KR20180060319A - New synthetic method for [10B]-L-4-boronophenylalanine (LBPA) using [10B]pinacolborane - Google Patents
New synthetic method for [10B]-L-4-boronophenylalanine (LBPA) using [10B]pinacolborane Download PDFInfo
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- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 238000010189 synthetic method Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- -1 aryl alcohol Chemical compound 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- KGBXLFKZBHKPEV-BJUDXGSMSA-N trihydroxyborane Chemical compound O[10B](O)O KGBXLFKZBHKPEV-BJUDXGSMSA-N 0.000 claims description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 19
- 238000003786 synthesis reaction Methods 0.000 abstract description 19
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract description 14
- 229910052796 boron Inorganic materials 0.000 abstract description 13
- 238000002560 therapeutic procedure Methods 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 6
- 230000002194 synthesizing effect Effects 0.000 abstract description 6
- 239000004327 boric acid Substances 0.000 abstract description 4
- 150000001639 boron compounds Chemical group 0.000 abstract description 4
- PQMFVUNERGGBPG-UHFFFAOYSA-N (6-bromopyridin-2-yl)hydrazine Chemical compound NNC1=CC=CC(Br)=N1 PQMFVUNERGGBPG-UHFFFAOYSA-N 0.000 abstract 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 2
- 206010028980 Neoplasm Diseases 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 7
- 230000008569 process Effects 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 238000006795 borylation reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000004992 fission Effects 0.000 description 2
- 230000001678 irradiating effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- NFIVJOSXJDORSP-QMMMGPOBSA-N (2s)-2-amino-3-(4-boronophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(B(O)O)C=C1 NFIVJOSXJDORSP-QMMMGPOBSA-N 0.000 description 1
- AUGGFFANDMBCPZ-QMMMGPOBSA-N (2s)-2-amino-3-[4-(trifluoromethylsulfonyloxy)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(OS(=O)(=O)C(F)(F)F)C=C1 AUGGFFANDMBCPZ-QMMMGPOBSA-N 0.000 description 1
- PZNQZSRPDOEBMS-QMMMGPOBSA-N 4-iodo-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(I)C=C1 PZNQZSRPDOEBMS-QMMMGPOBSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical compound [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- HNCUXLSIVYDGBW-LBPRGKRZSA-N methyl (2s)-3-(4-iodophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=C(I)C=C1 HNCUXLSIVYDGBW-LBPRGKRZSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/1616—Coordination complexes, e.g. organometallic complexes, immobilised on an inorganic support, e.g. ship-in-a-bottle type catalysts
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Abstract
Description
본 발명은 새로운 항암 치료 기법인 BNCT (Boron neutron capture therapy, 붕소 중성자 포획 시술)에 이용되는 붕소화합물인 [10B]LBPA를 합성하는 방법에 대한 것이다. 더욱 자세하게는, 합성을 위해 중요한 중간체인 [10B]pinacolborane의 합성법 및 이를 이용한 [10B]LBPA의 합성 방법에 관한 것이다.
The present invention relates to a method for synthesizing [ 10 B] LBPA, which is a boron compound used in a new chemotherapy treatment technique, boron neutron capture therapy (BNCT). More specifically, the present invention relates to important intermediates of [B 10] Synthesis and method Synthesis of [B 10] LBPA using the same for the synthesis of pinacolborane.
인간의 중요 질병으로서 가장 큰 관심이 모이고 있는 암 치료 기술에는 수술 등의 외과적 방법, 약물 투여 등에 의한 내과적 방법 및 감마선 조사에 의한 방사선치료법 등이 있다. 이러한 암 치료방법은 암세포뿐만 아니라 암세포 주위의 정상세포들까지 손상을 입히게 될 뿐만 아니라 화학요법(chemotherapy)의 경우는 내성을 갖는 암세포를 생성하는 문제점이 있다.Cancer treatment techniques, which are of greatest interest as human important diseases, include surgical methods such as surgery, internal medicine methods such as drug administration, and radiation therapy by gamma irradiation. Such a cancer treatment method not only damages not only cancer cells but also normal cells around cancer cells, but also has a problem of producing cancer cells having resistance in the case of chemotherapy.
