KR101963570B1 - Method for the Preparation of Amorphous Dinucleoside Polyphosphate Compound - Google Patents
Method for the Preparation of Amorphous Dinucleoside Polyphosphate Compound Download PDFInfo
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- KR101963570B1 KR101963570B1 KR1020180084950A KR20180084950A KR101963570B1 KR 101963570 B1 KR101963570 B1 KR 101963570B1 KR 1020180084950 A KR1020180084950 A KR 1020180084950A KR 20180084950 A KR20180084950 A KR 20180084950A KR 101963570 B1 KR101963570 B1 KR 101963570B1
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- uridine
- tetraphosphate
- hydrate
- salt
- amorphous
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- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 title description 12
- 229920000388 Polyphosphate Polymers 0.000 title description 3
- 239000001205 polyphosphate Substances 0.000 title description 3
- 235000011176 polyphosphates Nutrition 0.000 title description 3
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims abstract description 78
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims abstract description 39
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229940045145 uridine Drugs 0.000 claims abstract description 39
- YDHWWBZFRZWVHO-UHFFFAOYSA-H [oxido-[oxido(phosphonatooxy)phosphoryl]oxyphosphoryl] phosphate Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O YDHWWBZFRZWVHO-UHFFFAOYSA-H 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 239000000126 substance Substances 0.000 claims abstract description 5
- 235000002639 sodium chloride Nutrition 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000012296 anti-solvent Substances 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 23
- 238000004108 freeze drying Methods 0.000 abstract description 6
- 238000001694 spray drying Methods 0.000 abstract description 4
- 150000004677 hydrates Chemical class 0.000 abstract description 2
- 238000010298 pulverizing process Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- -1 tetraphosphate compound Chemical class 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- XCCTYIAWTASOJW-XVFCMESISA-N Uridine-5'-Diphosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 XCCTYIAWTASOJW-XVFCMESISA-N 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 239000005630 Diquat Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 229930182474 N-glycoside Natural products 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- PGAVKCOVUIYSFO-XVFCMESISA-N UTP Chemical group O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-XVFCMESISA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000005280 amorphization Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 229940125714 antidiarrheal agent Drugs 0.000 description 1
- 239000003793 antidiarrheal agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012777 commercial manufacturing Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- SYJFEGQWDCRVNX-UHFFFAOYSA-N diquat Chemical compound C1=CC=[N+]2CC[N+]3=CC=CC=C3C2=C1 SYJFEGQWDCRVNX-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940046466 freeze it Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DZIBYQIEKQLDES-UHFFFAOYSA-N tetraazanium;hydrogen sulfate Chemical compound [NH4+].[NH4+].[NH4+].[NH4+].OS([O-])(=O)=O.OS([O-])(=O)=O.OS([O-])(=O)=O.OS([O-])(=O)=O DZIBYQIEKQLDES-UHFFFAOYSA-N 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 229940048102 triphosphoric acid Drugs 0.000 description 1
- PGAVKCOVUIYSFO-UHFFFAOYSA-N uridine-triphosphate Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)OC1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 무정형 디뉴클레오사이드 폴리포스페이트 화합물의 제조 방법에 관한 것으로, 무정형을 제조하기 위한 별도의 장치 또는 대량 생산에 부적합한 공정을 이용하지 않고 간편하고 안정적으로 P1,P4-디(우리딘 5'-)테트라포스페이트 화합물, 이의 염 또는 이의 수화물의 무정형을 제조하는 방법에 관한 것이다.5-di (uridine-present invention relates to a method of producing amorphous dinyu nucleoside polyphosphate compound, a simply and reliably without the use of inappropriate processing on a separate device or a mass-produced for the production of amorphous P 1, P 4 '-) tetraphosphate compound, a salt thereof or a hydrate thereof.
뉴클레오사이드(Nucleoside)는 핵 염기와 오탄당이 N-글리코사이드 결합을 이룬 배당체 화합물로, 인산화 효소에 의해 뉴클레오사이드에 인산기가 결합되면 DNA 사슬의 기본 구성 성분인 뉴클레오타이드(Nucleotide)가 된다.Nucleoside is a glycoside compound in which an N-glycoside bond is formed between a nucleotide and a pentose. When a phosphate group is bonded to a nucleoside by a phosphorylation enzyme, the nucleotide becomes a basic component of the DNA chain.
이러한 뉴클레오타이드의 일종인 디뉴클레오사이드 폴리포스페이트 또는 이의 염은 생체 내 물질과 유사하여 체내에서 안정하고 그에 따른 질병 치료에 효과를 가진다고 알려져 있다.Dynucleoside polyphosphate or a salt thereof, which is a kind of nucleotides, is known to be stable in the body and to be effective in the treatment of diseases, similar to a substance in vivo.
