CN103664943A - Preparation method of purine derivative as well as intermediate and application of purine derivative - Google Patents

Preparation method of purine derivative as well as intermediate and application of purine derivative Download PDF

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CN103664943A
CN103664943A CN201210330336.5A CN201210330336A CN103664943A CN 103664943 A CN103664943 A CN 103664943A CN 201210330336 A CN201210330336 A CN 201210330336A CN 103664943 A CN103664943 A CN 103664943A
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CN103664943B (en
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王喆
应律
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Shanghai Longwood Biopharmaceuticals Co Ltd
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Tianjin Chang Sen Pharmaceutcal Corp Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/16—Acetic acid esters of dihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888

Abstract

The invention relates to a preparation method of a purine derivative of a compound shown in a formula IV, and also relates to a novel intermediate, compounds in the formulas V and VI, and application of the intermediate in preparation of the compound in the formula IV.

Description

The Preparation Method And Their Intermediate of purine derivative and application
Invention field
The present invention relates to the preparation method of a kind of purine derivative (formula IV compound), also relate to intermediate formula V and VI compound and their application in preparation formula IV compound of preparing this compounds.An example in formula IV compound is exactly 2-amido-9-[(1S, 3R, 4S)-4-hydroxyl-3-(hydroxymethyl)-2-methylene cyclopentane base]-6,9-dimethyl-3 hydrogen-purine-6-one.
Background technology
Hepatitis B is that a kind of hepatitis B virus (HBV) infection people apes comprise the mankind's liver, and causes the communicable disease of the inflammation that is called hepatitis.That this disease has caused that Asia and Africa are widely current, and popular in selected areas of China as " serum hepatitis " at first.Approximately world population 1/3rd, surpasses 2,000,000,000 people, has infected hepatitis B virus.This comprises 3.5 hundred million slow virus carrier.The body fluid that spreading comes from contact blood or contains blood.This acute illness causes liver inflammation, vomiting, jaundice.Chronic hepatitis B, finally may cause liver cirrhosis and liver cancer, a kind of at present to the very low fatal disease of chemotherapy induction.
Hepatitis B virus is a kind of member of hepadnaviruse.This virus is comprised of the core of a covering and an icosahedron lipid core capsid protein.Nucleocapsid is wrapping viral DNA and archaeal dna polymerase, has the similar reverse transcriptase activity of retrovirus.The embedded virus albumen comprising in covering relates to virus contact, and then enters permissive cell.This virus is one of minimum coating animal virus, and particle dia is 42 nanometers.
Entecavir, a hydration 2-amido-9-[(1S namely, 3R, 4S)-4-hydroxyl-3-(hydroxymethyl)-2-methylene cyclopentane base]-6,9-dimethyl-3 hydrogen-purine-6-one, is used as a kind of hepatitis b virus infected medicine for the treatment of at present.It is a kind of nucleoside analog, in viral reproduction process, suppresses reverse transcription, DNA replication dna and transcribing.Entecavir is the monohydrate of the Compound I shown in following structure.
Figure BDA00002105900400011
Entecavir and as the use of antiviral, by Zahler etc., invented patent U.S.Pat.No.5, describe for 206,244.Through the preparation technology who improves, in following patent, describe: Zhou, et al., US2009/014358, Bisacchi et al., WO 98/09964, and Pendri et al., in WO2004/052310 and US20040192912.What Colonno et al. described in patent WO 01/64221 is hepatitis B infected and/or and the infection for daily treatment of some combination ingredients that comprise low dosage Entecavir.
Current Entecavir is produced the achirality starting raw material that starts from needing chiral separation, and as patent, WO2004/052310 exemplifies.For fear of chiral separation step and then reduce production costs, utilize that the chirality of the chirality starting raw material that is easy to get or high efficiency introducing chiral centre is synthetic selects just to become target as other.
This patent is disclosed is novel, can amplify and the technique of high efficiency production Entecavir and intermediate thereof, and cost is low.
Here the discussion about background of invention is as explaining the present invention.This is not used as any preferential date of any claim of the material of admitting the reference of any institute.
Summary of the invention
Preparation method provided by the invention can amplify and produce expeditiously purine derivative and the intermediate thereof that comprises Entecavir, and cost is low.In this technique, starting raw material cheap and that be easy to get is used to introduce the chirality and the key that need and connects, and comprising methylene cyclopentane, by the short cyclization of a kind of high efficiency titanium, constructs.This technique is produced Entecavir for the starting raw material from being applicable to industrial cheapness and being easy to get novel method is provided.
According to an aspect of the present invention, the present invention relates to the preparation method of a kind of purine derivative (formula IV compound) or its hydrate (as monohydrate), it comprises the step as reactant by formula II.For example, comprise by compound ii as follows and compound III and carry out coupling;
Figure BDA00002105900400021
Wherein, R 1for H or R 1a; R 2for H or R 2a; R 3for halogen, OH or OR 3a; R 4for H or R 4a; R 5for H or R 5a;
Wherein, R 1afor CH 2oR 1a', C (O) R 1a', C (O) OR 1a', C (O) NHR 1a', CH 2r 1d', SiR 1a' R 1b' R 1c' or C (O) NR 1b' R 1c';
R 2afor CH 2oR 2a', C (O) R 2a', C (O) OR 2a', C (O) NHR 2a', CH 2r 2d', SiR 2a' R 2b' R 2c' or C (O) NR 2b' R 2c';
R 3afor CH 2oR 3a', C (O) R 3a', C (O) OR 3a', C (O) NHR 3a', CH 2r 3d', SiR 3a' R 3b' R 3c' or C (O) NR 3b' R 3c';
R 4afor CH 2oR 4a', C (O) R 4a', C (O) OR 4a', C (O) NHR 4a', CH 2r 4d', SiR 4a' R 4b' R 4c' or C (O) NR 4b' R 4c';
R 5afor OC (O) R 5a', C (O) R 5a', OC (O) OR 5a' or OSO 2r 5a';
Wherein, R 1a', R 2a', R 3a', R 4a', R 1b', R 2b', R 3b', R 4b', R 1c', R 2c', R 3c', R 4c' and R 5a' be independently:
(1) straight or branched alkyl, is preferably the straight or branched alkyl with 1 ~ 8 carbon or 1 ~ 6 carbon; Straight or branched thiazolinyl, is preferably the straight or branched thiazolinyl with 2 ~ 8 carbon or 2 ~ 6 carbon; Straight or branched alkynyl, is preferably the straight or branched alkynyl with 2 ~ 8 carbon or 2 ~ 6 carbon; Cycloalkyl, is preferably the cycloalkyl with 3 ~ 8 or 3 ~ 6 carbon; Or heterocyclic radical, be preferably the saturated heterocyclyl with 3 ~ 8 or 3 ~ 6 carbon;
(2) substituted alkyl, thiazolinyl, alkynyl, cycloalkyl or heterocyclic radical as described in (1);
(3) aryl, is preferably the aryl with 6 ~ 12 or 6 ~ 10 carbon;
(4) substituted aryl as described in (3);
(5) heteroaryl, is preferably the heteroaryl with 3～12 or 3 ~ 10 or 3 ~ 8 or 3 ~ 6 carbon; Or
(6) substituted heteroaryl as described in (5); Or
R 1b' and R 1c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings; R 2b' and R 2c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings; R 3b' and R 3c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings; R 4b' and R 4c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings;
