JPH0931092A - Process for producing 2'-3'-di-O-acyl ATP - Google Patents
Process for producing 2'-3'-di-O-acyl ATPInfo
- Publication number
- JPH0931092A JPH0931092A JP21091595A JP21091595A JPH0931092A JP H0931092 A JPH0931092 A JP H0931092A JP 21091595 A JP21091595 A JP 21091595A JP 21091595 A JP21091595 A JP 21091595A JP H0931092 A JPH0931092 A JP H0931092A
- Authority
- JP
- Japan
- Prior art keywords
- atp
- salt
- group
- acyl
- producing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000003863 ammonium salts Chemical group 0.000 claims description 6
- 150000003973 alkyl amines Chemical class 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 150000007933 aliphatic carboxylic acids Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- -1 acyl ATP Chemical compound 0.000 description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 11
- 239000002904 solvent Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000002253 acid Substances 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 150000001735 carboxylic acids Chemical group 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000003512 tertiary amines Chemical class 0.000 description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical class CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- HQWDKLAIDBOLFE-UHFFFAOYSA-M 2-fluoro-1-methylpyridin-1-ium;4-methylbenzenesulfonate Chemical compound C[N+]1=CC=CC=C1F.CC1=CC=C(S([O-])(=O)=O)C=C1 HQWDKLAIDBOLFE-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IIFFFBSAXDNJHX-UHFFFAOYSA-N 2-methyl-n,n-bis(2-methylpropyl)propan-1-amine Chemical compound CC(C)CN(CC(C)C)CC(C)C IIFFFBSAXDNJHX-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 102100037601 P2X purinoceptor 4 Human genes 0.000 description 1
- 108010085249 Purinergic P2 Receptors Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- YAOQCOUSDPCULI-UHFFFAOYSA-N di(propan-2-yloxy)phosphorylformonitrile Chemical compound CC(C)OP(=O)(C#N)OC(C)C YAOQCOUSDPCULI-UHFFFAOYSA-N 0.000 description 1
- LPMHDYUMNBBOKR-UHFFFAOYSA-N dimethoxyphosphorylformonitrile Chemical compound COP(=O)(OC)C#N LPMHDYUMNBBOKR-UHFFFAOYSA-N 0.000 description 1
- PDIOPTPBTWLDDG-UHFFFAOYSA-N diphenoxyphosphorylformonitrile Chemical compound C=1C=CC=CC=1OP(C#N)(=O)OC1=CC=CC=C1 PDIOPTPBTWLDDG-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical compound CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 description 1
- OOHAUGDGCWURIT-UHFFFAOYSA-N n,n-dipentylpentan-1-amine Chemical compound CCCCCN(CCCCC)CCCCC OOHAUGDGCWURIT-UHFFFAOYSA-N 0.000 description 1
- CYQYCASVINMDFD-UHFFFAOYSA-N n,n-ditert-butyl-2-methylpropan-2-amine Chemical compound CC(C)(C)N(C(C)(C)C)C(C)(C)C CYQYCASVINMDFD-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Abstract
(57)【要約】
【解決手段】 本発明はホスホン酸エステル誘導体の存
在下に、ATP又はその塩とアシル化剤を反応させるこ
とを特徴とする、2’−3’−ジ−O−アシルATPの
製造法に関する。また、本発明はホスホン酸エステル誘
導体及び塩基の存在下に、ATP又はその塩とアシル化
剤を反応させることを特徴とする、2’−3’−ジ−O
−アシルATPの製造法に関する。本発明の方法は、高
収率でかつ、汎用性のあるATPのアシル化方法を提供
するものである。(57) Abstract: The present invention is characterized in that 2'-3'-di-O-acyl is characterized by reacting ATP or a salt thereof with an acylating agent in the presence of a phosphonate derivative. The present invention relates to a method for producing ATP. Further, the present invention is characterized by reacting ATP or a salt thereof with an acylating agent in the presence of a phosphonate derivative and a base, 2'-3'-di-O.
-A method for producing acyl ATP. The method of the present invention provides a high-yield and versatile method for acylating ATP.
Description
【0001】[0001]
【産業上の利用分野】本発明は、2’−3’−ジ−O−
アシルアデノンシン−5’−トリフォスフェート(以
下、2’−3’−ジ−O−アシルATPと略称する)又
はその塩の新規な製造法に関する。The present invention relates to 2'-3'-di-O-
The present invention relates to a novel method for producing acyladenosine-5'-triphosphate (hereinafter abbreviated as 2'-3'-di-O-acyl ATP) or a salt thereof.