특히, 하기 화학식 1로 표시되는 P1,P4-디(우리딘 5'-)테트라포스페이트(이하, “UP4U”라 표기함) 또는 이의 염은 안구 건조증 또는 눈물 건조증에 수반되는 각결막 상피 장애의 치료제로 이용되고 있으며, 가래 배출 유도 작용을 가지기 때문에 거담제 또는 폐렴 치료제로서 개발이 기대되는 화합물이다.In particular, P 1 , P 4 -di (uridine 5'-) tetraphosphate (hereinafter referred to as "UP 4 U") or a salt thereof represented by the following formula (1) It is used as a therapeutic agent for epithelial disorders and has a guiding action of phlegm discharge, so it is a compound expected to be developed as an antidiarrheal agent or a therapeutic agent for pneumonia.
[화학식 1][Chemical Formula 1]
Bioorganic & Medicinal Chemistry Letters, 11, (2001), 157-160, 국제공개공보 제2008/012949호, 국제공개공보 제1999/05155호에 의하면 UP4U는, 우리딘 5'-트리인산 또는 우리딘 5'-환상 트리인산 또는 우리딘 5'-디인산 또는 우리딘 5'-모노인산을 이용하여 탈수 축합반응을 통해 합성될 수 있다고 보고되어 있다.According to Bioorganic & Medicinal Chemistry Letters, 11, (2001), 157-160, International Publication No. 2008/012949, International Publication No. 1999/05155, UP 4 U is Uridine 5'-triphosphate or Uridine It has been reported that it can be synthesized through dehydration condensation reaction using 5'-cyclic triphosphoric acid or uridine 5'-diphosphoric acid or uridine 5'-monophosphoric acid.
또한, 국제공개공보 제1999/05155호에 의하면 당시 고체의 UP4U 테트라나트륨염을 산출하기 위해 동결건조를 이용하였고, 국제공개공보 제2000/020430호에 의하면 동결건조 화합물의 여러 가지 단점을 극복하기 위해 수용액 형태의 화합물에 적절한 유기 용매를 첨가함으로써 결정형 화합물을 개발했다고 보고되어 있다. Also, according to International Publication No. 1999/05155, lyophilization was used to produce solids of UP 4 U tetrasodium salt at that time, and according to International Publication WO 2000/020430, various drawbacks of freeze- It has been reported that crystalline compounds have been developed by adding an appropriate organic solvent to the compound in the form of an aqueous solution.
한편, 원료 의약품의 무정형 고체를 합성하는 방법에는 통상적으로 용매증발법, 분무건조법, 동결건조법 등의 방법이 이용되어 왔다. 용매증발법은 실험실의 규모에서 용매를 감압농축 등으로 제거하여 폼 형태의 고체를 형성시키고 이를 분쇄하여 얻을 수 있지만, 반응기 내부에 쌓이는 형태로 상업적인 제조 단위에 적용이 불가하다. 분무건조법은 높은 온도의 열풍기류에 액상 시료를 분사함으로써 순간적으로 증발 및 건조되어 분말 형태의 고체를 얻는 방법인데, 시료가 고온에 노출되는 단점이 있다. 동결건조법은 열에 민감한 물질에 손상을 최소화할 수 있고 안정적으로 무정형을 수득할 수 있는 방법이지만, 수행하기 위한 전용 장치가 필요하며 용액의 동결-승화-잔류수분의 제거를 위하여 추가 건조의 여러 단계를 거치게 되어 에너지 소비가 크고 공정에 소요되는 시간이 매우 길다.On the other hand, methods such as solvent evaporation, spray drying and freeze-drying have been used to synthesize amorphous solids of drug substance. The solvent evaporation method can be obtained by removing the solvent at a scale of a laboratory by vacuum concentration or the like to form a solid in the form of a foam and pulverizing it, but it is not applicable to a commercial manufacturing unit in a form piled up inside the reactor. The spray drying method is a method in which a liquid sample is sprayed to a hot air stream at a high temperature to evaporate and dry instantaneously to obtain a powdery solid, which is disadvantageous in that the sample is exposed to high temperatures. The freeze-drying method is a method that can minimize damage to heat-sensitive materials and can obtain stable amorphous form. However, a dedicated device is required to perform and several steps of freeze-sublimation- The energy consumption is high and the time required for the process is very long.
일반적으로 원료 의약품으로서 무정형 고체는 약제학적으로 유용하게 사용될 수 있음에도 불구하고, 위 살핀 바와 같이 제조방법에 있어 별도의 대규모 시설투자가 필요하고 에너지와 시간의 소모가 큰 단점이 있어 효율적이지 않다고 판단되어 왔다.Although amorphous solids can be used as pharmaceuticals in general, it is considered that the manufacturing method requires separate large-scale facility investment as well as energy and time consuming. come.