Wherein, R 1d', R 2d', R 3d' and R 4d' be independently:
(1) there is the straight or branched thiazolinyl of 2 ~ 8 carbon or 2 ~ 6 carbon; The straight or branched alkynyl with 2 ~ 8 carbon or 2 ~ 6 carbon;
(2) substituted alkenyl or alkynyl as described in (1);
(3) aryl, is preferably the aryl with 6～12 or 6～10 carbon;
(4) substituted aryl as described in (3);
(5) heteroaryl, is preferably the heteroaryl with 3～12 or 3 ~ 10 or 3 ~ 8 or 3 ~ 6 carbon; Or
(6) substituted heteroaryl as described in (5); Or
R 1b' and R 1c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings; R 2b' and R 2c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings; R 3b' and R 3c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings; R 4b' and R 4c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings;
Wherein, described " substituted " refers to one, two, more than three or three, hydrogen atom is replaced by one or more following group independently: the amino of the hydroxyl of fluorine, chlorine, bromine, iodine, hydroxyl, protection, nitro, cyano group, amino, protection, carbonyl, thiocarbonyl ,-NH-(C 1-C 12Alkyl) ,-NH-(C 2-C 8Thiazolinyl) ,-NH-(C 2-C 8Alkynyl) ,-NH-(C 3-C 12Cycloalkyl) ,-NH-(C 6-C 12Aryl) ,-NH-(C 3-C 12Heteroaryl) ,-NH-(C 3-C 12Saturated heterocyclyl) ,-NH-(C 3-C 12Unsaturated heterocycle base), two (C 1-C 12Alkyl) replace amino, two (C 6-C 12Aryl) replace amino, two (C 3-C 12Heteroaryl) replace amino ,-O-(C 1-C 12Alkyl) ,-O-(C 2-C 8Thiazolinyl) ,-O-(C 2-C 8Alkynyl) ,-O-(C 3-C 12Cycloalkyl) ,-O-(C 6-C 12Aryl) ,-O-(C 3-C 12Heteroaryl) ,-O-(C 3-C 12Saturated heterocyclyl) ,-O-(C 3-C 12Unsaturated heterocycle base) ,-C (O)-(C 1-C 12Alkyl) ,-C (O)-(C 2-C 8Thiazolinyl) ,-C (O)-(C 2-C 8Alkynyl) ,-C (O)-(C 3-C 12Cycloalkyl) ,-C (O)-(C 6-C 12Aryl) ,-C (O)-(C 3-C 12Heteroaryl) ,-C (O)-(C 3-C 12Saturated heterocyclyl) ,-C (O)-(C 3-C 12Unsaturated heterocycle base) ,-CONH 2,-CONH-(C 1-C 12Alkyl),-CONH-(C 2-C 8Thiazolinyl) ,-CONH-(C 2-C 8Alkynyl) ,-CONH-(C 3-C 12Cycloalkyl) ,-CONH-(C 6-C 12Aryl) ,-CONH-(C 3-C 12Heteroaryl) ,-CONH-(C 3-C 12Saturated heterocyclyl) ,-CONH-(C 3-C 12Unsaturated heterocycle base) ,-OCO 2-(C 1-C 12Alkyl) ,-OCO 2-(C 2-C 8Thiazolinyl) ,-OCO 2-(C 2-C 8Alkynyl) ,-OCO 2-(C 3-C 12Cycloalkyl) ,-OCO 2-(C 6-C 12Aryl) ,-OCO 2-(C 3-C 12Heteroaryl) ,-OCO 2-(C 3-C 12Saturated heterocyclyl) ,-OCO 2-(C 3-C 12Unsaturated heterocycle base) ,-OCONH 2,-OCONH-(C 1-C 12Alkyl) ,-OCONH-(C 2-C 8Thiazolinyl) ,-OCONH-(C 2-C 8Alkynyl) ,-OCONH-(C 3-C 12Cycloalkyl) ,-OCONH-(C 6-C 12Aryl) ,-OCONH-(C 3-C 12Heteroaryl) ,-OCONH-(C 3-C 12Saturated heterocyclyl) ,-OCONH-(C 3-C 12Unsaturated heterocycle base) ,-NHC (O)-(C 1-C 12Alkyl) ,-NHC (O)-(C 2-C 8Thiazolinyl) ,-NHC (O)-(C 2-C 8Alkynyl) ,-NHC (O)-(C 3-C 12Cycloalkyl) ,-NHC (O)-(C 6-C 12Aryl) ,-NHC (O)-(C 3-C 12Heteroaryl) ,-NHC (O)-(C 3-C 12Saturated heterocyclyl) ,-NHC (O)-(C 3-C 12Unsaturated heterocycle base) ,-NHCO 2-(C 1-C 12Alkyl) ,-NHCO 2-(C 2-C 8Thiazolinyl) ,-NHCO 2-(C 2-C 8Alkynyl) ,-NHCO 2-(C 3-C 12Cycloalkyl) ,-NHCO 2-(C 6-C 12Aryl) ,-NHCO 2-(C 3-C 12Heteroaryl) ,-NHCO 2-(C 3-C 12Saturated heterocyclyl) ,-NHCO 2-(C 3-C 12Unsaturated heterocycle base) ,-NHC (O) NH 2,-NHC (O) NH-(C 1-C 12Alkyl) ,-NHC (O) NH-(C 2-C 8Thiazolinyl) ,-NHC (O) NH-(C 2-C 8Alkynyl) ,-NHC (O) NH-(C 3-C 12Cycloalkyl) ,-NHC (O) NH-(C 6-C 12Aryl) ,-NHC (O) NH-(C 3-C 12Heteroaryl) ,-NHC (O) NH-(C 3-C 12Saturated heterocyclyl) ,-NHC (O) NH-(C 3-C 12Unsaturated heterocycle base) ,-NHC (S) NH 2,-NHC (S) NH-(C 1-C 12Alkyl) ,-NHC (S) NH-(C 2-C 8Thiazolinyl) ,-NHC (S) NH-(C 2-C 8Alkynyl),-NHC (S) NH-(C 3-C 12Cycloalkyl) ,-NHC (S) NH-(C 6-C 12Aryl) ,-NHC (S) NH-(C 3-C 12Heteroaryl) ,-NHC (S) NH-(C 3-C 12Saturated heterocyclyl) ,-NHC (S) NH-(C 3-C 12Unsaturated heterocycle base) ,-NHC (NH) NH 2,-NHC (NH) NH-(C 1-C 12Alkyl) ,-NHC (NH) NH-(C 2-C 8Thiazolinyl) ,-NHC (NH) NH-(C 2-C 8Alkynyl) ,-NHC (NH) NH-(C 3-C 12Cycloalkyl) ,-NHC (NH) NH-(C 6-C 12Aryl) ,-NHC (NH) NH-(C 3-C 12Heteroaryl) ,-NHC (NH) NH-(C 3-C 12Saturated heterocyclyl) ,-NHC (NH) NH-(C 3-C 12Unsaturated heterocycle base),-NHC (NH)-(C 1-C 12Alkyl) ,-NHC (NH)-(C 2-C 8Thiazolinyl) ,-NHC (NH)-(C 2-C 8Alkynyl) ,-NHC (NH)-(C 3-C 12Cycloalkyl) ,-NHC (NH)-(C 6-C 12Aryl) ,-NHC (NH)-(C 3-C 12Heteroaryl) ,-NHC (NH)-(C 3-C 12Saturated heterocyclyl) ,-NHC (NH)-(C 4-C 12Unsaturated heterocycle base) ,-C (NH) NH-(C 1-C 12Alkyl) ,-C (NH) NH-(C 2-C 8Thiazolinyl) ,-C (NH) NH-(C 2-C 8Alkynyl) ,-C (NH) NH-(C 3-C 12Cycloalkyl) ,-C (NH) NH-(C 6-C 12Aryl) ,-C (NH) NH-(C 3-C 12Heteroaryl),-C (NH) NH-(C 3-C 12Saturated heterocyclyl) ,-C (NH) NH-(C 3-C 12Unsaturated heterocycle base) ,-S (O)-(C 1-C 12Alkyl) ,-S (O)-(C 2-C 8Thiazolinyl) ,-S (O)-(C 2-C 8Alkynyl) ,-S (O)-(C 3-C 12Cycloalkyl) ,-S (O)-(C 6-C 12Aryl) ,-S (O)-(C 3-C 12Heteroaryl) ,-S (O)-(C 3-C 12Saturated heterocyclyl) ,-S (O)-(C 3-C 12Unsaturated heterocycle base) ,-SO 2NH 2,-SO 2NH-(C 1-C 12Alkyl) ,-SO 2NH-(C 2-C 8Thiazolinyl) ,-SO 2NH-(C 2-C 8Alkynyl) ,-SO 2NH-(C 3-C 12Cycloalkyl) ,-SO 2NH-(C 6-C 12Aryl) ,-SO 2NH-(C 3-C 12Heteroaryl) ,-SO 2NH-(C 3-C 12Saturated heterocyclyl) ,-SO 2NH-(C 3-C 12Unsaturated heterocycle base) ,-NHSO 2-(C 1-C 12Alkyl) ,-NHSO 2-(C 2-C 8Thiazolinyl) ,-NHSO 2-(C 2-C 8Alkynyl) ,-NHSO 2-(C 3-C 12Cycloalkyl) ,-NHSO 2-(C 6-C 12Aryl) ,-NHSO 2-(C 3-C 12Heteroaryl) ,-NHSO 2-(C 3-C 12Saturated heterocyclyl) ,-NHSO 2-(C 3-C 12Unsaturated heterocycle base) ,-CH 2NH 2,-CH 2SO 2CH 3, C 6-C 12Aryl, C 6-C 12The C that aryl replaces 1-C 12Alkyl, C 3-C 12Heteroaryl, C 3-C 12The C that heteroaryl replaces 1-C 12Alkyl, C 3-C 12Saturated heterocyclyl, C 3-C 12Unsaturated heterocycle base, C 3-C 12Cycloalkyl, 1 C that alkoxyl replaces 1-C 12Alkyl, methoxymethoxy, methoxy ethoxy, sulfydryl ,-S-(C 1-C 12Alkyl) ,-S-(C 2-C 8Thiazolinyl) ,-S-(C 2-C 8Alkynyl) ,-S-(C 3-C 12Cycloalkyl) ,-S-(C 6-C 12Aryl) ,-S-(C 3-C 12Heteroaryl) ,-S-(C 3-C 12Saturated heterocyclyl) ,-S-(C 3-C 12Unsaturated heterocycle base) or methylthiomethyl; Wherein said aryl, heteroaryl, saturated heterocyclyl, unsaturated heterocycle base, alkyl, thiazolinyl, alkynyl, cycloalkyl, alkoxyl are without replacement or by the one or more further replacement in above-mentioned substituting group.
Above-mentioned coupling of the present invention can be passed through SN1 or SN2 substitution reaction, and for example light prolongs reaction (Mitsunobu reaction) or other SN1 or SN2 linked reaction and completes.
Figure BDA00002105900400061
According to an embodiment of the invention, above-mentioned R 1and R 2independently selected from H or hydroxyl protecting group; R 3for F, Cl, Br, I, OH, hydroxyl protecting group or O-basic metal; R 4for H or amino protecting group; R 5for H.
According to an embodiment of the invention, above-mentioned R 1for H, benzyl or tertiary butyl dimethyl-silicon (TBS); R 2for H or benzyl; R 3for F, Cl, Br, I or OH; R 4for H or tertbutyloxycarbonyl.For example, in formula II, R 1and R 2independently selected from hydroxyl protecting group, as benzyl and tertiary butyl dimethyl-silicon; In formula III, R 3for F, Cl, Br or I, R 4for H or tertbutyloxycarbonyl; In formula IV, R 1and R 2be all hydroxyl protecting group (as Bn or TBS), R 3for F, Cl, Br or I, R 4for amino protecting group (as Boc); R 1and R 2in one of be that hydroxyl protecting group (as Bn or TBS) and another are H, R 3for OH, R 4for H; R 1and R 2be all hydroxyl protecting group (as Bn or TBS), R 3for OH, R 4for H; Or R 1and R 2be all H, R 3for OH, R 4for H.
According to an embodiment of the invention, purine derivative of the present invention is R in formula IV 1and R 2be all H, R 3for OH, R 4compound for H.