【0002】[0002]
【従来の技術】2’−3’−ジ−O−アシルATPは、
プリナージックATPレセプターの拮抗薬等として医薬
の分野で有用である。従来、2’−3’−ジ−O−アシ
ルATPの製造法としては、例えば1,1’−カルボニ
ルジイミダゾールを縮合剤として用い、ATPのナトリ
ウム塩とカルボン酸を水溶液中、室温下で1ないし2日
反応させる方法[Am.J.Physiol.,257
(6)2834(1982)]、2−フルオロ−1−メ
チルピリジニウムパラトルエンスルホネートを縮合剤と
して用い、ATPのトリブチルアンモニウム塩とカルボ
ン酸をジクロロメタン、室温下で1ないし2日反応させ
る方法[New J.Chem.,17,325(19
93)]などが知られている。しかしながら、これらの
方法はいずれも収率が30%以下でかつ、2’−又は
3’−モノアシル化合物との混合物として得られたの
で、工業的に適用することができず、収率の良い製造法
の開発が望まれていた。また、これらのアシル化反応は
反応性も低く、多くのアシル化剤に適用できる一般的な
方法として好ましいものではなかった。2. Description of the Prior Art 2'-3'-di-O-acyl ATP is
It is useful in the field of medicine as an antagonist of a plinazic ATP receptor. Conventionally, as a method for producing 2′-3′-di-O-acyl ATP, for example, 1,1′-carbonyldiimidazole is used as a condensing agent, and a sodium salt of ATP and a carboxylic acid are mixed in an aqueous solution at room temperature at a temperature of 1 To the reaction for 2 days [Am. J. Physiol. , 257
(6) 2834 (1982)], 2-fluoro-1-methylpyridinium p-toluenesulfonate as a condensing agent, and a method of reacting a tributylammonium salt of ATP with a carboxylic acid in dichloromethane at room temperature for 1 to 2 days [New J . Chem. , 17, 325 (19
93)] and the like are known. However, since all of these methods had a yield of 30% or less and were obtained as a mixture with a 2'- or 3'-monoacyl compound, they cannot be industrially applied and the production with a good yield is possible. Development of law was desired. Further, these acylation reactions are low in reactivity, which is not preferable as a general method applicable to many acylating agents.
【0003】[0003]
【発明が解決しようとする課題】従って、本発明の目的
は、2’−3’−ジ−O−アシルATPを高収率で製造
できる工業的に有用な方法を提供すると共に、2’−
3’−ジ−O−アシルATPを製造する汎用の方法を提
供することである。Therefore, an object of the present invention is to provide an industrially useful method capable of producing 2'-3'-di-O-acyl ATP in high yield, and to provide 2'-
It is an object of the present invention to provide a general method for producing 3′-di-O-acyl ATP.
【0004】[0004]
【課題を解決するための手段】かかる実情において、本
発明者らは鋭意検討を行った結果、公知方法に比べて極
めて高収率でかつ、一般性のある2’−3’−ジ−O−
アシルATPを製造できる方法を見出し、本発明を完成
した。本発明は、ATP又はその塩をアシル化して2’
−3’−ジ−O−アシルATP又はその塩を製造する方
法において、当該反応を次式、 (R1O)2P(O)R2 (式中、R1は低級アルキル基又は置換基を有してもよ
いアリール基若しくはアラルキル基を、R2はシアノ基
又はアジド基を示す。)で示されるホスホン酸エステル
誘導体の存在下に行うことを特徴とする2’−3’−ジ
−O−アシルATP又はその塩の製造方法に関する。ま
た、本発明は、縮合剤として次式、 (R1O)2P(O)R2 (式中、R1は低級アルキル基又は置換基を有してもよ
いアリール基若しくはアラルキル基を、R2はシアノ基
又はアジド基を示す。)で示されるホスホン酸エステル
誘導体を用い、ATP又はその塩とアシル化剤を反応さ
せて2’−3’−ジ−O−アシルATPを製造する方法
を提供するものである。本発明の方法は、好ましくはさ
らに塩基の存在下に行うことができる。すなわち、本発
明はATP又はその塩をアシル化して2’−3’−ジ−
O−アシルATP又はその塩を製造する方法において、
当該反応を次式、 (R1O)2P(O)R2 (式中、R1は低級アルキル基又は置換基を有してもよ
いアリール基若しくはアラルキル基を、R2はシアノ基
又はアジド基を示す。)で示されるホスホン酸エステル
誘導体及び塩基の存在下に行うことを特徴とする2’−
3’−ジ−O−アシルATP又はその塩の製造方法に関
する。Under such circumstances, the inventors of the present invention have conducted extensive studies and as a result, as a result, 2'-3'-di-O, which has an extremely high yield and generality as compared with the known method, has been obtained. −
The present invention has been completed by finding out a method capable of producing acyl ATP. In the present invention, ATP or a salt thereof is acylated to obtain 2 '.