따라서 위와 같은 이유로, 별도의 설비투자 없이 상업적으로 대량 생산에 적합한 고순도의 무정형 P1,P4-디(우리딘 5'-)테트라포스페이트, 이의 염 또는 이의 수화물 제조하는 방법이 요구되고 있다.Therefore, there is a demand for a method for producing high purity amorphous P 1 , P 4 -di (uridine 5'-) tetraphosphate, a salt thereof or a hydrate thereof, which is suitable for commercial mass production without any facility investment.
본 발명의 목적은 대량 생산에 적합하고 효율적이며 별도의 장치를 사용하지 않고도 P1,P4-디(우리딘 5'-)테트라포스페이트, 이의 염 또는 이의 수화물의 무정형을 고순도로 대량생산이 가능한 제조방법을 제공하는 것이다.It is an object of the present invention to provide a process for producing amorphous P 1 , P 4 -di (uridine 5'-) tetraphosphate, a salt thereof or a hydrate thereof, which is suitable for mass production, And a method for manufacturing the same.
또한 본 발명의 목적은 무정형의 P1,P4-디(우리딘 5'-)테트라포스페이트, 이의 염 또는 이의 수화물을 제공하는 것이다. It is also an object of the present invention to provide an amorphous P 1 , P 4 -di (uridine 5'-) tetraphosphate, a salt thereof or a hydrate thereof.
본 발명은 P1,P4-디(우리딘 5'-)테트라포스페이트, 이의 염 또는 이의 수화물의 무정형을 제조하는 방법을 제공한다. The present invention provides a process for preparing amorphous forms of P 1 , P 4 -di (uridine 5'-) tetraphosphate, its salts or hydrates thereof.
본 발명의 제조방법은, (S-1) 하기 화학식 1로 표시되는 조(crude) P1,P4-디(우리딘 5'-)테트라포스페이트를 제조하는 단계; (S-2) 상기 조(crude) P1,P4-디(우리딘 5'-)테트라포스페이트에 물을 가하여 P1,P4-디(우리딘 5'-)테트라포스페이트, 이의 염 또는 이의 수화물을 포함하는 용액을 농축하는 단계; 및 (S-3) 상기 농축 용액에 반용매를 가하는 단계를 포함한다. The production method of the present invention comprises the steps of: (S-1) preparing crude P 1 , P 4 -di (uridine 5'-) tetraphosphate represented by the following
[화학식 1][Chemical Formula 1]
본 발명에 있어서, 상기 (S-1) 단계는 P1,P4-디(우리딘 5'-)테트라포스페이트를 합성한 후 물, 유기 용매 또는 이들의 혼합용매를 가하여 고체화시키는 것일 수 있다. In the present invention, the step (S-1) may be a step of synthesizing P 1 , P 4 -di (uridine 5'-) tetraphosphate and solidifying it by adding water, an organic solvent or a mixed solvent thereof.
본 발명의 구체예에 따르면, 상기 (S-1) 단계를 통하여 제조된 고체는 무정형일 수 있다.According to an embodiment of the present invention, the solid produced through step (S-1) may be amorphous.
상기 (S-1) 단계에서, 상기 유기 용매는 C1-C8 알코올, C3-C10 케톤, 1,4-디옥산, 아세토니트릴, N,N-디메틸포름아미드 및 디메틸설폭사이드로 이루어진 군으로부터 선택된 어느 하나 이상일 수 있다. 구체적으로 상기 유기 용매는 C1-C4 알코올일 수 있다. 다만, 이에 한정되지 않는다.In the step (S-1), the organic solvent may be selected from the group consisting of C 1 -C 8 alcohols, C 3 -C 10 ketones, 1,4-dioxane, acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide May be any one or more selected from the group consisting of Specifically, the organic solvent may be a C 1 -C 4 alcohol. However, the present invention is not limited thereto.
또한, 상기 (S-1) 단계는 0 내지 50 ℃에서 수행될 수 있다. 구체적으로, 10 내지 30℃에서 수행될 수 있다. 다만, 이에 한정되지 않는다.Further, the step (S-1) may be carried out at 0 to 50 ° C. Specifically, it may be carried out at 10 to 30 占 폚. However, the present invention is not limited thereto.
본 발명의 구체예에 따르면, 상기 P1,P4-디(우리딘 5'-)테트라포스페이트, 이의 염 또는 이의 수화물은 하기 화학식 1a로 표시되는 P1,P4-디(우리딘 5'-)테트라포스페이트의 테트라나트륨염 또는 이의 수화물일 수 있다. According to an embodiment of the present invention, the P 1 , P 4 -di (uridine 5'-) tetraphosphate, a salt thereof or a hydrate thereof is represented by P 1 , P 4 -di (uridine 5 ' -) < / RTI > tetraphosphate, or a hydrate thereof.