According to an embodiment of the invention, the coupling in above-mentioned steps is to be prolonged and reacted by light.Preferably, under the effect of diethyl azodiformate (DEAD) and triphenylphosphine, complete coupling.Preferably, in reaction, add trifluoroacetic acid.Above-mentioned steps also optionally comprises the deprotection reaction of hydroxyl protecting group.
According to an embodiment of the invention, above-mentioned reaction is carried out under the existence of organic solvent.Preferably, described organic solvent is aprotic solvent.
According to an embodiment of the invention, the consumption of above-mentioned compound III is 0.1 ~ 3 times of compound ii molar weight, more preferably 0.2 ~ 2.5 times, and more preferably 0.5 ~ 2 times.
According to an embodiment of the invention, the temperature of reaction of above-mentioned reaction is-20 ~ 180 ℃, more preferably-20 ~ 100 ℃, and more preferably-20 ~ 60 ℃.
According to an embodiment of the invention, above-claimed cpd II is made by following either method:
(1) work as R 2for R 2atime, compound ii is made by following reaction:
Figure BDA00002105900400071
Wherein, radicals R 1, R 2aand R 5definition as aforementioned.Preferably, R 1for hydroxyl protecting group, for example benzyl (Bn) or t-Butyldimethylsilyl (TBS); R 2for hydroxyl protecting group, Bn for example; R 5for H or R 5a, R 5afor C (O) R 5a', and R 5a' be selected from the alkyl with 1 ~ 8 carbon of optional replacement, the optional thiazolinyl with 2 ~ 8 carbon replacing, the optional alkynyl that contains 2 ~ 8 carbon replacing, the optional cycloalkyl that contains 3 ~ 8 carbon replacing or the optional saturated heterocyclyl containing 2 ~ 8 carbon replacing.More preferably, R 1for TBS or Bn; R 5for H or R 5a, R 5afor the optional alkyl acyl with 1-6 carbon atom replacing, as ethanoyl (Ac); Or
(2) work as R 2during for H, compound ii is made by compound V:
Figure BDA00002105900400072
Wherein, radicals R 1and R 5definition described in (1).
According to an embodiment of the invention, aforesaid method (1) comprises the protected reaction of hydroxyl, and hydroxyl forms the hydroxyl of protection.For example: (i) in organic solvent, under the existence of alkali, incite somebody to action wherein R 2for the compound ii of H and the R that is being connected easy leavings group on it 2a(as R 2aoTf, R 2acl or R 2abr) react, wherein, OTf is trifluoro-methanesulfonyl oxy; (ii) in organic solvent, under sour existence, incite somebody to action wherein R 2compound ii and R for H 2ac (NH) CCl 3or 1-methyl-2-R 2ayl pyridines salt reacts.
In aforesaid method (1), also optionally comprise R in formula II 5the compound that is not H changes R into 5reaction for the compound of H.For example, the hydrolysis reaction of ester, concrete as the hydrolysis of acetic ester.
According to an embodiment of the invention, aforesaid method (2) is in organic solvent, compound V is reacted under the effect of tiron and reducing metal and make Compound I I.
According to an embodiment of the invention, in aforesaid method (1), the method (i) consumption of described alkali is compound ii (R 2for H) 0.5 ~ 100 times of molar weight, preferably 0.8 ~ 50 times, more preferably 1 ~ 10 times; Method is described R (i) 2aoTf, R 2acl or R 2athe consumption of Br is compound ii (R 2for H) 0.5 ~ 100 times of molar weight, preferably 0.7 ~ 20 times, more preferably 1 ~ 10 times; The method (i) temperature of described reaction is-78 ~ 100 ℃, preferably-60 ~ 80 ℃, and more preferably-42 ~ 50 ℃.
According to an embodiment of the invention, in aforesaid method (1), method (ii) described acid is one or more in methylsulfonic acid, p-methyl benzenesulfonic acid and hydrochloric acid; Method (ii) described sour consumption is compound ii (R 2for H) 0.5 ~ 30 times of molar weight, preferably 0.7 ~ 20 times, more preferably 1 ~ 10 times; Method is described R (ii) 2ac (NH) CCl 3or 1-methyl-2-R 2athe consumption of yl pyridines salt is compound ii (R 2for H) 0.5 ~ 100 times of molar weight, preferably 0.7 ~ 20, more preferably 1 ~ 10 times; The method (ii) temperature of described reaction is-20 ~ 180 ℃, preferably-20 ~ 100 ℃, and more preferably-20 ~ 60 ℃;
According to an embodiment of the invention, in aforesaid method (2), described organic solvent is one or more in tetrahydrofuran (THF), ether, methyl tertiary butyl ether, 2-methyltetrahydrofuran, toluene and methyl-sulphoxide.
According to an embodiment of the invention, in aforesaid method (2), described tiron is one or more in cyclopentadienyl titanium dichloride (IV), the luxuriant titanium of a chlorine two (III), tetraisopropoxy titanium (IV) and titanium tetrachloride (IV).Preferably, the consumption of described tiron is 0.0001 ~ 10 times of compound V molar weight, preferably 0.01 ~ 5 times, and more preferably 0.05 ~ 3 times.
According to an embodiment of the invention, in aforesaid method (2), described reducing metal is one or more in zinc, iron and magnesium.Preferably, the consumption of described reducing metal is 0.8 ~ 100 times of compound V molar weight, preferably 1 ~ 10 times, and more preferably 2 ~ 5 times.
According to an embodiment of the invention, in aforesaid method (2), the temperature of reaction of described reaction is-20 ~ 80 ℃, preferably--15 ~ 60 ℃, more preferably-10 ~ 40 ℃.
According to an embodiment of the invention, the described reaction of aforesaid method (2) is carried out under protonated ammonium salt exists, described protonated ammonium salt is preferably 2,4,6-trimethylpyridine hydrochloride, 2,6-dimethyl pyrazole thiamine hydrochloride, pyridine hydrochloride, one or more in triethylamine hydrochloride and ammonium chloride.Preferably, the consumption of described protonated ammonium salt is 0.8 ~ 100 times of compound V molar weight, preferably 1 ~ 10 times, and more preferably 1.2 ~ 5 times.
According to an embodiment of the invention, above-claimed cpd V is made by following method:
Formula VI compound epoxidation is obtained to formula V compound,
Figure BDA00002105900400081
Wherein, R 1and R 5definition as previously mentioned.Preferably, R 1for hydroxyl protecting group, for example Bn or TBS; R 5for H or the optional alkyl acyl with 1-6 carbon atom replacing, as Ac.
According to an embodiment of the invention, the described method of above-mentioned preparation formula V is one of following:
(1), in organic solvent, under the effect of superoxide, compound VI is carried out to epoxidation reaction;
(2), in organic solvent, under the existence of chiral catalyst and superoxide, compound VI is carried out to epoxidation reaction;
(3), in organic solvent, under the existence of chiral catalyst, superoxide and mineral alkali, compound VI is carried out to epoxidation reaction; Or
(4), in organic solvent, under the existence of superoxide and mineral alkali, compound VI is carried out to epoxidation reaction.
According to an embodiment of the invention, the organic solvent in the method for above-mentioned preparation formula V (1) is preferably methylene dichloride and/or chloroform.
According to an embodiment of the invention, the superoxide in the method for above-mentioned preparation formula V (1) is preferably one or more in hydrogen peroxide, metachloroperbenzoic acid and tertbutanol peroxide.
According to an embodiment of the invention, the consumption of the superoxide described in the method for above-mentioned preparation formula V (1) is 0.5 ~ 100 times of compound VI molar weight, preferably 0.8 ~ 10 times, and more preferably 1 ~ 5 times.
According to an embodiment of the invention, the temperature of the reaction described in the method for above-mentioned preparation formula V (1) is-20 ~ 80 ℃, preferred-15 ~ 60 ℃ of oC, more preferably-10 ~ 40 ℃.
According to an embodiment of the invention, the organic solvent described in the method for above-mentioned preparation formula V (2) is preferably methylene dichloride and/or chloroform.
According to an embodiment of the invention, the superoxide described in the method for above-mentioned preparation formula V (2) is preferably one or more in hydrogen peroxide, metachloroperbenzoic acid and tertbutanol peroxide.
According to an embodiment of the invention, the consumption of the superoxide described in the method for above-mentioned preparation formula V (2) is 0.5 ~ 100 times of compound VI molar weight, preferably 0.8 ~ 10 times, and more preferably 1 ~ 5 times.
According to an embodiment of the invention, the chiral catalyst in the method for above-mentioned preparation formula V (2) is preferably tetraisopropoxy titanium (IV) and diethyl tartrate catalyst system.Preferably, the consumption of described chiral catalyst is 0.01% ~ 100% of compound VI molar weight, preferably 0.05% ~ 80%, more preferably 0.1% ~ 50%.
According to an embodiment of the invention, the temperature of reaction in the method for above-mentioned preparation formula V (2) is-20 ~ 80 ℃, preferably-15 ~ 60 ℃, and more preferably-10 ~ 40 ℃.
According to an embodiment of the invention, the organic solvent in the method for above-mentioned preparation formula V (3) is methylene dichloride and/or chloroform.
According to an embodiment of the invention, the superoxide in the method for above-mentioned preparation formula V (3) is preferably one or more in hydrogen peroxide, metachloroperbenzoic acid and tertbutanol peroxide.Preferably, the consumption of described superoxide is 0.5 ~ 100 times of compound VI molar weight, preferably 0.8 ~ 10 times, and more preferably 1 ~ 5 times.
According to an embodiment of the invention, the chiral catalyst in the method for above-mentioned preparation formula V (3) is preferably tetraisopropoxy titanium (IV) and diethyl tartrate catalyst system.Preferably, the consumption of the chiral catalyst described in method (3) is 0.01% ~ 100% of compound VI molar weight, preferably 0.1% ~ 80%, more preferably 0.5% ~ 50%.