3'-di -O- acyl ATP or a process for the preparation of a salt thereof, the following equation the reaction, (R 1 O) 2 P (O) R 2 ( wherein, R 1 represents a lower alkyl group or a substituted group R 2 represents a cyano group or an azido group), and the aryl group or aralkyl group which may have 2′-3′-di- The present invention relates to a method for producing O-acyl ATP or a salt thereof. In addition, the present invention also provides, as a condensing agent, a compound represented by the following formula: (R 1 O) 2 P (O) R 2 (wherein R 1 represents a lower alkyl group or an aryl group or aralkyl group which may have a substituent, R 2 represents a cyano group or an azido group), and ATP or a salt thereof is reacted with an acylating agent to produce 2′-3′-di-O-acyl ATP. Is provided. The method of the present invention can be preferably carried out in the presence of a base. That is, the present invention acylates ATP or a salt thereof to produce 2'-3'-di-
In the method for producing O-acyl ATP or a salt thereof,
The reaction is represented by the following formula: (R 1 O) 2 P (O) R 2 (wherein, R 1 is a lower alkyl group or an aryl group or aralkyl group which may have a substituent, and R 2 is a cyano group or 2'-, which is carried out in the presence of a phosphonate derivative represented by azido group) and a base.
The present invention relates to a method for producing 3'-di-O-acyl ATP or a salt thereof.
【0005】本発明の方法で用いられるアシル化剤とし
ては、飽和又は不飽和の脂肪族カルボン酸、飽和又は不
飽和の環式脂肪族カルボン酸、芳香族カルボン酸、芳香
脂肪族カルボン酸、複素環式カルボン酸などのカルボン
酸又はそれらの反応性誘導体を用いることができる。ま
た、これらのカルボン酸は本発明の方法の反応を阻害し
ない置換基で置換されたものであってもよい。これらの
カルボン酸としては、例えば(1)分子中にアジド基、
ニトロ基、シアノ基、アセチルアミノ基、O−シリル基
などの官能基を有するカルボン酸又は通常、容易に酸ク
ロライドに変換できない不安定な官能基を有するカルボ
ン酸、(2)一般的に反応性が劣る長鎖カルボン酸、
(3)立体的に嵩高いカルボン酸、(4)難溶性のカル
ボン酸、(5)従来のエステル化方法、例えば酸無水物
法(ショッテン法)、WSC法(含水系縮合剤を用いる
方法)、CDI法(非水系縮合剤を用いる方法)、向山
法(縮合剤として2−フロロ−1−メチルピリジウム
p−トルエンスルホン酸を用いる非水系の方法)、DC
C法(非水系縮合剤を用いる方法)では反応しないカル
ボン酸、などを挙げることができる。As the acylating agent used in the method of the present invention, a saturated or unsaturated aliphatic carboxylic acid, a saturated or unsaturated cycloaliphatic carboxylic acid, an aromatic carboxylic acid, an araliphatic carboxylic acid, or a heterocyclic Carboxylic acids such as cyclic carboxylic acids or their reactive derivatives can be used. Further, these carboxylic acids may be substituted with a substituent that does not inhibit the reaction of the method of the present invention. Examples of these carboxylic acids include (1) an azido group in the molecule,
A carboxylic acid having a functional group such as a nitro group, a cyano group, an acetylamino group, an O-silyl group or a carboxylic acid having an unstable functional group which cannot be easily converted into an acid chloride, (2) Generally reactive Poor long-chain carboxylic acid,
(3) sterically bulky carboxylic acid, (4) sparingly soluble carboxylic acid, (5) conventional esterification method, for example, acid anhydride method (Schotten method), WSC method (method using water-containing condensing agent) , CDI method (method using non-aqueous condensing agent), Mukaiyama method (2-fluoro-1-methylpyridinium as condensing agent)
Non-aqueous method using p-toluenesulfonic acid), DC
Examples thereof include a carboxylic acid that does not react with Method C (method using a non-aqueous condensing agent).
【0006】本発明の方法で使用される好ましいアシル
化剤としては、置換基を有してもよい炭素数1から3
0、より好ましくは炭素数1から20のアルカン酸又は
アルケン酸、置換基を有してもよい炭素数7から15、
より好ましくは炭素数7から10の芳香族カルボン酸、
置換基を有してもよい炭素数8から16、より好ましく
は炭素数8から10のアリールアルカンカルボン酸又は
アリールアルケンカルボン酸、置換記を有してもよい1
個以上の窒素原子、酸素原子又は硫黄原子を異種原子と
して含有する4から7員の複素環式カルボン酸などを挙
げることができる。これらのカルボン酸の置換基として
は、炭素数1から10、好ましくは炭素数1から5の低
級アルキル基、水酸基、炭素数1から10、好ましくは
炭素数1から5の低級アルコキシ基、炭素数1から1
0、好ましくは炭素数1から5の低級アルキル基で置換
されていてもよいアミノ基、アジド基などを挙げること
ができる。The preferred acylating agent used in the method of the present invention has 1 to 3 carbon atoms which may have a substituent.
