CN116462622A - Preparation method of N-Boc-L-prolyl - Google Patents
Preparation method of N-Boc-L-prolyl Download PDFInfo
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- CN116462622A CN116462622A CN202310230343.6A CN202310230343A CN116462622A CN 116462622 A CN116462622 A CN 116462622A CN 202310230343 A CN202310230343 A CN 202310230343A CN 116462622 A CN116462622 A CN 116462622A
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- boc
- prolyl
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- solvent
- aldehyde
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- 238000002360 preparation method Methods 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims description 18
- 238000004821 distillation Methods 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 9
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 7
- 229950009390 symclosene Drugs 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 5
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- 150000008282 halocarbons Chemical group 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims 3
- YDBPZCVWPFMBDH-QMMMGPOBSA-N tert-butyl (2s)-2-formylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C=O YDBPZCVWPFMBDH-QMMMGPOBSA-N 0.000 claims 2
- 238000001035 drying Methods 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000012467 final product Substances 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 5
- 235000008206 alpha-amino acids Nutrition 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 2
- 150000001371 alpha-amino acids Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention discloses a preparation method of N-Boc-L-prolyl, which comprises the following steps: distilling the N-Boc-L-prolyl aldehyde under reduced pressure to obtain pure N-Boc-L-prolyl aldehyde. The preparation method has reasonable route design, simple and convenient operation, mild reaction conditions and high purity, reduces the cost of the final product and is convenient for industrial production.
Description
Technical Field
The invention belongs to the field of chemical synthesis processes, and particularly relates to a preparation method of N-Boc-L-prolyl.
Background
Alpha-amino aldehydes have enantiomeric forms of natural origin (alpha-amino acids) and have significant versatility due to the presence of formyl groups and properly protected amino functions in the molecule. Alpha-amino aldehydes are predominantly obtained from alpha-amino acids and can occasionally be prepared from other chiral precursors. Typically, the α -amino aldehyde is obtained by reduction of an ester or active amide of an α -amino acid; or the amino alcohol obtained from the alpha-amino acid is oxidized.
N-Boc-L-prolyl is an important organic synthetic building block, and is widely applied to pharmaceutical chemistry, and is not used as a catalyst for the catalytic reaction of organic small molecules. For example, N-Boc-L-prolyl is a key intermediate in the synthesis of dolastatin. To date, various literature reports the following three oxidation processes for the oxidation of N-Boc-L-prolyl to N-Boc-L-prolyl:
the first method is Swern oxidation, using oxalyl chloride, DMSO and triethylamine, to oxidize N-Boc-L-prolyl to N-Boc-L-prolyl at-78 ℃. (Beckett R.P., et al tetrahedron: asymmetry,1992,3 (1): 123-136;US 6403792 B1) but the reaction is absolutely anhydrous, and the reaction temperature must be carried out at a low temperature (-78 ℃), the operation is complicated, dimethyl sulfide is generated during the reaction, malodor smell is generated during the post-treatment, and the industrial production is not favored.
The second method is to use DMSO as oxidant and solid SO 3 -pyridine complex as activator and triethylamine as base, to oxidize N-Boc-L-prolyl to N-Boc-L-prolyl. (Masazumi I., et al, heteromyces, 1999,50 (1): 31-34) this process also produces malodorous dimethyl sulfide.
The third method is to oxidize N-Boc-L-prolyl to N-Boc-L-prolyl using DMP (dess-Martin oxidizer). (Souck M., et al 1995,60 (4): 693-696) but this reagent is relatively expensive and disadvantageous in terms of manufacturing costs.
Disclosure of Invention
In the preparation method of N-Boc-L-prolyl in the prior art, column chromatography is generally adopted for purification or direct simple post-treatment is adopted for removing the solvent. Column chromatography purification typically uses large amounts of organic solvents and is time consuming and labor intensive, not conducive to industrialization and environmental friendliness. The lack of purification of N-Boc-L-prolyl can lead to reduced purity or difficulty in subsequent applications.
In order to overcome the deficiencies of the prior art, the inventors have actively explored different purification methods, and have found that N-Boc-L-prolyl can be obtained very surprisingly in high yields and purity when distillation is carried out at a suitable pressure and temperature. In the first attempt of distillation, it was found that when the reduced pressure distillation temperature exceeded 200 ℃, the distillate was discolored and less N-Boc-L-prolyl could be obtained, and it was found that Boc protecting groups were unstable when the temperature was too high, so that the above problem was only seen.