따라서 최근에는 암세포가 증식된 곳에 집중적으로 다량의 방사선을 조사할 수 있는 방법으로서 붕소 등 특정 원소를 포함하고 있는 화합물을 적당한 운반 생화학 물질을 이용하여 암 세포에 선택적으로 축적시키고, 적당한 양의 열중성자를 암세포 증식 부위에 조사하여 해당 원소의 핵분열을 유발함으로써 이러한 핵분열에서 방출되는 에너지로 암세포만을 파괴하여 암을 치료하는 방법이 시도되고 있다.Recently, as a method of intensively irradiating a large amount of radiation to a place where cancer cells have been propagated, a compound containing a specific element such as boron is selectively accumulated in cancer cells using an appropriate transporting biochemical substance, and an appropriate amount of thermal neutrons A method of treating cancer by destroying only cancer cells with the energy released from such fission by irradiating the cancerous cell to the cancerous cell proliferation site to induce the fission of the element.
이러한 이원성 치료법을 중성자포획 치료요법(neutron capture therapy, NCT)이라고 하며, 특히 붕소 원소를 이용한 방법을 붕소 중성자포획 치료요법(boron neutron capture therapy, BNCT)이라 한다. 또한 이러한 목적에 이용되는 시약을 붕소 중성자 포획 치료 요법제(boron neutron capture therapy agent, BNCT agent)라고 한다.This dual therapy is called neutron capture therapy (NCT). Boron neutron capture therapy (BNCT) is a method that uses boron elements. The reagents used for this purpose are called boron neutron capture therapy agents (BNCT agents).
자연에서 발견되는 붕소 원자는 11B와 10B의 두 동위원소가 약 81.17:18.8의 비율로 존재하는데, 이 중 동위원소 10B에 열중성자를 조사하면 붕소 원자가 중성자를 포획하고 이어서 붕소 원자의 핵붕괴가 일어나며, 이어서 암세포를 파괴할 수 있는 에너지가 발생된다.Boron atoms that are found in nature, 11 B and 10 both have approximately 81.17 isotopes of B: to present in a proportion of 18.8, nuclear decay of the of the isotope is irradiated to thermal neutron the element 10 B capture the boron atom neutron and then boron atom And then energy that can destroy cancer cells is generated.
따라서, 환자에게 붕소(10B) 화합물을 투여한 후 중성자를 그 환자의 종양부위에 조사하게 되면, 그 종양세포가 상기 중성자의 핵심 표적이 됨으로써 결국 종양세포만을 선별적이고 안전하게 제거할 수 있게 되는 것이다. 이 때 원하는 효과를 달성하기 위해서는 중성자 조사를 받는 종양조직 대 정상조직의 붕소 축적 선택성은 가능한 한 커야 한다.Therefore, when a patient is irradiated with a neutron with a boron ( 10B ) compound to a tumor site of the patient, the tumor cell becomes a key target of the neutron, thereby selectively and safely removing only tumor cells . To achieve the desired effect, the boron accumulation selectivity of the tumor tissue versus the normal tissue under neutron irradiation should be as large as possible.
제1세대 붕소 중성자 포획 치료요법제로서 무기 붕소 화합물이 사용되었으나 세포막의 통과와 독성에 문제점이 있었다. 하지만 BSH를 포함하는 제2세대 치료요법제가 개발되어 새로운 전기를 맞게 되었다.Although inorganic boron compounds were used as the first-generation boron neutron capture therapy, there was a problem in the passage and toxicity of the cell membrane. However, second-generation therapies including BSH have been developed and new biomarkers have been introduced.
현재까지 BNCT에서 임상 시험에 허용된 화합물은 BSH (Sodium borocaptate)와 BPA (4-Boronophenylalanine)이다. 따라서 이 화합물들을 효과적으로 합성하는 방법은 BNCT 기술 개발에 있어 매우 중요하며, 또한 BNCT에서 효과를 나타내는 boron은 자연계에 비교적 적게 존재하는 10B으로써 일반적으로 사용하는 boron 화합물에는 10B와 11B가 약 1:4의 비율로 섞여 있다.To date, the compounds allowed for clinical trials in BNCT are BSH (sodium borocaptate) and BPA (4-Boronophenylalanine). Therefore, how the compounds effectively synthesized is very important for BNCT technology, and boron showing the effect in BNCT is, the boron compound commonly used as 10 B that is relatively low in nature 10 B and 11 B are approximately one : 4 ratio.