0, more preferably an alkanoic acid or alkenoic acid having 1 to 20 carbon atoms, 7 to 15 carbon atoms which may have a substituent,
More preferably, an aromatic carboxylic acid having 7 to 10 carbon atoms,
An arylalkanecarboxylic acid or an arylalkenecarboxylic acid having 8 to 16 carbon atoms, more preferably 8 to 10 carbon atoms, which may have a substituent, and optionally having 1
Examples thereof include 4- to 7-membered heterocyclic carboxylic acids containing one or more nitrogen atoms, oxygen atoms or sulfur atoms as different atoms. Substituents of these carboxylic acids include a lower alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, a hydroxyl group, a lower alkoxy group having 1 to 10 carbon atoms, preferably a lower alkoxy group having 1 to 5 carbon atoms, 1 to 1
Examples thereof include an amino group and an azido group which may be substituted with 0, preferably a lower alkyl group having 1 to 5 carbon atoms.
【0007】本発明の方法で使用する次式、 (R1O)2P(O)R2 (式中、R1は低級アルキル基又は置換基を有してもよ
いアリール基若しくはアラルキル基を、R2はシアノ基
又はアジド基を示す。)で示されるホスホン酸エステル
誘導体の置換基R1の低級アルキル基としては、炭素数
1から10、好ましくは炭素数1から5の低級アルキル
基、具体的には、メチル基、エチル基、イソプロピル基
などが挙げられる。また、置換基R1の置換基を有して
もよいアリール基若しくはアラルキル基としては、炭素
数6から12、好ましくは炭素数6から10のアリール
基又はアラルキル基、具体的にはフェニル基、ナフチル
基、ベンジル基などが挙げられる。これらの置換基とし
ては、反応を阻害しないものであればとくに制限はない
が、炭素数1から5の低級アルキル基などを挙げること
ができる。置換基R2としては、シアノ基(−CN)又
はアジド基(−N3)などが好ましい。本発明のホスホ
ン酸エステル誘導体の具体例としては、例えば、ジメチ
ルホスホロシアニデート[(MeO)2P(O)C
N]、ジエチルホスホロシアニデート[(EtO)2P
(O)CN]、ジイソプロピルホスホロシアニデート
[(i−PrO)2P(O)CN]、ジフェニルホスホ
ロシアニデート[(PhO)2P(O)CN]、ジフェ
ニルホスホロアジド[(PhO)2P(O)N3]など
が挙げられる。さらに好ましい例としては、ジエチルホ
スホロシアニデート[(EtO)2P(O)CN]を挙
げることができる。本発明で使用するホスホン酸エステ
ル誘導体は、公知の方法又はその方法に準じて製造する
ことができる。例えば、ジエチルホスホロシアニデート
は、塩入らの方法[J.Am.Chem.Soc.,9
4,603(1975)]に従って製造することができ
る。The following formula used in the method of the present invention: (R 1 O) 2 P (O) R 2 (wherein R 1 represents a lower alkyl group or an aryl group or aralkyl group which may have a substituent). , R 2 represents a cyano group or an azido group), and the lower alkyl group of the substituent R 1 of the phosphonate derivative represented by the formula ( 1) is a lower alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, Specific examples thereof include a methyl group, an ethyl group, an isopropyl group and the like. As the aryl group or aralkyl group which may have a substituent of the substituent R 1, an aryl group or an aralkyl group having 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms, specifically, a phenyl group, Examples thereof include naphthyl group and benzyl group. These substituents are not particularly limited as long as they do not inhibit the reaction, and examples thereof include a lower alkyl group having 1 to 5 carbon atoms. The substituent R 2, a cyano group (-CN) or azido group (-N 3) is preferable. Specific examples of the phosphonate derivative of the present invention include, for example, dimethylphosphorocyanidate [(MeO) 2 P (O) C.
N], diethylphosphorocyanidate [(EtO) 2 P
(O) CN], diisopropylphosphorocyanidate [(i-PrO) 2 P (O) CN], diphenylphosphorocyanidate [(PhO) 2 P (O) CN], diphenylphosphoroazide [(PhO)] 2 P (O) N 3 ] and the like. A more preferable example is diethylphosphorusocyanidate [(EtO) 2 P (O) CN]. The phosphonate derivative used in the present invention can be produced by a known method or according to the method. For example, diethylphosphorocyanidate can be prepared according to the method of Shioiri [J. Am. Chem. Soc. , 9
4, 603 (1975)].