[화학식 1a][Formula 1a]
본 발명에 있어서, 상기 화학식 1a의 화합물은 상기 (S-2) 단계에서 나트륨 공급원을 가하여 제조될 수 있다. 상기 나트륨 공급원은 염화나트륨, 탄산나트륨, 탄산수소나트륨, 아세트산나트륨, 황산나트륨 및 인산나트륨으로 이루어진 군으부터 선택된 어느 하나 이상일 수 있다. 다만, 이에 한정되지 않는다.In the present invention, the compound of formula (1a) may be prepared by adding a sodium source in step (S-2). The sodium source may be any one or more selected from the group consisting of sodium chloride, sodium carbonate, sodium bicarbonate, sodium acetate, sodium sulfate and sodium phosphate. However, the present invention is not limited thereto.
본 발명에 있어서, 상기 (S-3) 단계에서 반용매는 C1-C2 알코올일 수 있다. 구체적으로, 상기 반용매는 메탄올일 수 있다. In the present invention, the anti-solvent in step (S-3) may be C 1 -C 2 alcohol. Specifically, the semi-solvent may be methanol.
본 발명의 구체예에 따르면, 상기 반용매로 C3-C10 케톤, 1,4-디옥산, 아세토니트릴, N,N-디메틸포름아미드 및 디메틸설폭사이드로 이루어진 군으로부터 선택된 1 이상을 더 포함할 수 있다. 보다 구체적으로, 상기 반용매로 아세톤을 더 포함할 수 있다. According to an embodiment of the present invention, the semi-solvent further includes at least one selected from the group consisting of C 3 -C 10 ketone, 1,4-dioxane, acetonitrile, N, N-dimethylformamide and dimethylsulfoxide can do. More specifically, it may further include acetone as the semi-solvent.
본 발명에 있어서, 상기 (S-3) 단계에서 농축 용액과 반용매의 부피비는 1:5 내지 1:30 일 수 있다. 구체적으로, 상기 부피비는 1:7 내지 1:25일 수 있다. In the present invention, the volume ratio of the concentrated solution to the half-solvent in the step (S-3) may be 1: 5 to 1:30. Specifically, the volume ratio may be 1: 7 to 1:25.
본 발명에 있어서, 상기 (S-3) 단계에서 농축 용액과 C1-C2 알코올의 부피비는 1:4 내지 1:20 일 수 있다. 구체적으로, 상기 부피비는 1:5 내지 1:15 일 수 있다. In the present invention, the volume ratio of the concentrated solution and the C 1 -C 2 alcohol in the step (S-3) may be 1: 4 to 1:20. Specifically, the volume ratio may be 1: 5 to 1:15.
본 발명에 있어서, 상기 (S-3) 단계는 -10 내지 50 ℃에서 수행될 수 있다. 구체적으로 0 내지 30 ℃에서 수행될 수 있다.In the present invention, the step (S-3) may be carried out at -10 to 50 ° C. Concretely at 0 to 30 < 0 > C.
따라서, 본 발명의 제조 방법에 따르면, 동결건조기 또는 분무건조기를 사용하지 않고, 일반적인 교반기를 사용하여 P1,P4-디(우리딘 5'-)테트라포스페이트의 무정형을 형성하고 간단한 여과를 통해 수득함으로써, 생산에 필요한 설비의 감소, 사용되는 시간, 노력, 비용의 단축이 가능하여 경제적이며, 이에 따른 불순물의 발생이 최소화될 뿐만 아니라 추가적인 품질의 향상을 기대할 수 있다. Thus, according to the preparation method of the present invention, an amorphous form of P 1 , P 4 -d (uridine 5'-) tetraphosphate is formed using a general stirrer, without using a freeze dryer or a spray dryer, It is possible to reduce the equipment required for production, shorten the time, effort, and cost required for production, which is economical and minimizes the generation of impurities therefrom, and can further improve the quality.
본 발명은 또한, 상기 제조 방법으로 제조된 P1,P4-디(우리딘 5'-)테트라포스페이트, 이의 염 또는 이의 수화물의 무정형을 제공한다. The present invention also provides an amorphous form of P 1 , P 4 -di (uridine 5'-) tetraphosphate, a salt thereof or a hydrate thereof, prepared by the above process.
본 발명의 일 구체예에 따르면, 3 내지 17 중량%의 수분을 포함하는 P1,P4-디(우리딘 5'-)테트라포스페이트 4 나트륨의 무정형을 제공한다.According to one embodiment of the present invention, there is provided an amorphous form of P 1 , P 4 -di (uridine 5'-) tetraphosphate tetrasodium containing 3 to 17% by weight of water.
상기 언급된 사항은 서로 모순되지 않는 한 동일하게 적용될 수 있다.The above-mentioned matters can be equally applied as long as they do not contradict each other.