The invention provides a preparation method of N-Boc-L-prolyl. The preparation method has reasonable route design, simple and convenient operation and mild reaction conditions; the adopted purification method adopts specific temperature and pressure, so that the product has high purity and less loss; the cost of the final product is reduced, and the industrial production is facilitated.
The invention provides a preparation method of N-Boc-L-prolyl aldehyde, which comprises the following steps: distilling the crude N-Boc-L-prolyl product under reduced pressure to obtain pure N-Boc-L-prolyl product;
the pressure of the reduced pressure distillation is 0-20Pa;
the distillation range of the reduced pressure distillation is 80-100 ℃.
In one embodiment, the distillation range of the reduced pressure distillation is 80 to 85 ℃.
In one embodiment, the pressure of the reduced pressure distillation is 10 to 20Pa.
In one embodiment, the crude N-Boc-L-prolyl product has an N-Boc-L-prolyl content of not less than 80%.
In one embodiment, the crude N-Boc-L-prolyl has an N-Boc-L-prolyl content of not less than 85%.
In one embodiment, the method for preparing N-Boc-L-prolyl further comprises the following steps: in a solvent, reacting N-Boc-L-prolyl alcohol with TEMPO (2, 6-tetramethyl piperidine oxide) and trichloroisocyanuric acid (TCC) to obtain a crude product of the N-Boc-L-prolyl aldehyde;
the following conditions are preferred in the present invention:
the solvent may be a halogenated hydrocarbon solvent such as DCM, DCE or chloroform, preferably DCM.
The solvent is used in an amount that does not affect the reaction, and the solvent is preferably used in an amount that is 1:5 to 1:20, more preferably 1:10, of the substrate to the solvent.
The molar ratio of N-Boc-L-prolyl alcohol to TEMPO may be 1:0.2 to 0.01, e.g. 1:0.01 or 1:0.1.
The molar ratio of N-Boc-L-prolyl to trichloroisocyanuric acid may be 1:1-2, such as 1:1 or 1:1.5.
The temperature of the reaction may be from 0 to 50 ℃, preferably from 20 to 25 ℃.
The reaction time is such that the reaction product is not regenerated, for example 1 hour.
Post-treatment may also be included after the reaction is completed. The post-treatment may comprise the steps of: removing solid after the reaction is finished, quenching, separating liquid, extracting an aqueous phase by using an organic solvent, combining the organic phases, and removing the solvent to obtain a crude product of the N-Boc-L-prolyl; the post-treatment preferably comprises the following steps: after the reaction is completed, the solid is removed, the sodium sulfite solution is quenched (for example, saturated sodium sulfite solution is quenched), the aqueous phase is extracted by a halogenated hydrocarbon solvent (for example, DCM), the organic phases are combined, dried and the solvent is removed to obtain the crude N-Boc-L-prolyl.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the preparation method has reasonable route design, simple and convenient operation, mild reaction conditions and high purity, reduces the cost of the final product and is convenient for industrial production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The reagents used in the examples were all commercially available, unless otherwise specified.
Example 1
N-Boc-L-prolyl alcohol (II) (48.8 g,1.0 eq), methylene dichloride (490 mL, 10.0V) and TEMPO (0.4 g,0.01 eq) are added into a 1L three-mouth bottle, magnetically stirred, cooled to 0 ℃, added with trichloroisocyanuric acid (56.4 g,1.0 eq) in batches at a temperature of 0-5 ℃ for 0.5 hours, and then heated to 20-25 ℃ for reaction for 1 hour. After the reaction is finished, removing solids by suction filtration, adding 600mL of saturated sodium sulfite solution into the yellow filtrate for quenching, and separating to obtain an organic phase and a water phase; the aqueous phase was extracted with 500mL of methylene chloride, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a yellow oil. Vacuum distillation, vacuum pressure of 0-20Pa, collecting 80-85deg.C fraction to obtain 41.4g colorless oily substance with yield of 85.7% and purity of 98.57%. 1 H NMR(400MHz,CDCl 3 ,ppm):δ＝1.37(s,9H,Boc),1.80-2.11(m,4H,CH 2 ),3.34-3.59(m,2H,CH 2 ),3.98-4.04(m,1H,CH),9.40(s,1H,CHO)。
Claims (10)
1. A method for preparing N-Boc-L-prolyl, which comprises the following steps: distilling the crude N-Boc-L-prolyl product under reduced pressure to obtain pure N-Boc-L-prolyl product;
the pressure of the reduced pressure distillation is 0-20Pa;
the distillation range of the reduced pressure distillation is 80-100 ℃.