【0008】本発明の方法で用いるATPは、その塩と
して使用することが好ましい。ATPの塩としては種々
のものを使用することができるが、そのアンモニウム塩
が好ましい。ATPのアンモニウム塩としては、ATP
と一般的なアミン、より好ましくは3級アミンとで通常
の方法で製造できるアンモニウム塩を用いることができ
る。3級アミンとしては、同一又は異なる炭素数1から
10、より好ましくは炭素数1から6のアルキル基から
なるトリアルキルアミン、5から7員の脂環式基を有す
るアミン、ピリジン、ピコリンなどの置換基を有しても
よい複素環式アミンなどを挙げることができる。より具
体的には、例えばトリメチルアミン、トリエチルアミ
ン、トリプロピルアミン、トリイソプロピルアミン、ト
リ−n−ブチルアミン、トリイソブチルアミン、トリ−
t−ブチルアミン、トリ−n−アミルアミン、トリ−n
−ヘキシルアミン、ジメチルエチルアミン、ジメチルプ
ロピルアミン等の炭素数1〜6のアルキル基からなるト
リ低級アルキルアミン、ピリジンなどが挙げられる。本
発明のATPのアンモニウム塩は、例えばATP、好ま
しくはATPの有機塩、例えばピリジン塩、と3級アミ
ンとを溶媒中で反応させることによって製造することが
できる。溶媒としては、メタノール、エタノール、プロ
パノール等のアルコール類、などが用いられる。反応は
0〜50℃、好ましくは室温付近で、瞬時に進行する。
この方法で得られるアムモニウム塩は通常の方法で精製
できるが、精製せずにそのまま次の反応に用いることが
できる。The ATP used in the method of the present invention is preferably used as its salt. Although various salts of ATP can be used, ammonium salts thereof are preferred. The ammonium salt of ATP includes ATP
An ammonium salt which can be produced by a usual method with a general amine, more preferably a tertiary amine can be used. Examples of the tertiary amine include trialkylamines having the same or different C1 to C10, more preferably C1 to C6 alkyl groups, amines having a 5- to 7-membered alicyclic group, pyridine, picoline, etc. Examples thereof include a heterocyclic amine which may have a substituent. More specifically, for example, trimethylamine, triethylamine, tripropylamine, triisopropylamine, tri-n-butylamine, triisobutylamine, tri-
t-butylamine, tri-n-amylamine, tri-n
Examples thereof include tri-lower alkylamines having an alkyl group having 1 to 6 carbon atoms such as hexylamine, dimethylethylamine, and dimethylpropylamine, and pyridine. The ammonium salt of ATP of the present invention can be produced, for example, by reacting ATP, preferably an organic salt of ATP, for example, a pyridine salt, with a tertiary amine in a solvent. As the solvent, alcohols such as methanol, ethanol and propanol are used. The reaction proceeds instantaneously at 0 to 50 ° C., preferably around room temperature.
Although the ammonium salt obtained by this method can be purified by a usual method, it can be directly used for the next reaction without purification.
【0009】本発明のATP又はその塩とカルボン酸な
どのアシル化剤との反応は、両者とジ低級アルキルホス
ホロシアニデートを無水溶媒中で、より好ましくは塩基
の存在下に反応させると、目的の2’−3’−ジ−O−
アシルATPが得られる。溶媒としては例えば、無水の
ジメチルホルムアミド、ジメチルスルホキサイド、テト
ラヒドロフラン、トルエン、ジクロロメタン、クロロホ
ルムなどを用いることができる。塩基としては例えば、
先に例示したトリ低級アルキルアミンの他、水素化ナト
リウム、DBU(1,5−ジアザビシクロ[5.4.
0]ウンデセン−5)、炭酸カリウム、水酸化ナトリウ
ムなどを用いることができる。反応は0〜50℃、好ま
しくは室温付近で、数時間〜数日で進行する。目的物の
分離・精製は通常の方法、例えば、溶媒抽出法、塩交換
法、クロマトグラフィー法、再結晶法、凍結乾燥法など
を単独又は適宜組み合わせて行うことができる。目的化
合物は塩の形で単離することもできる。本反応を塩基と
して3級アミンの存在下で行った場合は通常、対応する
アミンの塩が得られるが、他の塩を望む場合は、通常の
塩交換法によって新たな塩とすることができる。The reaction of ATP or a salt thereof of the present invention with an acylating agent such as a carboxylic acid is carried out by reacting both with a di-lower alkylphosphorusanidate in an anhydrous solvent, more preferably in the presence of a base, The target 2'-3'-di-O-
Acyl ATP is obtained. As the solvent, for example, anhydrous dimethylformamide, dimethylsulfoxide, tetrahydrofuran, toluene, dichloromethane, chloroform and the like can be used. As the base, for example,
In addition to the tri-lower alkylamines exemplified above, sodium hydride, DBU (1,5-diazabicyclo [5.4.
