CN105348147A - Synthetic method of Fmoc-Dab(Boc)-OH - Google Patents

Synthetic method of Fmoc-Dab(Boc)-OH Download PDF

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Publication number
CN105348147A
CN105348147A CN201510641291.7A CN201510641291A CN105348147A CN 105348147 A CN105348147 A CN 105348147A CN 201510641291 A CN201510641291 A CN 201510641291A CN 105348147 A CN105348147 A CN 105348147A
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China
Prior art keywords
dab
fmoc
boc
synthetic method
fluorenylmethyloxycarbonyl
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CN201510641291.7A
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Chinese (zh)
Inventor
徐红岩
林崔建
朱红雷
李英杰
马瑛
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Glbetter Biochemical (shanghai) Co Ltd
Shanghai GL peptide Ltd
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Glbetter Biochemical (shanghai) Co Ltd
Shanghai GL peptide Ltd
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Priority to CN201510641291.7A priority Critical patent/CN105348147A/en
Publication of CN105348147A publication Critical patent/CN105348147A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a synthetic method of Fmoc-Dab(Boc)-OH in order to mainly solve the technical problems of too many steps and very difficult treatment caused by avoiding the use of palladium on activated carbon in an existing preparation method. The technical scheme of the invention is that the synthetic method of Fmoc-Dab(Boc)-OH is characterized by comprising the following steps: reaction of step one, namely adding DiPa into a mixed solvent of Fmoc-Gln-OH suspension, acetonitrile, ethyl acetate and water for reaction and then carrying out treatment to obtain Fmoc-Dab-OH; and reaction of step two, namely adding (Boc)2O into Fmoc-Dab-OH in the presence of acetone and water, adjusting the pH value to be 7.5-8 by using NaOH, and carrying out treatment after reaction to obtain Fmoc-Dab(Boc)-OH. The invention provides a method for large-scale production of Fmoc-Dab(Boc)-OH.