According to an embodiment of the invention, the mineral alkali in the method for above-mentioned preparation formula V (3) is preferably sodium bicarbonate and/or disodium-hydrogen.Preferably, the consumption of described mineral alkali is 0.5 ~ 100 times of compound VI molar weight, is preferably 0.8 ~ 10 times, more preferably 1 ~ 5 times.
According to an embodiment of the invention, the temperature of reaction in the method for above-mentioned preparation formula V (3) is-20 ~ 80 ℃, is preferably-15 ~ 60 ℃, more preferably-10 ~ 40 ℃.
According to an embodiment of the invention, the organic solvent in the method for above-mentioned preparation formula V (4) is preferably methylene dichloride and/or chloroform.
According to an embodiment of the invention, the superoxide in the method for above-mentioned preparation formula V (4) is preferably one or more in hydrogen peroxide, metachloroperbenzoic acid and tertbutanol peroxide.Preferably, the consumption of described superoxide is 0.5 ~ 100 times of compound VI molar weight, is preferably 0.8 ~ 10 times., more preferably 1 ~ 5 times.
According to an embodiment of the invention, the mineral alkali in the method for above-mentioned preparation formula V (4) is preferably sodium bicarbonate and/or disodium-hydrogen.Preferably, the consumption of described mineral alkali is 0.5 ~ 100 times of compound VI molar weight, is preferably 0.8 ~ 10 times, more preferably 1 ~ 5 times.
According to an embodiment of the invention, the temperature of the reaction in the method for above-mentioned preparation formula V (4) is-20 ~ 80 ℃, is preferably-15 ~ 60 ℃, more preferably-10 ~ 40 ℃.
According to an embodiment of the invention, compound VI of the present invention can be made by following either method:
(1) compound VI (R wherein 5for R 5a) by compound VI (R wherein 5for H) make;
Figure BDA00002105900400101
Wherein, radicals R 1and R 5adefinition as previously mentioned.Preferably, R 1for hydroxyl protecting group, for example Bn or TBS; R 5afor the optional alkyl acyl with 1-6 carbon atom replacing, as ethanoyl (Ac); Or
(2) compound VI (R wherein 5for H) by compound VI I, made:
Figure BDA00002105900400111
Wherein, radicals R 1definition as previously mentioned.Preferably, R 1for hydroxyl protecting group, for example Bn or TBS.
According to an embodiment of the invention, in preparation formula VI compound method (1), it is preferably the method for one of following two kinds: (i) in organic solvent, under the existence of alkali, by VII compound and reagent with active leavings group, it includes but not limited to R 5aoTf, R 5acl or R 5abr reacts; (ii) in organic solvent, under sour existence, incite somebody to action wherein R 5compound VI and R for H 5ac (NH) CCl 3or 1-methyl-2-R 5ayl pyridines reactant salt; Or, (iii) by R 5for the hydroxyl in the compound VI of H carries out acidylate, as acetylize.
According to an embodiment of the invention, the method for preparation formula VI compound (2) be selected from following any one:
(i) in organic solvent, by compound VII with
Figure BDA00002105900400112
reaction;
Figure BDA00002105900400113
Wherein, radicals R 1definition as previously mentioned.Preferably, R 1for hydroxyl protecting group, for example Bn or TBS; Or
(ii) in organic solvent, the reagent that compound VII and acetylene end is had to a protecting group as
Figure BDA00002105900400114
or
Figure BDA00002105900400115
reaction, obtains for example compound VII '; Again by compound VII ' carry out the reaction of Deprotection;
Figure BDA00002105900400116
Wherein, radicals R 1definition as previously mentioned.Preferably, R 1for hydroxyl protecting group, for example Bn or TBS.
According to an embodiment of the invention, in the method for preparation formula VI compound (1), method (i) described alkali includes but not limited to butyllithium, ethylmagnesium bromide and tertiary butyl potassium oxide.Preferably, the consumption of alkali is compound VI (R 5for H) 0.5 ~ 100 times of molar weight, be preferably 0.8 ~ 10 times, more preferably 1 ~ 5 times.
According to an embodiment of the invention, the (i) described R in the method for preparation formula VI compound (1) 5aoTf, R 5acl or R 5athe consumption of Br is compound VI (R 5for H) 0.5 ~ 100 times of molar weight, be preferably 0.8 ~ 10 times, more preferably 1 ~ 5 times.
According to an embodiment of the invention, the (i) described temperature of reaction in the method for preparation formula VI compound (1) is-78 ~ 100 ℃, is preferably-60 ~ 80 ℃, more preferably-42 ~ 50 ℃.
According to an embodiment of the invention, in the method for preparation formula VI compound (1), method (ii) described acid is preferably one or more in methylsulfonic acid, p-methyl benzenesulfonic acid and hydrochloric acid.Preferably, the consumption of described acid is compound VI (R 5for H) 0.5 ~ 30 times of molar weight, be preferably 0.8 ~ 20 times, more preferably 1 ~ 10 times.
According to an embodiment of the invention, in the method for preparation formula VI compound (1), method is described R (ii) 5ac (NH) CCl 3or 1-methyl-2-R 5athe consumption of yl pyridines salt is compound VI (R 5for H) 0.5 ~ 100 times of molar weight, be preferably 0.8 ~ 10 times, more preferably 1 ~ 5 times.
According to an embodiment of the invention, in the method for preparation formula VI compound (1), method temperature of reaction is (ii)-20 ~ 180 ℃, is preferably-15 ~ 100 ℃, more preferably-10 ~ 60 ℃.
According to an embodiment of the invention, in the method for preparation formula VI compound (2), method is (i) described consumption be preferably 0.5 ~ 10 times of compound VII molar weight, be preferably 0.8 ~ 8 times, more preferably 1 ~ 5 times.
According to an embodiment of the invention, in the method for preparation formula VI compound (2), method (i) described temperature of reaction is-78 ~ 80 ℃, is preferably-60 ~ 60 ℃, more preferably-42 ~ 50 ℃.
According to an embodiment of the invention, in the method for preparation formula VI compound (2), the method (ii) organic solvent of described nucleophilic addition is preferably one or more in tetrahydrofuran (THF), toluene, ether, methyl tertiary butyl ether and methylene dichloride.
According to an embodiment of the invention, in the method for preparation formula VI compound (2), method is (ii) in described nucleophilic addition
Figure BDA00002105900400122
consumption be 0.5 ~ 10 times of compound VII molar weight, be preferably 0.8 ~ 8 times, more preferably 1 ~ 5 times.
According to an embodiment of the invention, in the method for preparation formula VI compound (2), the method (ii) temperature of described nucleophilic addition is-78 ~ 80 ℃, is preferably-60 ~ 60 ℃, more preferably-42 ~ 40 ℃.
According to an embodiment of the invention, in the method for preparation formula VI compound (2), the method (ii) described reaction that removes silicon protecting group can comprise the following steps: method (a), by compound VII ' in protonated solvent, react under the existence of mineral alkali; Or method (b), in solvent, by compound VII ' react with the reagent of fluoride ion.
According to an embodiment of the invention, in the method for preparation formula VI compound (2), the reaction of method (i) and (ii) carried out under chiral catalyst exists, described chiral catalyst is preferably tetraisopropoxy titanium and S-dinaphthol or derivatives thereof catalyst system, trifluoromethanesulfonic acid zinc and N-methylephedrine or derivatives thereof catalyst system, or trifluoromethanesulfonic acid zinc and (1R, 2R)-3-tert.-butoxy-2-dimethylamino-1-phenyl propyl-1-alcohol catalysis system.Preferably, the consumption of described chiral catalyst is 0.001 ~ 3 times of compound VII molar weight, is preferably 0.01 ~ 2 times, more preferably 0.05 ~ 1 times.
According to an embodiment of the invention, in the method for preparation formula VI compound (2), method is (i) described
Figure BDA00002105900400131
by acetylene, in organic solvent, made with alkali reaction; Wherein, described alkali is preferably one or more in triethylamine, ethylmagnesium bromide, zinc ethyl and n-Butyl Lithium.The consumption of described alkali is preferably 0.5 ~ 10 times of acetylene molar weight, is preferably 0.8 ~ 8 times, more preferably 1 ~ 5 times.The temperature of reaction of this reaction is-78 ~ 100 ℃, is preferably-60 ~ 60 ℃, more preferably-42 ~ 50 ℃.
According to an embodiment of the invention, in the method for preparation formula VI compound (2), method is (ii) described
Figure BDA00002105900400132
respectively by Me 3siC ≡ CH, Et 3siC ≡ CH or in organic solvent, make with alkali reaction; Described alkali is preferably one or more in triethylamine, ethylmagnesium bromide, zinc ethyl and n-Butyl Lithium.The consumption of described alkali is Me 3siC ≡ CH, Et 3siC ≡ CH or
Figure BDA00002105900400134
0.5 ~ 10 times of molar weight, is preferably 0.8 ~ 8 times, more preferably 1 ~ 5 times; The temperature of described reaction is-78 ~ 100 ℃, is preferably-60 ~ 60 ℃, more preferably-42 ~ 40 ℃.
According to an embodiment of the invention, in the method for preparation formula VI compound (2), method is (ii) in the described reaction that removes silicon protecting group, and the described protonated solvent of method (a) is preferably one or more in methyl alcohol, second alcohol and water.The described mineral alkali of method (a) is preferably one or more in salt of wormwood, sodium carbonate and sodium hydroxide.The consumption of the mineral alkali that method (a) is described is compound VII ' 0.1 ~ 10 times of molar weight, be preferably 0.5 ~ 5 times, more preferably 0.8 ~ 3 times.The temperature of reaction of method (a) is-20 ~ 100 ℃, is preferably-15 ~ 80 ℃, more preferably-10 ~ 60 ℃.The reagent of the fluoride ion that method (b) is described is preferably one or more in Potassium monofluoride, tetrabutyl ammonium fluoride and Methanaminium, N,N,N-trimethyl-, fluoride.Preferably, the consumption of the reagent of the fluoride ion that method (b) is described is compound VII ' 0.8 ~ 100 times of molar weight, be preferably 1 ~ 10 times, more preferably 1 ~ 3 times.The temperature of the reaction that method (b) is described is-78 ~ 100 ℃, is preferably-60 ~ 60 ℃, more preferably-42 ~ 40 ℃.