[0] Undecene-5), potassium carbonate, sodium hydroxide and the like can be used. The reaction proceeds at 0 to 50 ° C., preferably around room temperature, for several hours to several days. Separation / purification of the desired product can be carried out by an ordinary method, for example, a solvent extraction method, a salt exchange method, a chromatography method, a recrystallization method, a lyophilization method, or the like alone or in combination. The target compound can also be isolated in the form of a salt. When this reaction is carried out in the presence of a tertiary amine as a base, a salt of the corresponding amine is usually obtained, but when another salt is desired, it can be converted into a new salt by a usual salt exchange method. .
【0010】本発明方法によって製造される2’−3’
−ジ−O−アシルATPの具体例として、以下のものを
挙げることができる。2’−3’−ジ−O−アセチルー
ATP、2’−3’−ジ−O−プロピオニル−ATP、
2’−3’−ジ−O−n−ブチリル−ATP、2’−
3’−ジ−O−イソブリチル−ATP、2’−3’−ジ
−O−n−バレリル−ATP、2’−3’−ジ−O−イ
ソバレリル−ATP、2’−3’−ジ−O−カプリロイ
ル−ATP、2’−3’−ジ−O−エナンシル−AT
P、2’−3’−ジ−O−カプリリル−ATP、2’−
3’−ジ−O−ペラルゴニル−ATP、2’−3’−ジ
−O−パルミトイル−ATP、2’−3’−ジ−O−ス
テアロイル−ATP、2’−3’−ジ−O−オレオイル
−ATP、2’−3’−ジ−O−ベンゾイル−ATP、
2’−3’−ジ−O−p−トルオイル−ATP、2’−
3’−ジ−O−(4−t−ブチルベンゾイル)−AT
P、2’−3’−ジ−O−(2−アミノベンゾイル)−
ATP、2’−3’−ジ−O−(4−アミノベンゾイ
ル)−ATP、2’−3’−ジ−O−(3,4,5−ト
リメトキシベンゾイル)−ATP、2’−3’−ジ−O
−サルチロイル−ATP、2’−3’−ジ−O−シンナ
モイル−ATP、2’−3’−ジ−O−ナフトイル−A
TP、2’−3’−ジ−O−(5−アジドナフトイル)
−ATP、2’−3’−ジ−O−ニコチノイル−AT
P、2’−3’−ジ−O−イソニコチノイル−ATP、
及びこれらの塩。2'-3 'produced by the method of the present invention
Specific examples of -di-O-acyl ATP include the following. 2'-3'-di-O-acetyl-ATP, 2'-3'-di-O-propionyl-ATP,
2'-3'-di-On-butyryl-ATP, 2'-
3'-di-O-isobrityl-ATP, 2'-3'-di-O-n-valeryl-ATP, 2'-3'-di-O-isovaleryl-ATP, 2'-3'-di-O -Capryloyl-ATP, 2'-3'-di-O-enanthyl-AT
P, 2'-3'-di-O-caprylyl-ATP, 2'-
3'-di-O-pelargonyl-ATP, 2'-3'-di-O-palmitoyl-ATP, 2'-3'-di-O-stearoyl-ATP, 2'-3'-di-O-ole. Oil-ATP, 2'-3'-di-O-benzoyl-ATP,
2'-3'-di-Op-toluoyl-ATP, 2'-
3'-di-O- (4-t-butylbenzoyl) -AT
P, 2'-3'-di-O- (2-aminobenzoyl)-
ATP, 2'-3'-di-O- (4-aminobenzoyl) -ATP, 2'-3'-di-O- (3,4,5-trimethoxybenzoyl) -ATP, 2'-3 ' -The-O
-Sartyloyl-ATP, 2'-3'-di-O-cinnamoyl-ATP, 2'-3'-di-O-naphthoyl-A
TP, 2'-3'-di-O- (5-azidonaphthoyl)
-ATP, 2'-3'-di-O-nicotinoyl-AT
P, 2'-3'-di-O-isonicotinoyl-ATP,
And their salts.