Description

The synthetic method of a kind of N α-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-2,4-diaminobutyric acid
Technical field
The present invention relates to the synthetic method of a kind of N α-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-2,4-diaminobutyric acid (fmoc-dab (Boc)-oh).
Background technology
Existing preparation N α-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-L-2, 4-DAB fmoc-dab (boc)-oh method is generally four step synthesis: the first step, in dimethyl formamide (DMF) and water, carbobenzoxy-(Cbz)-glutamine z-gln-oh and iodobenzene diacetate Dipa reacts and generates N α-carbobenzoxy-(Cbz)-L-2, 4-DAB z-dab-oh, second step, z-dab-oh and (Boc) 2O reacts and generates z-dab (boc)-oh in acetone and water, 3rd step, z-dab (boc)-oh obtains H-dab (boc)-oh through hydrogenation hydrogenation, 4th step, H-dab (boc)-oh and Fmoc-osu generates fmoc-dab (boc)-oh in the basic conditions.This kind of method obvious complex steps cost is higher, and the bad process intermediate of hydrogenation process, is unfavorable for a large amount of production.
Summary of the invention
The invention discloses the synthetic method of a kind of N α-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-2,4-diaminobutyric acid.Mainly solve the loaded down with trivial details cost of existing method steps higher, and the bad process intermediate of hydrogenation process, be unfavorable for mass-produced technical problem.
Technical scheme of the present invention: a kind of N α-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-L-2, the synthetic method of 4-DAB, it is characterized in that comprising the following steps: the first step is reacted, in Fmoc-Gln-OH suspension and acetonitrile, ethyl acetate and water mixed solvent, add iodobenzene diacetate (DiPa) post-reaction treatment and obtain Fmoc-Dab-OH.Second step reacts, and Fmoc-Dab-OH adds (Boc) under the condition of acetone and water 2o, regulates pH=7.5-8 with NaOH, and post-reaction treatment obtains Fmoc-Dab(Boc)-OH.
Described the first step reaction, acetonitrile, ethyl acetate and water mixed solvent add 20 times that volume is Fmoc-Gln-OH, ethyl acetate: acetonitrile: water=2:1:1(v/v/v), temperature of reaction 20-30 DEG C, reaction times 48-72 hour, the preferred reaction time is 72 hours; Iodobenzene diacetate add-on 1:1mol-1:1.5mol.
Described second step reaction, Fmoc-Dab-OH and (Boc) 2o add-on 1:1.2mol, regulates pH, 4 hours reaction times with the NaOH of 0.5N.
Beneficial effect of the present invention: synthesis is simple, and avoid hydrogenation hydrogenation, be conducive to environmental protection, and cost is low, productive rate is high, is convenient to large-scale production.
In the present invention, some conventional abbreviations have following implication:
Fmoc-: fluorenylmethyloxycarbonyl
DiPa: iodobenzene diacetate
(Boc) 2o: tert-Butyl dicarbonate
Fmoc-Gln-OH:N-fluorenylmethyloxycarbonyl-L-glutaminate
Fmoc-Dab-OH:N α-fluorenylmethyloxycarbonyl-2,4-diaminobutyric acid
Fmoc-Dab (Boc)-OH:N α-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-2,4-diaminobutyric acid.
Accompanying drawing explanation
Fig. 1: Fmoc-Dab-OH infared spectrum.
Fig. 2: Fmoc-Dab-OH nuclear magnetic spectrum.
Fig. 3: Fmoc-Dab (Boc)-OH infared spectrum.
Fig. 4: Fmo-Dab (Boc)-OH nuclear magnetic spectrum.
Embodiment
Referring to example, the present invention is described in further detail, but the present invention does not limit and these specific exampless.
Embodiment 1
A. by 100g271.5nmolFmoc-Gln-OH suspension and 2L ethyl acetate: acetonitrile: water=2:1:1(v/v/v) in mixing solutions, at 20 ~ 30 DEG C, add 105.1g325.9nmolDipa, react 72 hours, aftertreatment obtains product Fmoc-Dab-OH80g.Productive rate is 86.5%, HPLC:99.6%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 1, Fig. 2.
B. by 50g146.8nmolFmoc-Dab-OH suspension and 700ml acetone: water=1:1(v/v) in, at 0 ~ 10 DEG C, add 38.4g176.1nmol (Boc) 2o, 0.5NNaOH regulate pH=7.5-8, react aftertreatment in 4 hours and obtain product Fmoc-Dab (Boc)-OH55g, productive rate 85.07%, HPLC99.33%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 3, Fig. 4.
Embodiment 2
A. by 100g271.5nmolFmoc-Gln-OH suspension and 1L ethyl acetate: acetonitrile: water=2:1:1(v/v/v) in mixing solutions, at 20 ~ 30 DEG C, add 105.1gDipa, react 72 hours, aftertreatment obtains product Fmoc-Dab-OH61g, productive rate is 65.98%, HPLC99.1%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 1, Fig. 2.
B. by 50g146.8nmolFmoc-Dab-OH suspension and 700ml acetone: water=1:1(v/v) in, at 0 ~ 10 DEG C, add 38.4g176.1nmol (Boc) 2o, 0.5NNaOH regulate pH=8-8.5, react aftertreatment in 4 hours and obtain product Fmoc-Dab (Boc)-OH50g, productive rate 77.34%, HPLC98.56%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 3, Fig. 4.
Embodiment 3
A. by 100g271.5nmolFmoc-Gln-OH suspension and 2L ethyl acetate: acetonitrile: water=2:1:1(v/v/v) in mixing solutions, at 10 ~ 20 DEG C, add 105.1gDipa, react 72 hours, aftertreatment obtains product Fmoc-Dab-OH75g, productive rate is 81.12%, HPLC99.5%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 1, Fig. 2.
B. by 50g146.8nmolFmoc-Dab-OH suspension and 700ml acetone: water=1:1(v/v) in, at 0 ~ 10 DEG C, add 38.4g176.1nmol (Boc) 2o, 0.5NNaOH regulate pH=7.5-8, react aftertreatment in 4 hours and obtain product Fmoc-Dab (Boc)-OH54g, productive rate 83.52%, HPLC99.2%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 3, Fig. 4.
Embodiment 4
A. by 100g271.5nmolFmoc-Gln-OH suspension and 2L ethyl acetate: acetonitrile: water=2:1:1(v/v/v) in mixing solutions, at 20 ~ 30 DEG C, add 105.1gDipa, react 48 hours, aftertreatment obtains product Fmoc-Dab-OH70g, productive rate is 75.71%, HPLC99.1%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 1, Fig. 2.
B. by 50g146.8nmolFmoc-Dab-OH suspension and 700ml acetone: water=1:1(v/v) in, at 0 ~ 10 DEG C, add 38.4g176.1nmol (Boc) 2o, 0.5NNaOH regulate pH=7.5-8, react aftertreatment in 4 hours and obtain product Fmoc-Dab (Boc)-OH56g, productive rate 86.62%, HPLC99.4%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 3, Fig. 4.
Embodiment 5
A. by 100g271.5nmolFmoc-Gln-OH suspension and 2L ethyl acetate: acetonitrile: water=2:1:1(v/v/v) in mixing solutions, at 20 ~ 30 DEG C, add 87.5gDipa, react 72 hours, aftertreatment obtains product Fmoc-Dab-OH67g, productive rate is 72.47%, HPLC98.5%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 1, Fig. 2.
B. by 50g146.8nmolFmoc-Dab-OH suspension and 700ml acetone: water=1:1(v/v) in, at 0 ~ 10 DEG C, add 38.4g176.1nmol (Boc) 2o, 0.5NNaOH regulate pH=7.5-8, react aftertreatment in 4 hours and obtain product Fmoc-Dab (Boc)-OH55g, productive rate 85.07%, HPLC99.3%.
Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 3, Fig. 4.
Embodiment 6
A. by 100g271.5nmolFmoc-Gln-OH suspension and 2L ethyl acetate: acetonitrile: water=2:1:1(v/v/v) in mixing solutions, at 20 ~ 30 DEG C, add 122.5gDipa, react 72 hours, aftertreatment obtains product Fmoc-Dab-OH76g, productive rate is 82.2%, HPLC99.6%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 1, Fig. 2.
B. by 50g146.8nmolFmoc-Dab-OH suspension and 700ml acetone: water=1:1(v/v) in, at 0 ~ 10 DEG C, add 38.4g176.1nmol (Boc) 2o, 0.5NNaOH regulate pH=7.5-8, react aftertreatment in 4 hours and obtain product Fmoc-Dab (Boc)-OH55g, productive rate 85%, HPLC99.2%.Confirm that structure is correct through infrared, nuclear-magnetism, see Fig. 3, Fig. 4.