현재까지 보고된 [10B]LBPA의 합성법은 대부분 이미 알려진 LBPA의 합성법(Snyder, H. R.; Reedy, A. J.; Lennarz, W. J. J. Am. Chem. Soc. 1958, 80, 835 등)에 10B와 11B가 섞여 있는 붕소 시약 대신에 10B이 농축된 시약을 사용하는 방법이다.Reported to date [10 B] Synthesis of LBPA in most synthesis method known LBPA (Snyder, HR; Reedy, AJ;... Lennarz, WJJ Am Chem Soc 1958, 80, 835 , etc.) are 10 B and 11 B for Instead of the mixed boron reagent, 10 B is a method of using a concentrated reagent.
LBPA를 합성하는 방법 중 L-4-iodophenylalanine과 L-tyrosine triflate를 기질로 이용하고 pinacolborane과 금속 촉매 하에서 결합 반응을 하는 것은 매우 직접적이고 효율적인 방법이다. 그러나 이 방법이 [10B]LBPA를 합성하는 과정에는 응용되지 못하고 있는데, 그 이유는 중간물질인 [10B]pinacolborane의 제법이 알려져 있지 않기 때문이다.It is a very direct and efficient method to use L-4-iodophenylalanine and L-tyrosine triflate as substrate for the coupling reaction of LBPA with pinacolborane under metal catalyst. However, there is a method is not being applied, the process for synthesis of [B 10] LBPA, because the preparation of intermediates of [B 10] pinacolborane is unknown.
이에 본 발명자들은 중간물질인 [10B]pinacolborane의 합성 방법을 착안하고, 이를 이용하여 [10B]LBPA를 합성할 수 있음을 확인하여 발명을 완성하였다.
The present inventors have completed the invention by paying attention it confirmed that the synthesis of the intermediates of [B 10] pinacolborane, and by using this, to synthesize [10 B] LBPA.
본 발명의 목적은, 에서는 상업적으로 구매할 수 있는 10B 원료인 [10B]boric acid로부터 시작하여 [10B]pinacolborane을 합성하는 새로운 합성 방법을 제시하고, 이를 이용하여 실제로 [10B]LBPA를 합성한 것을 확인하여 [10B]LBPA의 새로운 제조방법을 제공함에 있다.
The object of the present invention is to propose a new synthesis method for synthesizing [ 10 B] pinacolborane starting from [ 10 B] boric acid which is a commercially available 10 B raw material, and using this, actually, [ 10 B] LBPA And confirmed the synthesis, thereby providing a new method for producing [ 10 B] LBPA.
상기 목적을 달성하기 위하여, 본 발명은 하기의 반응식 1과 같이, (A) [10B]붕산(10B(OH)3)을, 알콜로 치환시켜 [10B]alkyl pinacolborate (1)로 변환시키는 단계; 및 (B) 상기 [10B]alkyl pinacolborate (1)를 환원제로 환원시켜 [10B]pinacolborane (2)을 얻는 단계;를 포함하는 [10B]피나콜보란([10B]pinacolborane)의 제조방법을 제공한다.In order to achieve the above object, the present invention is converted to as
[반응식 1][Reaction Scheme 1]
상기 R-OH는, 메탄올, 에탄올, 이소프로판올, 아릴 알콜로 구성된 군에서 선택되는 하나의 알콜일 수 있다.The R-OH may be an alcohol selected from the group consisting of methanol, ethanol, isopropanol, and aryl alcohol.
상기의 제조방법에 의해 제조된 [10B]피나콜보란([10B]pinacolborane)과 N-Boc-L-4-iodophenylalanine methyl ester를 반응시키고, 금속촉매를 사용하는 단계;를 포함하는 [10B]LBPA의 제조방법을 제공하는 것을 다른 측면으로 한다.The method comprising reacting the [10-B] pinacol borane ([10 B] pinacolborane) and N-Boc-L-4- iodophenylalanine methyl ester produced by the method described above, using a metal catalyst; [containing 10 B] LBPA is provided as another aspect of the present invention.
[반응식 2][Reaction Scheme 2]
상기 금속 촉매는, PdCl2(dppf) 촉매일 수 있다.
The metal catalyst may be a PdCl2 (dppf) catalyst.
상기와 같은 본 발명에 따르면, 정상 세포에 대한 부작용이 최소화 된 새로운 항암 치료 기법인 BNCT의 임상 시험에 사용되는 [10B]LBPA를 높은 10B 효율성과 쉬운 합성법으로 대량 생산할 수 있는 효과가 있다.