【0011】[0011]
【実施例】次に実施例をあげて本発明をさらに詳細に説
明するが、本発明はこれに限定されるものではない。The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
【0012】実施例1 2’−3’−ジ−O−イソニコチノイル−ATPの製
造: (a)ATPのジナトリウム塩(3水和物)1.0gを
水20mlに溶解し、4℃以下で陽イオン交換樹脂、ダ
ウエックス50W×8(200−400mesh.ピリ
ジニウム型:ダウコーニング社製)10mlに対し、水
150mlで溶出した。この溶出液を凍結乾燥して、A
TPのピリジニウム塩の粉末1.07gを得た。 (b)ATPのピリジニウム塩20mg(0.03mm
ol)をメタノール1mlとトリ−(n−ブチル)アミ
ン22mg(0.06mmol)の混液に溶解した。次
いで、減圧下に溶媒を留去して得られる無色のカラメル
をジメチルホルムアミド0.5mlに溶解した。この溶
液にトリ−(n−ブチル)アミン55mg(0.3m
l)を加え、続いてイソニコチン酸110mg(0.9
mmol)及びジエチルホスホロシアニデート147m
g(0.9mmol)を加えて室温で攪拌した。この反
応液にトリエチルアミン91mg(0.9mmol)を
徐々に滴下し、室温で72時間攪拌した。反応終了後、
浴温40℃以下で溶媒を減圧下に留去し、残渣に水10
mlを加えて逆抽出し、酢酸エチルで洗浄した。水層を
分取し、40℃以下で溶媒を減圧下に留去して淡黄色油
物状324mgを得た。この油物状をエタノール1ml
に溶解し、セファデックスLH−20に付し、エタノー
ルで溶出した。目的物を含む分画より溶媒を減圧下に留
去して、目的物化合物の2・トリ−n−ブチルアミン塩
27mg(収率:90%)を得た。Example 1 Preparation of 2'-3'-di-O-isonicotinoyl-ATP: (a) 1.0 g of the disodium salt of ATP (trihydrate) was dissolved in 20 ml of water and the temperature was kept at 4 ° C or lower. 150 ml of water was eluted with respect to 10 ml of cation exchange resin, Dowex 50W × 8 (200-400 mesh. Pyridinium type: manufactured by Dow Corning). The eluate was freeze-dried to give A
1.07 g of powder of TP pyridinium salt was obtained. (B) ATP pyridinium salt 20 mg (0.03 mm
was dissolved in a mixed solution of 1 ml of methanol and 22 mg (0.06 mmol) of tri- (n-butyl) amine. Next, the colorless caramel obtained by distilling off the solvent under reduced pressure was dissolved in 0.5 ml of dimethylformamide. 55 mg (0.3 m of tri- (n-butyl) amine was added to this solution.
l) was added, followed by 110 mg of isonicotinic acid (0.9
mmol) and diethyl phosphorocyanidate 147 m
g (0.9 mmol) was added and the mixture was stirred at room temperature. 91 mg (0.9 mmol) of triethylamine was gradually added dropwise to this reaction solution, and the mixture was stirred at room temperature for 72 hours. After the reaction,
The solvent was distilled off under reduced pressure at a bath temperature of 40 ° C or lower, and water was added to the residue.
The mixture was added with ml and back-extracted, and washed with ethyl acetate. The aqueous layer was separated and the solvent was distilled off under reduced pressure at 40 ° C. or lower to obtain 324 mg of a pale yellow oily substance. 1 ml of this oily substance is ethanol
The extract was dissolved in, and subjected to Sephadex LH-20, and eluted with ethanol. The solvent was distilled off from the fraction containing the target compound under reduced pressure to obtain 27 mg (yield: 90%) of 2-tri-n-butylamine salt of the target compound.
【0013】IR値 cm−1(KBr):17411 H−NMR値 δ(D2O)ppm: 4.42−4.52(2H,m,C5’−H×2) 5.0−5.1(1H,brs.C4’−H) 6.2−6.3(1H,m,C3’−H) 6.3−6.4(1H,m,C2’−H) 6.88(1H,d,C1’−H) 8.22(1H,m,Aden−H) 8.42(3H,d,Py−H) 8.52(2H,d,Py−H) 8.75(1H,s,Aden−H) 8.9 (2H,m,Py−H) 9.05(2H,d,Py−H)IR value cm −1 (KBr): 1741 1 H-NMR value δ (D 2 O) ppm: 4.42-4.52 (2H, m, C5′-H × 2) 5.0-5 .1 (1H, brs.C4'-H) 6.2-6.3 (1H, m, C3'-H) 6.3-6.4 (1H, m, C2'-H) 6.88 ( 1H, d, C1'-H) 8.22 (1H, m, Aden-H) 8.42 (3H, d, Py-H) 8.52 (2H, d, Py-H) 8.75 (1H , S, Aden-H) 8.9 (2H, m, Py-H) 9.05 (2H, d, Py-H)
【0014】実施例2−14 各種カルボン酸を用いて、実施例1と同様に処理し、次
の表1〜3に示される化合物を得た。Example 2-14 Various carboxylic acids were used and treated in the same manner as in Example 1 to obtain compounds shown in Tables 1 to 3 below.