According to an embodiment of the invention, described compound VII can be made by formula IX compound:
Figure BDA00002105900400135
Wherein, radicals R 1definition as previously mentioned; Preferably, R 1for hydroxyl protecting group, for example Bn or TBS.R 6the same R of definition 1a', as previously mentioned; Preferably, R 6be selected from the alkyl with 1 ~ 8 carbon of optional replacement, the optional thiazolinyl with 2 ~ 8 carbon replacing, the optional alkynyl that contains 2 ~ 8 carbon replacing, the optional cycloalkyl that contains 3 ~ 8 carbon replacing or the optional saturated heterocyclyl containing 2 ~ 8 carbon replacing.More preferably, R 6be selected from the alkyl with 1 ~ 6 carbon of optional replacement, as methyl.R 7halogen, preferred I or Br.
According to an embodiment of the invention, in the reaction of preparing compound VII by Compound I X, described reaction is carried out under the existence of reductive agent.Preferably, described reductive agent is selected from zinc, iron, magnesium, chromium dioxide and/or samarium diodide.Optionally, this reaction also adds acid-salt activator.Preferably, described acid-salt activator is selected from ammonium chloride and/or pyridine hydrochloride.Described reaction is carried out or contains in water simultaneously in organic solvent and consisting of phase-transferring agent, carrying out or carrying out in organic solvent in water.Consisting of phase-transferring agent is preferably selected from tetrabutylammonium iodide and/or tetrabutylammonium chloride etc.Organic solvent is preferably selected from tetrahydrofuran (THF), methyl alcohol, ethanol and/or Virahol.
According to an embodiment of the invention, described Compound I X is made by compounds X:
Figure BDA00002105900400141
Wherein, radicals R 1definition as previously mentioned; Preferably, R 1for H or hydroxyl protecting group, for example Bn or TBS; R 6definition ditto described in; Preferably, R 6for example, for the optional alkyl with 1-6 carbon atom replacing, methyl.R 7halogen, preferred I or Br.
According to an embodiment of the invention, by compounds X, prepared in the reaction of Compound I X, described step comprises the halogenating reaction of hydroxyl, and the method that this halogenating reaction can occur all can be used in this step, the iodide reaction that for example triphenylphosphine/imidazoles/iodine system is carried out.The organic solvent that reaction is selected preferably but be not limited to be selected from tetrahydrofuran (THF), methyl alcohol, ethanol and/or Virahol.Also can use other trivalent phosphine as reactant.This step also comprises the reaction that hydroxyl is protected by hydroxyl protecting group.
Till time of each step reaction can complete with detection reaction above, for example, by TLC detection reaction, complete or completely.
According to another aspect of the present invention, the invention provides compound V and VI:
Figure BDA00002105900400142
Wherein, the radicals R in formula 1and R 5definition as previously mentioned.Preferably, the R in formula 1hydroxyl protecting group; R 5for H or R 5a, R 5afor C (O) R 5a', and R 5a' be selected from the alkyl with 1 ~ 8 carbon of optional replacement, the optional thiazolinyl with 2 ~ 8 carbon replacing, the optional alkynyl that contains 2 ~ 8 carbon replacing, the optional cycloalkyl that contains 3 ~ 8 carbon replacing or the optional saturated heterocyclyl containing 2 ~ 8 carbon replacing.More preferably, R 1for TBS or Bn; R 5for H or ethanoyl.
According to a further aspect of the invention, the invention provides above-mentioned formula V and VI compound for the preparation of the application of formula IV compound of the present invention or its hydrate.
The detailed description of invention
1. what the present invention includes is the synthetic method of formula IV compound, especially formula (I) compound or its monohydrate:
Figure BDA00002105900400151
R wherein 1~ R 4the group that group independently represents as mentioned above.
The definition of term
Term " cycloalkyl " refers to the unsaturated monocycle of saturated or part, encircles or bridge joint carbocyclic ring substituting group more.For example, the ring that has a 3-20 carbon atom can be expressed as C 3-C 20cycloalkyl; The ring with 5-15 carbon atom can be expressed as C 5-C 15cycloalkyl; The ring with 3-8 carbon atom can be expressed as C 3-C 8cycloalkyl, etc.This term includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 1H-indenyl, 2, 3-indanyl, 1, 2, 3, 4-tetrahydrochysene-naphthyl, 5, 6, 7, 8-tetrahydrochysene-naphthyl, 8, 9-dihydro-7H-benzo ring heptene-6-base, 6, 7, 8, 9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, 5, 6, 7, 8, 9, 10-six hydrogen-benzo ring octenyl, fluorenyl, two ring [2.2.1] heptyl, two ring [2.2.1] heptenyls, two ring [2.2.2] octyl groups, two ring [3.1.1] heptyl, two ring [3.2.1] octyl groups, two ring [2.2.2] octenyl, two ring [3.2.1] octenyl, adamantyl, octahydro-4, 7-methylene radical-1H-indenyl and octahydro-2, 5-methylene radical-pentalene base etc.Cycloalkyl can be connected on central element through any carbon atom, and can further replace it.
Term " alkoxyl group " represents to connect by oxo bridge has described carbonatoms object ring-type or non-annularity alkyl.Thus, the definition that " alkoxyl group " comprises above alkyl and cycloalkyl.
Term " aryl " represents the aryl radical of the optional optional replacement replacing.It preferably has approximately 20 one-tenth ring carbon atoms of 6-or has 6 to approximately 12 one-tenth ring carbon atoms, or has 6 to approximately 10 one-tenth ring carbon atoms.Described aryl can be monocycle, dicyclo, three ring or more rings.Between many rings, can mutually condense.The non-limiting example of monocyclic aryl comprises phenyl; Fused rings aryl comprises naphthyl, phenanthryl, anthryl, Azulene base; Two aryl of non-condensed comprise xenyl.In described aryl, at least one ring is aromatic nucleus.The example of above-mentioned aryl comprises phenyl, naphthyl, tetralyl, 2,3-indanyl, xenyl, phenanthryl, anthryl or acenaphthenyl.At aryl substituent, be two ring substituents, and one of them ring is in the situation of non-aromatic ring, carries out with being connected by aromatic ring of central element.
Term " heteroaryl " represents the optional heteroaryl replacing, and it preferably has approximately 3 to approximately 20 or 3 to approximately 12 carbon atoms or 3 ~ 10,3 ~ 8,3 ~ 6 carbon atoms; Or there are 5 to approximately 20 or 5 to approximately 12 or 5 ~ 10 or 5 ~ 8 skeletons become annular atoms, and wherein one or more become annular atomses is heteroatoms, described heteroatoms is independently selected from the heteroatoms in oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin, but is not limited to this.Described heteroaryl can be monocycle, dicyclo, three ring or more rings.Between many rings, can mutually condense.Heteroaryl in this range of definition includes but not limited to: acridyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrahydroquinoline." heteroaryl " it should also be understood that to be the N-oxide derivative that comprises any nitrogen-containing hetero aryl.Heteroaryl substituting group is that two ring substituents and a ring are non-aromatic rings or do not comprise in heteroatomic situation therein, is appreciated that connection carries out by aromatic ring or by the heteroatoms that comprises ring respectively.
Term " alkyl " means to comprise to have the radical of saturated aliphatic alkyl of specifying carbonatoms object straight or branched.Preferably, the alkyl of described alkyl for containing 1 ~ 10 or 1 ~ 8 or 1 ~ 6 carbon atom.For example, the straight chained alkyl that contains 1 ~ 8 carbon is to be included in the group in linear chain structure with 1,2,3,4,5,6,7 or 8 carbon atom.For example, methyl, ethyl, n-propyl, normal-butyl, amyl group, hexyl, heptyl, octyl group, nonyl and decyl etc.
Term " thiazolinyl " refers to contain and specifies number carbon atom, and the straight or branched alkyl that contains at least one carbon-carbon double bond.It comprises the thiazolinyl that carbon-carbon double bond is connected with parent.Described thiazolinyl can have one or more carbon-carbon double bond, and for example it can have up to four non-aromatic carbon-carbon double bonds.Preferably, the thiazolinyl of described thiazolinyl for containing 2 ~ 10 or 2 ~ 8 or 2 ~ 6 carbon atoms.Two keys in described thiazolinyl can be cis or transoid conformation, and should be understood to comprise described two kinds of isomer.The example of described thiazolinyl includes but not limited to vinyl, propenyl and butenyl etc.
Term " alkynyl " refers to contain and specifies number carbon atom, and the alkyl that contains at least one carbon carbon triple bond.It comprises the alkynyl that carbon carbon triple bond is connected with parent.Described alkynyl can have one or more carbon carbon triple bond, and for example it can have up to three carbon carbon triple bonds.Preferably, the alkynyl of described alkynyl for containing 2 ~ 10 or 2 ~ 8 or 2 ~ 6 carbon atoms.The example of described alkynyl includes but not limited to ethynyl, proyl and butynyl etc.
Term " cycloalkyl " refers to the unsaturated monocycle of saturated or part, encircles or bridge joint carbocyclic ring substituting group more.Preferably, described cycloalkyl for containing 3 ~ 10 or 3 ~ 8 or 3 ~ 6 carbon atoms, there is the cycloalkyl of monocycle or dicyclo.Described cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 1H-indenyl, 2, 3-indanyl, 1, 2, 3, 4-tetrahydrochysene-naphthyl, 5, 6, 7, 8-tetrahydrochysene-naphthyl, 8, 9-dihydro-7H-benzo ring heptene-6-base, 6, 7, 8, 9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, 5, 6, 7, 8, 9, 10-six hydrogen-benzo ring octenyl, fluorenyl, two ring [2.2.1] heptyl, two ring [2.2.1] heptenyls, two ring [2.2.2] octyl groups, two ring [3.1.1] heptyl, two ring [3.2.1] octyl groups, two ring [2.2.2] octenyl, two ring [3.2.1] octenyl, adamantyl, octahydro-4, 7-methylene radical-1H-indenyl and octahydro-2, 5-methylene radical-pentalene base etc.Naphthenic substituent can be connected on central element through any suitable carbon atom.
