, D-l-arginine vitriol and the DL-l-arginine vitriol.
4. a kind of N according to claim 1 G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-arginine double-protective preparation technique is characterized in that: in second step, described solvent is one or more the mixing in dioxane, dioxane-water, acetone, acetone-water, THF and the THF-water.
5. a kind of N according to claim 2 G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-arginine double-protective preparation technique is characterized in that: described 2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl blocking group is 2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl chlorine.
6. a kind of N according to claim 2 G-(2,2,4,6,7-pentamethyl-benzo dihydrofuran--5-alkylsulfonyl)-N α-(9-fluorenylmethyloxycarbonyl)-arginine double-protective preparation technique is characterized in that: described fluorenylmethyloxycarbonyl blocking group is fluorenes methoxy carbonyl acyl succinimide or fluorenes methoxy dicarbonyl chloride.
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CN108864006A (en) * 2018-06-29 2018-11-23 上海吉奉生物科技有限公司 N- tertbutyloxycarbonyl-N '-（Pentamethyl Dihydrobenzofuranes -5- sulfonyl)-L-arginine synthetic method
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