【0015】[0015]
【表1】 [Table 1]
【0016】[0016]
【表2】 [Table 2]
【0017】[0017]
【表3】 [Table 3]
【0018】[0018]
【発明の効果】本発明は、ATP又はその塩から2’−
3’−ジ−O−アシルATPを高収率で製造できる工業
的に有用な方法を提供すると共に、2’−3’−ジ−O
−アシルATPを製造する汎用の方法を提供することが
できる。INDUSTRIAL APPLICABILITY The present invention uses 2'-from ATP or a salt thereof.
Provided is an industrially useful method capable of producing 3'-di-O-acyl ATP in high yield, and 2'-3'-di-O.
-A general method for producing acyl ATP can be provided.
Claims (6)
3’−ジ−O−アシルATP又はその塩を製造する方法
において、当該反応を次式、 (R1O)2P(O)R2 (式中、R1は低級アルキル基又は置換基を有してもよ
いアリール基若しくはアラルキル基を、R2はシアノ基
又はアジド基を示す。)で示されるホスホン酸エステル
誘導体の存在下に行うことを特徴とする2’−3’−ジ
−O−アシルATP又はその塩の製造方法。1. ATP or a salt thereof is acylated to obtain 2'-
In the method for producing 3′-di-O-acyl ATP or a salt thereof, the reaction is performed by the following formula: (R 1 O) 2 P (O) R 2 (wherein R 1 represents a lower alkyl group or a substituent). 2′-3′-di-O, which is carried out in the presence of a phosphonate derivative represented by R 2 which may have an aryl group or aralkyl group, wherein R 2 represents a cyano group or an azido group. -Method for producing acyl ATP or a salt thereof.
存在下に行うことを特徴とする2’−3’−ジ−O−ア
シルATP又はその塩の製造方法。2. A method for producing 2′-3′-di-O-acyl ATP or a salt thereof, which comprises performing the method according to claim 1 in the presence of a base.
項1又は2に記載の製造方法。3. The method according to claim 1, wherein the ATP salt is an ammonium salt.
項1から3のいずれか1項に記載の製造方法。4. The production method according to claim 1, wherein the salt of ATP is a pyridinium salt.
求項2から4のいずれか1項に記載の製造方法。5. The production method according to claim 2, wherein the base is tri-lower alkylamine.
芳香族カルボン酸又はこれらの反応性誘導体である請求
項1から5のいずれか1項に記載の製造方法。6. The production method according to claim 1, wherein the acylating agent is an aliphatic carboxylic acid, an aromatic carboxylic acid, or a reactive derivative thereof.
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114539338A (en) * | 2022-01-05 | 2022-05-27 | 苏州赜文医药科技有限公司 | Disodium adenosine triphosphate trihydrate crystal and preparation method thereof |
US11697666B2 (en) | 2021-04-16 | 2023-07-11 | Gilead Sciences, Inc. | Methods of preparing carbanucleosides using amides |
US11767337B2 (en) | 2020-02-18 | 2023-09-26 | Gilead Sciences, Inc. | Antiviral compounds |
US12030903B2 (en) | 2020-02-18 | 2024-07-09 | Gilead Sciences, Inc. | Antiviral compounds |
US12054507B2 (en) | 2020-02-18 | 2024-08-06 | Gilead Sciences, Inc. | Antiviral compounds |
US12116380B2 (en) | 2021-08-18 | 2024-10-15 | Gilead Sciences, Inc. | Phospholipid compounds and methods of making and using the same |
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1995
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11767337B2 (en) | 2020-02-18 | 2023-09-26 | Gilead Sciences, Inc. | Antiviral compounds |
US12030903B2 (en) | 2020-02-18 | 2024-07-09 | Gilead Sciences, Inc. | Antiviral compounds |
US12054507B2 (en) | 2020-02-18 | 2024-08-06 | Gilead Sciences, Inc. | Antiviral compounds |
US11697666B2 (en) | 2021-04-16 | 2023-07-11 | Gilead Sciences, Inc. | Methods of preparing carbanucleosides using amides |
US12116380B2 (en) | 2021-08-18 | 2024-10-15 | Gilead Sciences, Inc. | Phospholipid compounds and methods of making and using the same |
CN114539338A (en) * | 2022-01-05 | 2022-05-27 | 苏州赜文医药科技有限公司 | Disodium adenosine triphosphate trihydrate crystal and preparation method thereof |
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