본 발명에 따르면, P1,P4-디(우리딘 5'-)테트라포스페이트 화합물 또는 그의 금속염의 무정형을, 동결건조기 또는 분무건조기 등의 특수설비를 이용하거나 복잡하고 번거로운 공정 없이 간편하게 높은 수율 및 고품질로 얻을 수 있다. 또한, 본 발명의 제조방법은 공정 중에 높은 온도의 열이 가해지거나 오랜 시간 방치되는 과정이 없이 매우 온화한 조건에서 단시간에 고체화를 진행하고 간단한 여과공정을 통해 손쉽게 목적 화합물을 수득할 수 있다. 이에 따라 부반응물이 생성되지 않고 고체와 여액을 단리하는 과정 중에 정제 효과를 기대할 수 있기 때문에, 의약품 원료로 사용되기 위한 고품질의 화합물을 얻을 수 있다. According to the present invention, the amorphous form of the P 1 , P 4 -di (uridine 5'-) tetraphosphate compound or its metal salt can be easily and efficiently obtained by using special equipment such as freeze drier or spray dryer, It can be obtained with high quality. In addition, the method of the present invention can solidify the material in a very mild condition for a short period of time without any heat treatment at a high temperature or a long time during the process, and can easily obtain a desired compound through a simple filtration process. As a result, a side effect can not be produced and a purification effect can be expected during isolation of the solid and the filtrate. Thus, a high-quality compound to be used as a raw material for pharmaceuticals can be obtained.
도 1은 실시예 1에서 합성된 무정형 UP4U·4Na의 분말 X-선 회절분광도 (Powder X-ray Diffraction Spectrum) 데이터이다.
도 2는 실시예 1에서 합성된 무정형 UP4U·4Na의 시차주사열량분석 (Differential Scanning Calorimeter Spectrum) 데이터이다.
도 3은 실시예 1에서 합성된 무정형 UP4U·4Na을 현미경으로 관찰한 사진이다.
도 4는 비교예 4에서 합성된 결정형 UP4U·4Na의 분말 X-선 회절분광도 (Powder X-ray Diffraction Spectrum) 데이터이다.
도 5는 비교예 4에서 합성된 결정형 UP4U·4Na의 시차주사열량분석 (Differential Scanning Calorimeter Spectrum) 데이터이다.
도 6은 비교예 4에서 합성된 결정형 UP4U·4Na을 현미경으로 관찰한 사진이다.Figure 1 is an amorphous UP 4 · U powder X- ray diffraction spectra of Figure 4Na (Powder X-ray Diffraction Spectrum) data synthesized in Example 1.
2 is Example 1 an amorphous UP 4 U · 4Na of differential scanning calorimetry in the synthesis (Differential Scanning Calorimeter Spectrum) data.
3 is a photograph observed with the amorphous UP 4 U · 4Na synthesized in Example 1 under a microscope.
Figure 4 is a crystal form UP 4 U · a powder X- ray diffraction spectroscopy is also (Powder X-ray Diffraction Spectrum) data of 4Na synthesized in Comparative Example 4.
Figure 5 is a crystal form UP 4 U · a differential scanning calorimeter (Differential Scanning Calorimeter Spectrum) data of 4Na synthesized in Comparative Example 4.
Figure 6 is a photograph observing the crystal type UP 4 U · 4Na synthesized in Comparative Example 4 under a microscope.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예 및 실험예를 제시한다. 그러나 하기의 실시예 및 실험예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 실시예 및 실험예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred embodiments and experimental examples are provided to facilitate understanding of the present invention. However, the following examples and experimental examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples and experimental examples.
또한, 이하에서 언급된 시약 및 용매는 중국의 원료제조원, Sigma-Aldrich Korea 및 TCI 사로부터 구입한 것이며, HPLC는 Agilent Technoliges 사의 1200 Series를 사용하여 측정하였으며, 1H NMR은 Bruker(브루커) 사의 400 ultraShield NMR Spectrometer를 사용하여 측정하였으며, XRD 측정은 Bruker X-ray Diffractometer(XRD) D8 ADVANCE를 사용하였다. R/O 농축기는 Shinhan Sciencetec사의 UF filtration system을 사용하였으며, 분무건조는 Buchi사의 Spray Dryer B-290을 사용하였고 동결건조는 SP Scientific사의 Genesis SQ Super를 사용하였다.The reagents and solvents mentioned below were purchased from raw material suppliers in China, Sigma-Aldrich Korea and TCI. HPLC was measured using Agilent Technoliges 1200 series and 1 H NMR was performed by Bruker 400 ultraShield NMR spectrometer, and XRD was measured using a Bruker X-ray Diffractometer (XRD) D8 ADVANCE. The R / O concentrator was a UF filtration system from Shinhan Sciencetec. Spray Dryer B-290 from Buchi Co. was used for spray drying. Genesis SQ Super from SP Scientific was used for lyophilization.