Term " saturated heterocyclyl " represent to contain 1 ~ 4 heteroatomic 4 ~ 10 yuan or 3 ~ 8 yuan that are selected from O, N and S or 3 ~ 6 yuan not containing the carbon heterocyclic base of unsaturated link(age) (as carbon-carbon double bond).It can be monocycle or dicyclo or more rings.Other example of " saturated heterocyclyl " includes but not limited to following: morpholinyl, piperazinyl, piperidyl etc.Saturated heterocyclyl can connect through carbon atom or heteroatoms.
Term " unsaturated heterocycle base " represents to contain 1 ~ 4 heteroatoms that is selected from O, N and S, and contains 4 ~ 10 yuan of non-aromatic carbon heterocyclic bases of unsaturated link(age) (as carbon-carbon double bond or triple bond), and comprises bicyclic groups.Unsaturated heterocycle base can be former through carbon.
Hydrogen in term " hydroxyl of protection " expression hydroxyl is the group that hydroxyl protecting group replaced for the protection of hydroxyl by this area routine.Described hydroxyl protecting group includes but not limited to silicon ether protecting group SiR 1a' R 1b' R 1c', as trimethylsilyl (TMS), t-Butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), t-Butyldimethylsilyl (TBS); – CH 2r 1d';-CH 2oR 1a';-C (O) R 1a';-C (O) OR 1a';-C (O) NHR 1a';-C (O) NR 1b' R 1c'; Above-mentioned R 1a' R 1d' definition with aforementioned; Ethanoyl (Ac); Benzyl; 2-methoxy ethyl methyl ether (MEM); Methoxyl methyl ether (MOM); To methoxy-benzyl ether (PMB); First thiomethyl ether (MTM); Pivaloyl group (Piv); Tetrahydropyrans (THP); Methyl ether.
Term " amino of protection " represent one or two hydrogen in amino by this area routine for the protection of the amino group that amino protecting group replaced.The example of amino protecting group includes but not limited to carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (t-Boc), 9-fluorenylmethyloxycarbonyl (FMOC), benzyl (Bn), p-methoxyphenyl (PMP), ethanoyl, isobutyryl etc.
Term " purine derivative " includes but not limited to compound and the tautomer thereof of structure shown in formula IV.Tautomer can be for example the keto-acid isomer suc as formula enol structure shown in IV, as R 3tautomer during for hydroxyl, i.e. ketone.
The principal reaction that synthetic compound IV of the present invention relates to:
1. the synthetic method of formula IV is that Compound I I and compound III are coupled under certain condition, obtains compound IV.The structure of compound III and Compound I I is as follows:
Figure DEST_PATH_GDA00002825013700181
2. what the present invention includes is the synthetic method of compound (III), and its synthetic method is synthetic from compound V as follows
Figure BDA00002105900400182
Reaction adds cyclopentadienyl titanium dichloride (tetravalence), the luxuriant titanium of a chlorine two (trivalent), tetraisopropoxy titanium (tetravalence) or titanium tetrachloride (tetravalence) conventionally; Conventionally also add reducing metal for example but be not restricted to zinc, iron or magnesium; Optionally can also add protonated salt for example but be not restricted to ammonium chloride, hydrochloric acid hydroxylammonium, 2,6-dimethyl pyrazole thiamine hydrochloride, 2，4，6-trimethylpyridine hydrochloride or pyridine hydrochloride; Reaction is carried out conventionally in non-protonization solvent, for example but be not restricted to tetrahydrofuran (THF), ether, t-butyl methyl ether, dimethyl sulfoxide (DMSO); Conventionally the temperature of reaction is subzero 20 ℃ to 80 ℃ above freezing.
With the reagent of active leavings group for example but be not restricted to R after the product purification obtaining, can under existing, alkali add 2-OTf, R 2-Cl, R 2-B etc.; Or under existing, acid adds for example R 2c (NH) Cl 3or 1-methyl-2-R 2the salt of yl pyridines and obtain required Compound I I.
3. what the present invention includes is that compound V is as the important intermediate of synthetic compound IV.Wherein the epoxide group in V can be chirality can be also chirality mixture; R 1and R 5definition with aforementioned.It should be noted R 1and R 5can not be t-Butyldimethylsilyl simultaneously.
4. what the present invention includes is the synthetic method of compound V, and its synthetic method is synthetic from compound VI as follows
Figure BDA00002105900400183
Its synthetic method by compound VI with oxygenant for example but be not restricted to the processing such as hydrogen peroxide, metachloroperbenzoic acid, tertbutanol peroxide is, optionally can add tetraisopropoxy titanium (IV)/chiral catalysts such as diethyl tartrate.In reaction, can for example optionally add mineral alkali but be not restricted to sodium bicarbonate, disodium-hydrogen; Reaction is carried out conventionally between subzero 20 ℃ to 80 ℃ above freezing.
5. what the present invention includes is that compound VI is as the important intermediate of synthetic compound IV.It should be noted R 1and R 5can not be t-Butyldimethylsilyl simultaneously.
6. what the present invention includes is the synthetic method of compound VI, and its synthetic method is synthetic from compound VI I as follows
Figure BDA00002105900400191
Its synthetic method is to add acetylene, trimethylsilyl acetylene, triethyl silico acetylene, dimethyl trimethylsiloxy group methylacetylene etc. under compound VI I exists; For example, in the situation that alkali exists, but be not restricted to triethylamine, ethylmagnesium bromide, zinc ethyl, n-Butyl Lithium; Optionally can add chiral catalyst for example but be not restricted to S-dinaphthol and derivative/tetraisopropoxy titanium (IV) thereof, N-methylephedrine and derivative/trifluoromethanesulfonic acid zinc thereof, (1R, 2R)-3-tert.-butoxy-2-dimethylamino-1-phenyl propyl-1-alcohol/trifluoromethanesulfonic acid zinc; Reaction is carried out conventionally in without protonated solvent, for example but be not restricted to tetrahydrofuran (THF), toluene, ether, t-butyl methyl ether, methylene dichloride etc.Reaction is carried out conventionally between subzero 78 ℃ to 80 ℃ above freezing.The product obtaining is if alkynyl latter end has protection can for example optionally add protonated solvent but be not restricted to methyl alcohol, ethanol, water etc.; And add mineral alkali for example but be not restricted to salt of wormwood, sodium carbonate, sodium hydroxide etc.; Or directly add fluoride ion reagent for example but be not restricted to Potassium monofluoride, tetrabutyl ammonium fluoride, Methanaminium, N,N,N-trimethyl-, fluoride etc.
With the reagent of active leavings group for example but be not restricted to R after the product purification obtaining, can under existing, alkali add 2-OTf, R 2-Cl, R 2-B etc.; Or under existing, acid adds for example R 2c (NH) Cl 3or 1-methyl-2-R 2the salt of yl pyridines and obtain required compound VI.
7. what the present invention includes is that compound VI I is as the important intermediate of synthetic compound IV.
8. what the present invention includes is the synthetic method of compound VI I, and its synthetic method is synthetic from Compound I X as follows
Figure BDA00002105900400192
R wherein 6definition the same, R 7it is halogen.
Its synthetic method is that Compound I X is joined in a kind of reductive agent, for example but be not restricted to zinc, iron, magnesium, chromium dioxide, samarium diodide, etc.; And optionally add for example ammonium chloride of acid-salt activator, pyridine hydrochloride etc.; Reaction can be carried out in water, or adds organic solvent in water simultaneously, and adds consisting of phase-transferring agent for example but be not restricted to tetrabutylammonium iodide, tetrabutylammonium chloride etc.; Also can in other organic solvents, carry out, for example but be not restricted to tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol.
Embodiment
The present invention is better understood the example by below, and they are as explanation of the present invention rather than scope restriction of the present invention is described.To those, the professional person in this area is understandable in the modification of various variations and disclosed embodiment.These variations and modification, include but not limited to those chemical structures, substituting group, derivative, do not depart from purport of the present invention and additional claim.
Embodiment
Embodiment 1
Step 1a
Figure BDA00002105900400201
In tetrahydrofuran (THF) (38mL) solution of 1-methoxyl group-DRI (1.9g, 12.8mmol), add triphenyl to see (5.05g, 19.2mmol), imidazoles (1.75g, 25.6mmol) and iodine (4.94g, 19.2mmol).Reaction solution at room temperature stirs solvent evaporated after 18 hours, and the raffinate obtaining obtains required product colorless oil 2.33g, yield 70% through silicagel column purifying.
1HNMR(CDCl 3)5.07(s,1H),4.39(m,0.5H),4.03(m,1.5H),3.33(m,3H),3.19(m,1H),3.14(m,1H),2.96(br,1H),2.22(m,1H),2.05(m,0.5H),1.95(m,0.5H).
Step 1b
Figure BDA00002105900400202
DMF(300mL at step 1a product (51.4g, 0.2mol)) in solution, add benzyl bromine (34.0g, 0.2mol) and be cooled to subzero 10 ℃.In reaction solution, add in three batches 50wt% sodium hydrogen, every crowd of 3.2g, is total to 9.6g, 0.2mol.15 minutes, reinforced interval.After reinforced, react and at 0 ℃, stir after 2 hours, slowly splash into ammonium chloride saturated solution.The mixed solution obtaining is through n-hexane extraction (300mL X 3).Merge the normal hexane phase obtaining, with after dried over mgso, evaporate to dryness normal hexane obtains required product 65.0g, yield 93.3%.