Claims (7)

1. N α-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-L-2, the synthetic method of 4-DAB, it is characterized in that comprising the following steps: the first step is reacted, in Fmoc-Gln-OH suspension and acetonitrile, ethyl acetate and water mixed solvent, add iodobenzene diacetate post-reaction treatment and obtain Fmoc-Dab-OH; Second step reacts, and Fmoc-Dab-OH adds (Boc) under the condition of acetone and water 2o, regulates pH=7.5-8 with NaOH, and post-reaction treatment obtains Fmoc-Dab(Boc)-OH.
2. a kind of N α-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-L-2 according to claim 1, the synthetic method of 4-DAB, it is characterized in that the described the first step is reacted, acetonitrile, ethyl acetate and water mixed solvent add 20 times that volume is Fmoc-Gln-OH, ethyl acetate: acetonitrile: water volume ratio=2:1:1, in Fmoc-Gln-OH, iodobenzene diacetate add-on 1:1mol-1:1.5mol.
3. the synthetic method of a kind of N α according to claim 1-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-2,4-diaminobutyric acid, is characterized in that the described the first step is reacted, temperature of reaction 20-30 DEG C, reaction times 48-72 hour.
4. the synthetic method of a kind of N α according to claim 3-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-2,4-diaminobutyric acid, it is characterized in that the described the first step is reacted, the reaction times is 72 hours.
5. the synthetic method of a kind of N α according to claim 1-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-2,4-diaminobutyric acid, is characterized in that described second step reacts, Fmoc-Dab-OH and (Boc) 2o add-on 1:1.2mol.
6. the synthetic method of a kind of N α according to claim 1-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-2,4-diaminobutyric acid, is characterized in that described second step reacts, and regulates pH with the NaOH of 0.5N.
7. the synthetic method of a kind of N α according to claim 1-fluorenylmethyloxycarbonyl-N γ-tertbutyloxycarbonyl-2,4-diaminobutyric acid, is characterized in that described second step reacts, 4 hours reaction times.
CN201510641291.7A 2015-10-08 2015-10-08 Synthetic method of Fmoc-Dab(Boc)-OH Pending CN105348147A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106892845A (en) * 2017-02-28 2017-06-27 四川同晟生物医药有限公司 A kind of 2,4 diaminobutyric acid derivatives and preparation method thereof
CN109535035A (en) * 2019-01-08 2019-03-29 吉尔生化（上海）有限公司 A kind of preparation method of the N- benzyloxycarbonyl group -3- amino-alanine tert-butyl ester

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EP0505868A2 (en) * 1991-03-26 1992-09-30 F. Hoffmann-La Roche Ag N-Acyl-alpha-aminoacids derivatives
US5721338A (en) * 1995-12-07 1998-02-24 California Institute Of Technology Inhibitors of oligosaccharyl transferase
CN104327155A (en) * 2014-10-20 2015-02-04 张嘎 Tripeptide type wrinkle reduction compound containing 15N-L-proline residue as well as preparation method and application of tripeptide type wrinkle reduction compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0505868A2 (en) * 1991-03-26 1992-09-30 F. Hoffmann-La Roche Ag N-Acyl-alpha-aminoacids derivatives
US5721338A (en) * 1995-12-07 1998-02-24 California Institute Of Technology Inhibitors of oligosaccharyl transferase
CN104327155A (en) * 2014-10-20 2015-02-04 张嘎 Tripeptide type wrinkle reduction compound containing 15N-L-proline residue as well as preparation method and application of tripeptide type wrinkle reduction compound

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NAOKI SAKURA等: ""The Contribution of the N-Terminal Structure of Polymyxin B Peptides to Antimicrobial and Lipopolysaccharide Binding Activity"", 《BULL. CHEM. SOC. JPN.》 *
R. V. RAMANA RAO等: ""Practical and Efficient Synthesis of Orthogonally Protected a-2,3-Diaminopropionic Acid (2,3-Dap), 2,4-Diaminobutanoic Acid (2,4-Dab), and their N-Methylated Derivatives"", 《SYNTHETIC COMMUNICATIONS》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106892845A (en) * 2017-02-28 2017-06-27 四川同晟生物医药有限公司 A kind of 2,4 diaminobutyric acid derivatives and preparation method thereof
CN106892845B (en) * 2017-02-28 2018-10-30 四川同晟生物医药有限公司 A kind of 2,4- diaminobutyric acid derivatives and preparation method thereof
CN109535035A (en) * 2019-01-08 2019-03-29 吉尔生化（上海）有限公司 A kind of preparation method of the N- benzyloxycarbonyl group -3- amino-alanine tert-butyl ester

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