본 발명에서 사용된 HPLC 조건은 다음과 같다.The HPLC conditions used in the present invention are as follows.
검출기 : 자외부흡광광도계 (측정파장 : 262 nm) Detector: Ultraviolet absorptiometer (measuring wavelength: 262 nm)
칼 럼 : Thermo-Hypersil ODS (4.6 mm X 250 mm, 5 μm)Column: Thermo-Hypersil ODS (4.6 mm X 250 mm, 5 μm)
이동상 : 인산이수소칼륨 및 황산수소 테트라암모늄 수용액과 메탄올의 혼합액Mobile phase: a mixture of potassium dihydrogenphosphate and aqueous tetraammonium hydrogen sulfate solution and methanol
유 량 : 1.0 mL/minFlow rate: 1.0 mL / min
온 도 : 30 ℃Temperature: 30 ℃
시 료 : UP4U(디쿠아포솔) 10 mg / 이동상 20 mLSample: UP 4 U (Diquat phosol) 10 mg /
주입량 : 25 μlInjection volume: 25 μl
실시예 1. UPExample 1. UP 44 U·4Na 무정형의 제조U · 4Na amorphous manufacture
UDP·2Na염 (100 g, 0.223 mol)을 정제수 0.3 L에 용해하여 10 ℃에서 교반한 후, EDC·HCl (42.8 g, 0.223 mol)과 CaCl2·2H2O (32.8 g, 0.223 mmol)을 순서대로 적가하여 10 ℃에서 4 시간 30 분 동안 교반하였다. 상기 반응 종료 후, 정제수 0.3 L와 EtOH 1.2 L를 주입하여 화합물을 고체화시키고 상온에서 약 1 시간 동안 교반하였다. 생성된 고체를 여과하고 건조하여 crude UP4U 화합물 105 g (순도 약 95%, 무정형)을 얻었다.UDP · 2Na salt (100 g, 0.223 mol) was dissolved in 0.3 L of purified water and stirred at 10 ° C. EDC · HCl (42.8 g, 0.223 mol) and CaCl 2 · 2H 2 O (32.8 g, 0.223 mmol) And the mixture was stirred at 10 ° C for 4 hours and 30 minutes. After completion of the reaction, 0.3 L of purified water and 1.2 L of EtOH were injected to solidify the compound, and the mixture was stirred at room temperature for about 1 hour. The resulting solid was filtered and dried to give 105 g of crude UP 4 U compound (purity about 95%, amorphous).
얻어진 고체를 탈이온수에 녹여 약염기성음이온교환수지 (Amberlite IRA 계열)에 흡착시킨 후 탈이온수, 저농도의 염산 용액, 염화나트륨 용액으로 순차적으로 용출하여 고품질의 분획을 R/O 농축한 후 강양이온교환수지(Diaion PK228L)에 통과시키고 다시 R/O 농축하여 UP4U·4Na 약 14% 용액으로 농축하였다.The resulting solids were dissolved in deionized water and adsorbed on a weakly basic anion exchange resin (Amberlite IRA series), followed by sequential elution with deionized water, low-concentration hydrochloric acid solution and sodium chloride solution to concentrate the high-quality fraction R / through the (Diaion PK228L) and concentrated again R / O and concentrated to approximately 14% solution UP 4 U · 4Na.
UP4U·4Na 약 14% 용액 750 ml를 10 ℃로 냉각된 메탄올 4.0 L에 주입하여 1 시간 동안 교반하였다. 형성된 고체를 여과한 후, 진공 건조하여 목적하는 무정형 UP4U·4Na을 얻었다 (75g, 수율 73 %, 순도 99.81 %).UP 4 U · 4Na 750 ml of about 14% solution was poured into 4.0 L of methanol cooled to 10 ° C and stirred for 1 hour. The formed solid was filtered and vacuum dried to obtain the desired amorphous UP 4 U. 4Na (75 g, yield 73%, purity 99.81%).
도 1 내지 3의 결과로부터 실시예 1에서 수득된 화합물은 무정형임을 확인할 수 있다.From the results of Figs. 1 to 3, it can be confirmed that the compound obtained in Example 1 is amorphous.
실시예 1에서 무정형을 만들기 전 농축 용액과 수득한 무정형 고체의 물리적 성질과 유연 물질을 비교하면 다음 표 1과 같이 정리된다.The physical properties of the concentrated solution and the obtained amorphous solid before the amorphization in Example 1 are compared with the flexible material as shown in Table 1 below.