According to the present invention, [ 10 B] LBPA used in clinical tests of BNCT, which is a new chemotherapeutic technique with minimal adverse effects on normal cells, can be mass-produced with high 10 B efficiency and easy synthesis method.
도 1은 boric acid에서 [10B]Pinacolborane를 만드는 방법
도 2는 [10B]Pinacolborane을 이용한 [10B]LBPA의 합성 전략을 위한 역합성도.
도 3은 [10B]Pinacolborane을 이용한 [10B]LBPA의 합성 과정도 (1).
도 4는 [10B]Pinacolborane을 이용한 [10B]LBPA의 합성 과정도 (2).
도 5는 [10B]Pinacolborane에 대한 PinB-OEt NMR 측정 결과도.
도 6은 [10B]Pinacolborane에 대한 PinB-H NMR 측정 결과도.Figure 1 shows a method for making [ 10 B] pinacolborane in boric acid
Figure 2 [B 10]-band synthesis for [B 10] Synthesis strategy LBPA with Pinacolborane FIG.
FIG. 3 is a process diagram of synthesis of [ 10 B] LBPA using [ 10 B] pinacolborane (1).
4 [B 10] FIG synthesis of [B 10] LBPA with Pinacolborane (2).
Figure 5 is a PinB-OEt NMR measurement result for [ 10 B] pinacolborane.
FIG. 6 is a result of PinB-1 H NMR measurement of [ 10 B] pinacolborane. FIG.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일 형태는, 하기의 반응식 1과 같이, (A) [10B]붕산(10B(OH)3)을, 알콜로 치환시켜 [10B]alkyl pinacolborate (1)로 변환시키는 단계; 및 (B) 상기 [10B]alkyl pinacolborate (1)를 환원제로 환원시켜 [10B]pinacolborane (2)을 얻는 단계;를 포함하는 [10B]피나콜보란([10B]pinacolborane)의 제조방법을 제공한다.One aspect of the present invention is a process for preparing a compound represented by the formula (1), comprising the steps of: (A) converting [ 10 B] boric acid ( 10 B (OH) 3 ) into an alcohol and converting it into [ 10 B] alkyl pinacolborate Preparation of [10 B] pinacol borane ([10 B] pinacolborane) containing; and (B) the [10 B] alkyl pinacolborate (1 ) a step of obtaining a by reduction with a reducing agent [10 B] pinacolborane (2) ≪ / RTI >
[반응식 1][Reaction Scheme 1]
상기 R-OH는, 메탄올, 에탄올, 이소프로판올, 아릴 알콜로 구성된 군에서 선택되는 하나의 알콜인 것이 바람직하다.The R-OH is preferably an alcohol selected from the group consisting of methanol, ethanol, isopropanol, and aryl alcohol.
본 발명의 다른 형태는, 상기의 제조방법에 의해 제조된 [10B]피나콜보란([10B]pinacolborane)과 N-Boc-L-4-iodophenylalanine methyl ester를 반응시키고, 금속촉매를 사용하는 단계;를 포함하는 [10B]LBPA의 제조방법을 제공한다.Another aspect of the present invention, the [10 B] pinacol borane ([10 B] pinacolborane) and reacting with N-Boc-L-4- iodophenylalanine methyl ester produced by the method described above, using a metal catalyst [ 10 B] LBPA.
[반응식 2][Reaction Scheme 2]
상기 금속 촉매는, PdCl2(dppf) 촉매인 것이 바람직하다.
The metal catalyst is preferably a PdCl2 (dppf) catalyst.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.
실시예 1. pinacolborane의 합성Example 1. Synthesis of pinacolborane
현재까지 알려져 있는 pinacolborane의 모든 합성법은 상업적으로 구매할 수 있는 borane(BH3)를 시작 물질로 한다. 그러나 10B의 경우에는 상업적으로 구매할 수 있는 원료가 [10B]boric acid (10B(OH)3)로 한정되어 있어서 자연적인 pinacolborane을 합성할 때와는 다른 합성 방법이 필요하다.All known methods of pinacolborane synthesis are commercially available borane (BH 3 ) as starting material. However, in the case of 10 B, the commercially available raw material is limited to [ 10 B] boric acid ( 10 B (OH) 3 ), and therefore, a synthesis method different from the synthesis of natural pinacolborane is required.