2. The method for producing N-Boc-L-prolyl aldehyde according to claim 1, wherein the distillation range of reduced pressure distillation is 80 to 85 ℃;
and/or the pressure of the reduced pressure distillation is 10-20 Pa.
3. The method for producing N-Boc-L-prolyl aldehyde according to claim 1, wherein the method for producing N-Boc-L-prolyl aldehyde further comprises the steps of: in a solvent, reacting N-Boc-L-prolyl alcohol with TEMPO and trichloroisocyanuric acid to obtain a crude product of the N-Boc-L-prolyl aldehyde;
4. the method for producing N-Boc-L-prolyl according to claim 3, wherein the solvent is a halogenated hydrocarbon solvent;
and/or the molar ratio of the N-Boc-L-prolyl alcohol to the TEMPO is 1:0.2-0.01;
and/or the molar ratio of the N-Boc-L-prolyl alcohol to the trichloroisocyanuric acid is 1:1-2.
5. The method for producing N-Boc-L-prolyl according to claim 4 wherein the solvent is DCM, DCE or chloroform;
and/or the molar ratio of the N-Boc-L-prolyl alcohol to TEMPO is 1:0.01 or 1:0.1;
and/or the molar ratio of the N-Boc-L-prolyl alcohol to the trichloroisocyanuric acid is 1:1 or 1:1.5.
6. The method for producing N-Boc-L-prolinal according to claim 5, wherein the solvent is DCM.
7. The method for producing N-Boc-L-prolyl aldehyde according to claim 3, wherein the temperature of the reaction is 0 to 50 ℃;
and/or the reaction time is 1 hour.
8. The method for producing N-Boc-L-prolinal according to claim 7, wherein the reaction temperature is 20 to 25 ℃.
9. The method for producing N-Boc-L-prolyl according to any one of claims 3 to 8, wherein the method for producing N-Boc-L-prolyl further comprises the steps of: and removing solids after the reaction is finished, quenching, separating liquid, extracting an aqueous phase by using an organic solvent, combining the organic phases, and removing the solvent to obtain the crude N-Boc-L-prolyl.
10. The method for producing N-Boc-L-prolyl aldehyde according to claim 9, wherein the method for producing N-Boc-L-prolyl aldehyde further comprises the steps of: after the reaction is finished, removing solids, quenching a saturated sodium sulfite solution, separating a liquid, extracting an aqueous phase by using DCM, combining organic phases, drying and removing a solvent to obtain the crude product of the N-Boc-L-prolyl.
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| CN116462622A true CN116462622A (en) | 2023-07-21 |
| CN116462622B CN116462622B (en) | 2024-02-09 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1960965A (en) * | 2004-06-02 | 2007-05-09 | 霍夫曼-拉罗奇有限公司 | Synthesis of amino-alkoxy-heptanoic alkyl ester |
| CN102741241A (en) * | 2009-11-04 | 2012-10-17 | 爱尔兰詹森研发公司 | Benzimidazole-imidazole derivatives |
| WO2022094172A2 (en) * | 2020-10-30 | 2022-05-05 | Newave Pharmaceutical Inc. | Inhibitors of btk |
| CN114920683A (en) * | 2022-06-24 | 2022-08-19 | 苏州富士莱医药股份有限公司 | Preparation method of Boc-prolinaldehyde and (R, E) - (1-methylpyrrolidine-2-yl) acrylic acid |
-
2023
- 2023-03-10 CN CN202310230343.6A patent/CN116462622B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1960965A (en) * | 2004-06-02 | 2007-05-09 | 霍夫曼-拉罗奇有限公司 | Synthesis of amino-alkoxy-heptanoic alkyl ester |
| CN102741241A (en) * | 2009-11-04 | 2012-10-17 | 爱尔兰詹森研发公司 | Benzimidazole-imidazole derivatives |
| WO2022094172A2 (en) * | 2020-10-30 | 2022-05-05 | Newave Pharmaceutical Inc. | Inhibitors of btk |
| CN114920683A (en) * | 2022-06-24 | 2022-08-19 | 苏州富士莱医药股份有限公司 | Preparation method of Boc-prolinaldehyde and (R, E) - (1-methylpyrrolidine-2-yl) acrylic acid |
Non-Patent Citations (1)
| Title |
|---|
| LIDIA DE LUCA等: "A Very Mild and Chemoselective Oxidation of Alcohols to Carbonyl Compounds", 《ORG. LETT.》, vol. 3, no. 19, pages 3041 - 3043, XP002570708, DOI: 10.1021/OL016501M * |
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| CN116462622B (en) | 2024-02-09 |
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