[표 1] [Table 1]
실시예 2 및 3. UPExamples 2 and 3. UP 44 U·4Na 무정형의 제조U · 4Na amorphous manufacture
실시예 1의 과정에서 수득된 UP 4 U·4Na 약 14% 용액 7 mL를 약 2 mL까지 감압농축한 후, 아래 표 2과 같이 다양한 용매에 주입하여 30 분간 교반한 후 형성된 고체를 여과 (뷰흐너 깔때기 직경 5cm)한 후, 진공건조하여 UP 4 U·4Na을 얻었다.7 mL of a solution of about 14% of UP 4 U. 4Na obtained in the procedure of Example 1 was concentrated to about 2 mL under reduced pressure, and the solution was poured into various solvents as shown in Table 2 below. After stirring for 30 minutes, the formed solid was filtered
[표 2][Table 2]
위와 같이 UP4U·4Na의 무정형을 동결건조기 등의 특수한 설비 없이 수득할 수 있음을 확인하였다. As described above, it was confirmed that the amorphous form of UP 4 U. 4Na can be obtained without any special equipment such as a freeze dryer.
실시예 4 내지 8. UPExamples 4 to 8. UP 44 U·4Na 무정형의 제조U · 4Na amorphous manufacture
실시예 1의 과정에서 수득된 UP4U·4Na 약 14% 용액 7 mL를 약 2 mL까지 감압농축한 후 아래 표 3의 조건으로 메탄올에 주입하여 30 분간 교반한 후 형성된 고체를 여과 (뷰흐너 깔때기 직경 5cm)한 후, 진공건조하여 UP4U·4Na을 얻었다.7 mL of the about 14% solution of UP 4 U. 4Na obtained in the procedure of Example 1 was concentrated to about 2 mL under reduced pressure, and the solution was poured into methanol under the conditions shown in Table 3 below. After stirring for 30 minutes, the solid formed was filtered
[표 3][Table 3]
위와 같이 UP4U·4Na의 무정형을 동결건조기 등의 특수한 설비 없이 수득할 수 있음을 확인하였다. As described above, it was confirmed that the amorphous form of UP 4 U. 4Na can be obtained without any special equipment such as a freeze dryer.
비교예 1 내지 3. UPComparative Examples 1 to 3. UP 44 U·4Na 결정형의 제조Manufacturing of U · 4Na crystal form
실시예 1의 과정에서 수득된 UP 4 U·4Na 약 14% 용액 7 mL를 약 2 mL까지 감압농축한 후, 아래 표 4와 같이 다양한 용매에 주입하여 30 분간 교반한 후 형성된 고체를 여과 (뷰흐너 깔때기 직경 5cm)한 후, 진공건조하여 UP 4 U·4Na을 얻었다.7 mL of a solution of about 14% of UP 4 U. 4Na obtained in the procedure of Example 1 was concentrated to about 2 mL under reduced pressure, and the solution was poured into various solvents as shown in Table 4 below, stirred for 30 minutes,
[표 4][Table 4]
비교예 4. UPComparative Example 4. UP 44 U·4Na 결정형의 제조Manufacturing of U · 4Na crystal form
실시예 1에 기재된 제조방법으로 수득된 UP4U·4Na 약 14% 용액 200 mL에 메탄올 400 mL를 주입하고 2 시간 동안 교반하여 결정을 생성하였다. 결정을 여과하고 18 시간 동안 진공건조하여 결정형 UP4U·4Na을 얻었다 (25.2 g, 결정형, 수분 7.9 %).400 mL of methanol was poured into 200 mL of a 14% UP 4 U. 4Na solution obtained by the method described in Example 1, and stirred for 2 hours to form crystals. The crystals were filtered and vacuum dried for 18 hours to obtain crystalline UP 4 U. 4Na (25.2 g, crystalline, 7.9% moisture).
도 4 내지 6의 결과로부터 비교예 4에서 수득된 화합물은 결정형임을 확인할 수 있다.From the results of Figs. 4 to 6, it is confirmed that the compound obtained in Comparative Example 4 is in a crystalline form.
비교예 5. UPComparative Example 5. UP 44 U·4Na 무정형의 제조 (동결건조법)Production of U · 4Na amorphous (freeze-drying method)
실시예 1의 과정에서 수득된 UP4U·4Na 약 14% 용액 200 mL를 48 시간 동안 동결건조하여 목적하는 무정형 UP4U·4Na을 얻었다 (26.1 g, 무정형, 수분 15.0%).200 mL of a 14% solution of UP 4 U. 4Na obtained in the procedure of Example 1 was lyophilized for 48 hours to obtain the desired amorphous UP 4 U. 4Na (26.1 g, amorphous, moisture 15.0%).