1H?NMR(CDCl 3)7.35(m,5H),5.16(dd,0.5H),5.08(dd,0.5H),4.55(m,2H),4.28(m,0.5H),4.17(m,0.5H),3.98(dd,0.5H),3.83(dt,0.5H),3.40(s,1.5H),3.36(s,1.5H),3.29(m,1H),3.20(m,1H),2.22(m,1H),2.05(m,0.5H),1.95(m,0.5H).
Step 1c-1
Figure BDA00002105900400211
In methylene dichloride (28ml) solution of the product (1.1g, 5.73mmol) of step 1b, add zinc powder (650mg, 10mmol), saturated ammonium chloride (10mL).The reaction solution obtaining at room temperature stirs separated organic phase after 45 minutes.Organic phase, through dried over sodium sulfate, is revolved steaming, and silicagel column filters, and obtains 912 milligrams of colorless oil products, yield 83%.
1H?NMR(CDCl 3)9.76(s,1H),7.31(m,5H),5.81(m,1H),5.32(m,2H),4.62(d,1H),4.40(d,1H),4.33(m,1H),2.74(m,1H),2.56(m,1H).
Step 1c-2
In normal hexane (28ml) solution of the product (1.1g, 5.73mmol) of step 1b, add zinc powder (650mg, 10mmol), saturated ammonium chloride (10mL).The reaction solution obtaining at room temperature stirs separated organic phase after 45 minutes.Organic phase, through dried over sodium sulfate, is revolved steaming, and silicagel column filters, and obtains 903 milligrams of colorless oil products, yield 82%.
Spectroscopic data is with step 1c-1
Step 1c-3
In tetrahydrofuran (THF) (28ml) solution of the product (1.1g, 5.73mmol) of step 1b, add zinc powder (650mg, 10mmol), 10% acetic acid (10mL).The reaction solution obtaining at room temperature stirs separated organic phase after 45 minutes.Organic phase, through dried over sodium sulfate, is revolved steaming, and silicagel column filters, and obtains 450 milligrams of colorless oil products, yield 41%.
Spectroscopic data is with step 1c-1
Step 1d-1
In ethylmagnesium bromide (6.72ml, the tetrahydrofuran solution of 1M), slowly add trimethylsilyl acetylene (1mL).The reaction solution obtaining at room temperature stirs in the dichloromethane solution that joins step 1c-1 product (912mg, 4.8mmol) at subzero 78 ℃ after 45 minutes.Reaction solution is slowly warmed up to room temperature and stirs and after 16 hours, is chlorinated aqueous ammonium essence and goes out.Water through dried over sodium sulfate, revolves steaming through the latter incorporated organic phase of dichloromethane extraction, and silicagel column filters, and obtains 981 milligrams of colorless oil products, yield 72%.
1H?NMR(CDCl 3)7.31(m,5H),5.79(m,1H),5.30(d,1H),5.27(s,1H),4.61(d,1H),4.59(m,1H),4.35(d,1H),4.05(m,1H),2.88(d,1H),2.13(m,1H),1.89(m,1H),0.15(s,9H).
Step 1d-2
In zinc ethyl (6.72ml, the toluene solution of 2M), slowly add trimethylsilyl acetylene (1mL).The reaction solution obtaining at room temperature stirs in the dichloromethane solution that joins step 1c-1 product (912mg, 4.8mmol) at subzero 78 ℃ after 45 minutes.Reaction solution is slowly warmed up to room temperature and stirs and after 16 hours, is chlorinated aqueous ammonium essence and goes out.Water through dried over sodium sulfate, revolves steaming through the latter incorporated organic phase of dichloromethane extraction, and silicagel column filters, and obtains 655 milligrams of colorless oil products, yield 48%.
Spectroscopic data is with step 1d-1
Step 1d-3
In zinc ethyl (6.72ml, the toluene solution of 2M), slowly add trimethylsilyl acetylene (1mL).The reaction solution obtaining at room temperature stirs after 45 minutes and adds S-biphenyl naphthols (0.29g, 1mmol), titanium tetrachloride (1mL).The dichloromethane solution that finally adds product (912mg, 4.8mmol).Reaction solution is slowly warmed up to 35 ℃ and stir and after 16 hours, be chlorinated aqueous ammonium essence and go out.Water through dried over sodium sulfate, revolves steaming through the latter incorporated organic phase of dichloromethane extraction, and silicagel column filters, and obtains 980 milligrams of colorless oil products, yield 72%.
Spectroscopic data is with step 1d-1
Step 1e
Figure BDA00002105900400221
In the methyl alcohol of step 1d-1 product (654mg, 2.27mmol) (20mL) solution, add salt of wormwood (300mg).The reaction solution obtaining stirs organic phase evaporate to dryness after 16 hours.The raffinate obtaining stirs phase-splitting in water and methylene dichloride.Water, revolves to steam and obtains crude product and be dissolved in pyridine (5mL) through dried over sodium sulfate through the latter incorporated organic phase of dichloromethane extraction.After adding aceticanhydride (1.5mL) and 4-dimethyl amine yl pyridines (27mg), reaction solution at room temperature stirs three hours.After organic phase evaporate to dryness, raffinate is dissolved in methylene dichloride, and washes with dilute hydrochloric acid (0.5M).Organic phase, through dried over sodium sulfate, is revolved steaming, and short silicagel column filters, and obtains required product oily liquids 532mg, yield 93%.
1H?NMR(CDCl 3):7.33(m,5H),5.76(ddd,1H),5.54(m,1H),5.29(d,1H),5.26(s,1H),4.60(d,1H),4.36(d,1H),4.01(m,1H),2.43(s,1H),2.19(m,1H),2.04(s,3H),1.95(m,1H).
Step 1f
Figure BDA00002105900400231
In the methylene dichloride (10mL) of step 1e product (131mg, 0.48mmol), add metachloroperbenzoic acid (414mg, 70% purity).The reaction solution obtaining at room temperature stirs after 48 hours and is gone out by aqueous sodium hydroxide solution (1M) essence.
Organic phase, through dried over sodium sulfate, is revolved steaming, and short silicagel column filters, and obtains required product colourless oil liquid 132mg, yield 95%.
1H?NMR(CDCl 3):7.29(m,5H,m),5.48(m,1H,m),4.79(d,0.5H,d),4.61(d,0.5H),4.46(q,1H,q),3.49(m,0.5H,m),3.29(m,0.5H,m),3.00(m,0.5H,m),2.89(m,0.5H),2.72(m,1H,m),2.68(m,0.5H,m),2.48(m,0.5H),2.39(d,1H,d),2.03(m,1H,m),1.98(s,3H,s),1.89(m,1H).
Step 1g-1
Figure BDA00002105900400232
Step 1f product (120 milligrams, add zinc powder (84mg, 1.3mmol) in tetrahydrofuran solution 0.43mmol) (12mL), cyclopentadienyl titanium dichloride (VI) (12mg, 0.084mmol), 2,6-dimethyl pyrazole thiamine hydrochloride (180mg, 0.22mmol).Reaction solution stirs 15 hours under nitrogen atmosphere room temperature.After reacting liquid filtering, solvent is by evaporate to dryness, and the raffinate obtaining is dissolved in 150 milliliters of methylene dichloride and washes with 10% aqueous solution of malic acid and saturated sodium bicarbonate aqueous solution.Organic phase, through dried over sodium sulfate, is revolved steaming, and silicagel column filters, and obtains 90 milligrams of colorless oil products, yield 75%.
1H?NMR(CDCl 3)7.32(s,5H,s),5.39(t,1H,t),5.24(d,1H,d),5.12(d,1H),4.55(dd,2H,dd),3.88(q,1H,q),3.69(m,2H,m),2.85(br,1H,br),2.53(q,1H,p),2.11(br,1H),2.05(3H,s),1.75(q,1H).
Step 1g-2
Step 1f product (120 milligrams, add zinc powder (84mg, 1.3mmol) in toluene solution 0.43mmol) (12mL), cyclopentadienyl titanium dichloride (VI) (12mg, 0.084mmol), 2，4，6-trimethylpyridine hydrochloride (200mg, 0.22mmol).Reaction solution stirs 15 hours under nitrogen atmosphere room temperature.After reacting liquid filtering, solvent is by evaporate to dryness, and the raffinate obtaining is dissolved in 150 milliliters of methylene dichloride and washes with 10% aqueous solution of malic acid and saturated sodium bicarbonate aqueous solution.Organic phase, through dried over sodium sulfate, is revolved steaming, and silicagel column filters, and obtains 62 milligrams of colorless oil products, yield 53%.
Spectroscopic data is with step 1g-1.
Step 1g-3
Step 1f product (120 milligrams, add zinc powder (84mg, 1.3mmol) in tetrahydrofuran solution 0.43mmol) (12mL), cyclopentadienyl titanium dichloride (VI) (12mg, 0.084mmol), ammonium chloride (12mg, 0.22mmol).Reaction solution stirs 15 hours under nitrogen atmosphere room temperature.After reacting liquid filtering, solvent is by evaporate to dryness, and the raffinate obtaining is dissolved in 150 milliliters of methylene dichloride and washes with 10% aqueous solution of malic acid and saturated sodium bicarbonate aqueous solution.Organic phase, through dried over sodium sulfate, is revolved steaming, and silicagel column filters, and obtains 90 milligrams of colorless oil products, yield 75%.
Spectroscopic data is with step 1g-1.
Step 1h
Figure BDA00002105900400241
In ethylene dichloride (100 milliliters) solution of step 1g-1 product (200 milligrams, 0.72 mmole), at room temperature add 1-methyl-2-benzyloxy pyridine fluoroform sulphonate (1.15 grams, 2.82 mmoles) and magnesium oxide (300 milligrams, 7.5 mmoles).Through oil bath 88 ℃ heating 12 hours after reaction mixture be cooled to room temperature.Solvent is revolved the crude product obtaining after steaming and is obtained 230 milligrams of required product sterlings, yield 67% through silicagel column purifying.