이전에 보고된 문헌들에 따르면 alkyl pinacolborate는 특정한 치환 조건 하에서 다양한 alkyl pinacolboronate로 변환된다(K. Hong et. al., J. Am. Chem. Soc. 2014, 10581-10584 (R=Me), B. H. Lipshutz et. al., Angew. Chem. Int. Ed. 2013, 10952-1095 등) 이와 같은 반응 양상을 참고하여 [10B]pinacolborane의 합성 방법을 다음과 같이 새롭게 고안하였다(도 1). 첫 반응 단계에서는 boric acid를 출발물질로 하고, pinacol 등 alcohol을 이용한 치환반응을 수행한 후, 이를 중간 물질로 하여 환원제를 이용한 환원 반응을 통해 pinacolborane을 합성할 수 있었다.According to previously reported documents, alkyl pinacolborate is converted to various alkyl pinacolboronates under specific substitution conditions (K. Hong et al., J. Am. Chem. Soc. 2014, 10581-10584 Lipshutz et al., Angew Chem. Int. Ed., 2013, 10952-1095, etc.) The synthesis of [ 10 B] pinacolborane was newly devised as follows (FIG. In the first reaction step, pinacolborane was synthesized by using boric acid as a starting material, substitution reaction using alcohols such as pinacol, and reduction reaction using a reducing agent as an intermediate.
(도 1)을 보면, 1단계에서 메탄올, 에탄올, 이소프로판올, 아릴 알콜 중, 에탄올 처리를 하여 100℃, 10 시간 동안 치환반응을 수행하였고, 2단계에서 환원제로 NaBH4를 이용하여 [10B]pinacolborane을 합성하는 과정을 확인할 수 있다. 반응 결과 전체적으로 35%의 수율을 내는 것을 확인할 수 있었다. [10B]pinacolborane이 합성되었는지 여부는 (도 5)와 (도 6) NMR데이터를 통해 확인하였다.
(FIG. 1), ethanol was treated in methanol, ethanol, isopropanol and aryl alcohol in
실시예 2. [Example 2. [ 1010 B]LBPA의 합성B] Synthesis of LBPA
[10B]LBPA의 합성법이 효율적이기 위해서 가장 중요한 부분은 고가의 시약인 [10B]pinacolborane의 사용 당량 및 반응 수율을 효과적으로 만드는 것이다. 반응 전체에서 10B의 사용량을 줄이기 위해서는 borylation 반응이 마지막 반응이 되는 것이 좋으며, 또한 borylation 과정에서 필요한 10B의 양도 1당량 정도인 것이 가장 효과 측면에서 최적이 된다.[ 10 B] For efficient synthesis of LBPA, the most important part is to make effective equivalents and reaction yield of [ 10 B] pinacolborane, an expensive reagent. In order to reduce the amount of 10 B in the whole reaction, it is preferable that the borylation reaction be the last reaction. In addition, 1 B equivalent of the amount of 10 B required in the borylation process is optimal in terms of the most effect.
상기 조건을 만족시키기 위해, 실시예 1에서 합성된 [10B]pinacolborane과 4번 위치에 이탈기가 도입되어 있는 L-phenylalanine을 기질로 사용하고(도 2참조. 이는 retrosynthetic pathway 전략을 표현한 것임) aryl pinacolboronate를 합성하는데 널리 이용되는 금속 촉매 반응을 수행하여 [10B]LBPA를 수율 78%로 매우 효과적으로 합성할 수 있었다. 이는 기존에 bis(pinacolato)diboron을 사용했던 reference에서 82%의 수율을 얻은 것과 비교하면 동등한 것이고, 10B를 기준으로 따지면 효율성이 증가되었다고 말할 수 있다.In order to satisfy the above conditions, the [ 10 B] pinacolborane synthesized in Example 1 and the L-phenylalanine introduced with the leaving group at the 4-position were used as a substrate (see FIG. 2, which represents a retrosynthetic pathway strategy) [ 10 B] LBPA was synthesized very efficiently at a yield of 78% by performing a metal catalyzed reaction widely used for synthesizing pinacolboronate. This is equivalent to a yield of 82% for a reference that previously used bis (pinacolato) diboron, and it can be said that the efficiency is increased with respect to 10 B.