실험예 1. UPExperimental Example 1. UP 44 U·4Na 무정형 및 결정형 시료의 건조 시험U · 4Na Drying test of amorphous and crystalline samples
실시예 1, 비교예 4 및 5의 제조 방법으로 제조된 UP4U·4Na의 무정형 또는 결정형의 시료를 별도의 포장 없이 진공건조 조건인 25℃, 1 inchHg에 48 시간 동안 노출시켜 최종 수분의 양을 관찰한 결과는 아래 표 5와 같다. Amorphous or crystalline samples of UP 4 U. 4Na prepared by the method of Example 1, Comparative Examples 4 and 5 were exposed to vacuum drying conditions of 25 ° C and 1 inchHg for 48 hours without additional packaging, The results are shown in Table 5 below.
[표 5][Table 5]
상기 결과를 바탕으로, 본 발명에 따른 제조방법으로 P1,P4-디(우리딘 5'-)테트라포스페이트 화합물, 이의 염 또는 이의 수화물의 무정형를 제조할 수 있음을 확인하였다. Based on the above results, it was confirmed that the amorphous form of P 1 , P 4 -di (uridine 5'-) tetraphosphate compound, its salt or its hydrate can be prepared by the process according to the present invention.
본 발명에 따른 제조방법으로 제조하는 경우, 생산에 필요한 설비의 감소, 작업에 소요되는 시간과 노력의 단축이 가능하여 경제적이며, 이에 따른 불순물의 발생이 최소화될 뿐만 아니라, 추가적인 품질의 향상을 기대할 수 있다.In the case of the production method according to the present invention, it is possible to reduce the equipment required for production, shorten the time and effort required for the production, and is economical, thereby minimizing the generation of impurities and further improving the quality .
상기와 같은 결과로 볼 때, 본 발명에 따른 P1,P4-디(우리딘 5'-)테트라포스페이트, 이의 염 또는 이의 수화물의 무정형 제조방법은 대량 생산에 유용하게 적용될 수 있는 것을 확인할 수 있다. From the above results, it can be seen that the amorphous preparation method of P 1 , P 4 -di (uridine 5'-) tetraphosphate, its salt or its hydrate according to the present invention can be applied to mass production have.
Claims (18)
(S-2) 상기 조(crude) P1,P4-디(우리딘 5'-)테트라포스페이트에 물을 가하고, P1,P4-디(우리딘 5'-)테트라포스페이트, 이의 염 또는 이의 수화물을 포함하는 용액을 농축하는 단계; 및
(S-3) 상기 농축 용액에 반용매를 가하는 단계;
를 포함하고,
상기 (S-3) 단계에서 반용매는 C1-C2 알코올이며,
상기 (S-3) 단계에서 농축 용액과 C1-C2 알코올의 부피비는 1:4 내지 1:12 인,
P1,P4-디(우리딘 5'-)테트라포스페이트, 이의 염 또는 이의 수화물의 무정형 제조방법:
[화학식 1]
(S-2) Water is added to the crude P 1 , P 4 -di (uridine 5'-) tetraphosphate and P 1 , P 4 -di (uridine 5'-) tetraphosphate, Or a hydrate thereof; And
(S-3) adding an anti-solvent to the concentrated solution;
Lt; / RTI >
In the step (S-3), the anti-solvent is a C 1 -C 2 alcohol,
In the step (S-3), the volume ratio of the concentrated solution and the C 1 -C 2 alcohol is 1: 4 to 1:12,
Process for the amorphous preparation of P 1 , P 4 -di (uridine 5'-) tetraphosphate, its salt or hydrate thereof:
[Chemical Formula 1]
[화학식 1a]
[Formula 1a]
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| WO1999005155A2 (en) | 1997-07-25 | 1999-02-04 | Inspire Pharmaceuticals, Inc. | Salts of di(uridine 5'-tetraphosphate), method for preparation and uses thereof |
| WO2000020430A1 (en) | 1998-10-02 | 2000-04-13 | Yamasa Corporation | Crystal of diuridine tetraphosphate or salt thereof and method for preparing the same, and method for producing said compound |
| WO2008012949A1 (en) | 2006-07-26 | 2008-01-31 | Yamasa Corporation | Process for producing di(pyrimidine nucleoside 5'-)polyphosphate |
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| WO1999005155A2 (en) | 1997-07-25 | 1999-02-04 | Inspire Pharmaceuticals, Inc. | Salts of di(uridine 5'-tetraphosphate), method for preparation and uses thereof |
| KR20010013797A (en) * | 1997-07-25 | 2001-02-26 | 인스파이어 파마슈티컬스 인코퍼레이티드 | Salts of di(uridine 5'-tetraphosphate), method for preparation and uses thereof |
| WO2000020430A1 (en) | 1998-10-02 | 2000-04-13 | Yamasa Corporation | Crystal of diuridine tetraphosphate or salt thereof and method for preparing the same, and method for producing said compound |
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