[10B]LBPA의 합성 여부는 reference 화합물과 product NMR을 비교하여 확인하였다.[ 10 B] The synthesis of LBPA was confirmed by comparing the reference compound with product NMR.
(도 3)은 . N-Boc-L-4-iodophenylalanine methyl ester를 시작 기질로 하여, [10B]pinacolborane을 반응 물질로 사용하였으며, PdCl2(dppf)을 금속 촉매로 사용하여, 결합 반응을 수행한 과정을 나타낸다. 이는 reference(M. E. Jung et. al., J. Org. Chem. 1999, 64, 2976-2977)에서 N-Boc 4-iodophenylalanine methyl ester와 Bis(pinacolato)diboron을 이용하여 반응시킨 예를 응용하여, bis(pinacolato)diboron 대신 pinacolborane을 이용하여 반응을 수행하고 원하는 화합물을 합성할 수 있음을 보인 것이다.(Fig. 3). N-Boc-L-4-iodophenylalanine methyl ester was used as a starting substrate, [ 10 B] pinacolborane was used as a reactant, and PdCl 2 (dppf) was used as a metal catalyst. The reaction was carried out by using N-Boc 4-iodophenylalanine methyl ester and Bis (pinacolato) diboron in reference (ME Jung et al., J. Org. Chem. 1999, 64, 2976-2977) (pinacolato) diboron instead of pinacolborane, and the desired compound can be synthesized.
(도 4)는, (도 3)의 후속 과정이며, 최종적으로 [10B]LBPA가 합성되는 과정을 보인 것이다.
(FIG. 4) is a subsequent process of (FIG. 3), finally showing the process of synthesizing [ 10 B] LBPA.
이상, 본 발명내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적인 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의해 정의된다고 할 것이다. Having described specific portions of the present invention in detail, those skilled in the art will appreciate that these specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (4)
[반응식 1]
Converting (A) [ 10 B] boric acid ( 10 B (OH) 3 ) into an alcohol and converting it into [ 10 B] alkyl pinacolboronate (1), as shown in Reaction Scheme 1 below. Preparation of [10 B] pinacol borane ([10 B] pinacolborane) containing; and (B) the [10 B] alkyl pinacolboronate (1 ) a step of obtaining a by reduction with a reducing agent [10 B] pinacolborane (2) Way.
[Reaction Scheme 1]
상기 R-OH는, 메탄올, 에탄올, 이소프로판올, 아릴 알콜로 구성된 군에서 선택되는 하나의 알콜인 것을 특징으로 하는 [10B]피나콜보란([10B]pinacolborane)의 제조방법.
In Scheme 1,
The method of the R-OH are methanol, ethanol, isopropanol, [B 10] pinacol borane ([B 10] pinacolborane), characterized in that one of the alcohol is selected from the group consisting of an aryl alcohol.
[반응식 2]
As it is shown in Scheme 2 below, the method of claim 1. The [10 B] pinacol borane ([10 B] pinacolborane) and reacting with N-Boc-L-4- iodophenylalanine methyl ester prepared in the step of using a metal catalyst ≪ RTI ID = 0.0 > [ 10B ] < / RTI > LBPA.
[Reaction Scheme 2]
상기 금속 촉매는, PdCl2(dppf) 촉매인 것을 특징으로 하는 [10B]LBPA의 제조방법.The method of claim 3,
The metal catalyst, PdCl2 (dppf) [B 10] The method of LBPA, characterized in that the catalyst.
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| CN116655674A (en) * | 2023-01-16 | 2023-08-29 | 中国科学院兰州化学物理研究所 | Method for synthesizing high-abundance boron 10 isotope biboronate |
| WO2024077407A1 (en) * | 2022-10-09 | 2024-04-18 | 成都化润药业有限公司 | Chiral reducing agent and method for synthesizing chiral nicotine |
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| WO2024077407A1 (en) * | 2022-10-09 | 2024-04-18 | 成都化润药业有限公司 | Chiral reducing agent and method for synthesizing chiral nicotine |
| CN116655674A (en) * | 2023-01-16 | 2023-08-29 | 中国科学院兰州化学物理研究所 | Method for synthesizing high-abundance boron 10 isotope biboronate |
| CN116655674B (en) * | 2023-01-16 | 2024-04-16 | 中国科学院兰州化学物理研究所 | Method for synthesizing high-abundance boron 10 isotope biboronate |
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