1H?NMR(CDCl 3)7.32(m,10H),5.45(t,1H),5.24(d,1H),5.19(d,1H),4.51(m,4H),3.91(q,1H),3.54(m,2H),2.95(br,1H),2.51(br,1H),2.05(s,3H),1.82(q,1H).
Step 1i
Figure BDA00002105900400251
Step 1h product (230 milligrams, 0.63 mmole) at room temperature adds sodium methylate (200mg) in the solution of methyl alcohol (5 milliliters).Reaction solution was stirring at room 2 hours.Solvent is revolved the crude product obtaining after steaming and is obtained 205 milligrams of product sterlings, yield 93% through silicagel column purifying.
1HNMR(CDCl 3)7.35(m,10H),5.45(s,1H),5.18(s,1H),4.55(s,2H),4.51(q,2H),4.41(m,1H),4.08(m,1H),3.52(q,1H),3.30(t,1H),3.10(br,1H),,2.48(d,1H),1.90to?2.15(m,2H).
Step 1j
Figure BDA00002105900400252
In tetrahydrofuran (THF) (3mL) solution of step 1i product (40mg, 0.13mmol), add triphenyl to see (68mg, 0.26mmol), the chloro-2-aminopurine of 6-(44mg, 0.26mmol) and diethyl azodiformate (45mg, 0.26mmol).Reaction solution at room temperature stirs evaporate to dryness organic solvent after 16 hours, and raffinate is dissolved in trifluoroacetic acid (8mL) and water (2mL) again.The all solvents of evaporate to dryness after 8 hours are at room temperature stirred in reaction, and resistates obtains required product white solid 25mg, yield 45% after silicagel column purifying.
ESI-MS?m/z:458.1[M+H] +
Step 1k
Figure BDA00002105900400261
In methylene dichloride (1ml) solution of the product (25mg, 0.059mmol) of step 1j, at subzero 78 ℃, add boron trichloride (0.3mL, 1M dichloromethane solution).The reaction solution obtaining adds methyl alcohol (1mL) essence to go out in subzero 20 ℃ of stirrings after 30 minutes.It is water-soluble that all volatile matter are taken away rear resistates by nitrogen gas stream.Water, with after extracted with diethyl ether, is adjusted to neutrality with aqueous sodium hydroxide solution (1M).After the water of half is evaporated, the white suspension obtaining is collected after filtration, after being dried, obtains 11 milligrams of required product white solids, yield 73%.
1H?NMR(d 6-DMSO)10.81(s,1H),7.65(s,1H),6.70(br,2H),5.35(t,1H),5.09(s,1H),4.93(d,1H),4.55(s,1H),4.23(s,1H),3.53(t,2H),2.52(m,2H),2.20(m,1H),2.05(m,1H).
Embodiment 2
Step 2a
Figure BDA00002105900400262
N at the product (1.2g, 4.65mmol) of step 1a, adds imidazoles (380mg, 5.58mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (767mg, 5.11mmol) in N '-dimethyl formamide (19mL) solution.The reaction solution obtaining at room temperature stirs evaporate to dryness organic solvent after 18 hours, and the raffinate obtaining obtains the faint yellow oily matter 1.35g of required product, yield 78% through silicagel column purifying.
1H?NMR(CDCl 3)5.01(dd,0.5H),4.91(dd,0.5H),4.27(m,0.5H),3.86(m,1H),3.49(m,0.5H),3.39(dd,0.5H),3.31(s,1.5H),3.28(s,1.5H),3.22-3.14(m,1.5H),2.38(,m,0.5H),2.11(m,0.5H),2.00(m,0.5H),1.76(m,0.5H),0.78(s,9H),0.02(s,1.5H),0.00(s,3H),-0.01(s,1.5H).
Step 2b-1
Figure BDA00002105900400263
In methyl alcohol (1.5mL) solution of the product (100mg, 0.27mmol) of step 2a, add saturated aqueous ammonium chloride (1.5mL) and zinc powder (88mg, 1.35mmol).The mixed solution obtaining shakes water and normal hexane dilution after 15 minutes under ultrasonic wave.Organic phase dried over sodium sulfate, revolves steaming, and silicagel column filters, and obtains 51 milligrams of colorless oil products, yield 89%.
1H?NMR(CDCl 3)9.76(s,1H),5.86(m,1H),5.25(d,1H),5.10(d,1H),4.68(m,1H),2.55(m,2H),0.87(s,9H),0.06(s,3H),0.04(s,3H).
Step 2b-2
In tetrahydrofuran (THF) (1.5mL) solution of the product (100mg, 0.27mmol) of step 2a, add saturated aqueous ammonium chloride (1.5mL) and zinc powder (88mg, 1.35mmol).The mixed solution obtaining at room temperature stirs water and normal hexane dilution after 48 hours.Organic phase dried over sodium sulfate, revolves steaming, and silicagel column filters, and obtains 54 milligrams of colorless oil products, yield 93%.
Spectroscopic data is with step 2b-1.
Step 2b-3
In tetrahydrofuran (THF) (1.5mL) solution of the product (100mg, 0.27mmol) of step 2a, add ammonium chloride (10mg) and zinc powder (88mg, 1.35mmol).The mixed solution obtaining stirs water and normal hexane dilution after 16 hours at 60 ℃.Organic phase dried over sodium sulfate, revolves steaming, and silicagel column filters, and obtains 45 milligrams of colorless oil products, yield 81%.
Spectroscopic data is with step 2b-1.
Step 2b-4
In tetrahydrofuran (THF) (1.5mL) solution of the product (100mg, 0.27mmol) of step 2a, add ammonium chloride (10mg) and zinc powder (88mg, 1.35mmol).The mixed solution that must obtain shakes water and normal hexane dilution after 15 minutes under ultrasonic wave.Organic phase dried over sodium sulfate, revolves steaming, and silicagel column filters, and obtains 35 milligrams of colorless oil products, yield 62%.
Spectroscopic data is with step 2b-1.
Step 2c-1
Figure BDA00002105900400271
Utilize the product (1.5g) of step 2b-1 as raw material, according to the method for step 1d and 1e in embodiment 1, obtain required product (1.1g, two step yields 68%).
1H?NMR(CDCl 3)5.84(m,1H),5.18(d,1H),5.08(d,1H),4.33(m,1H),2.46(s,1H),1.94(m,1H),1.82(m,1H),0.87(s,9H),0.06(s,3H),0.04(s,3H).
Step 2c-2
In toluene (2.5mL) solution of (R)-dimethyl-pyrroline-2-base-methyl alcohol (130mg, 0.46mmol), add triethylamine (0.33mL) and trifluoromethanesulfonic acid zinc (170mg, 0.46mmol).The suspension obtaining at room temperature stirs after 2 hours and adds trimethylsilyl acetylene (0.39mL, 2.80mmol).Stir and after 15 minutes, add the product (500mg, 2.34mmol) of step 2b-1.Reaction solution stirs water and normal hexane dilution after 16 hours at 60 ℃.Organic phase dried over sodium sulfate, revolves steaming, and silicagel column filters, and obtains colorless oil product, by the method for step 1d and 1e, obtains 352 milligrams of required products, yield 62%.
Spectroscopic data is with step 2c-1.
Step 2c-3
In the toluene (19mL) of trimethylsilyl acetylene (2.62mL, 18.68mmol), add zinc methide (18.7mL, the hexane solution of 1M).The reaction solution reflux obtaining adds (S)-bis-to connect naphthols (667mg, 2.32mmol), tetraisopropoxy titanium (IV) (1.36mL, 4.67mmol) and ether (80mL) after 2 hours.Reaction solution at room temperature stirs the product (1.0g, 4.67mmol) that adds step 2c-1 after 1 hour.Reaction is at room temperature stirred after 16 hours and is added aqueous tartaric acid solution essence to go out.Organic phase dried over sodium sulfate, revolves steaming, and silicagel column filters, and obtains colorless oil product and obtains 850 milligrams of required products, yield 72% by the method for step 1d and 1e.
Spectroscopic data is with step 2c-1.
Step 2d
Figure BDA00002105900400281
Utilize the product (1.5g) of step 2c-1 as raw material, according to the method for step 1e and 1f in embodiment 1, obtain required product (1.3g, two step yields 88%).
1H?NMR(CDCl 3)5.54(m,1H),3.53(q,0.5H),3.50(m,0.5H),2.98(m,0.5H),2.92(m,0.5H),2.82(t,0.5H),2.74(dd,0.5H),2.68(dd,0.5H),2.60(dd,0.5H),2.50(dt,1H),2.10(s,3H),2.08(m,1.5H),1.95(m,0.5H),0.94(s,4.5H),0.91(s,4.5H),0.16(s,1.5H),0.13(s,1.5H),0.12(s,1.5H),0.09(s,1.5H).
Step 2e
Figure BDA00002105900400291
Utilize the product (1.0g) of step 2d-1 as raw material, according to the method for step 1g-1 in embodiment 1, obtain required product (520mg, yield 52%).
1H?NMR(CDCl 3)5.38(dt,1H),5.26(q,1H),5.13(t,1H),4.05(m,1H),3.79(m,1H),2.68(m,1H),2.48(m,1H),2.09(s,3H),1.78(m,2H),0.89(s,9H),0.09(s,3H),0.08(s,3H).
Step 2f:
Figure BDA00002105900400292
Step 2e products therefrom (1.0g) is dissolved in to 20ml methylene dichloride, benzyl chlorine and hydrolith (CaH 2, 139mg) also at room temperature stir 12 hours.In reaction mixture, add 0.5ml 0.5N potassium hydroxide solution and at room temperature stir 2 hours.Then to add water (5ml) in reaction mixture and with 0.1N hydrochloric acid adjust pH to 5-6; The compound 610mg of separating and extracting.
1H?NMR(CDCl 3)：7.33-7.29,m,5H;5.37,s,1H;5.13,s,1H;4.54-4.53,d,2H;4.37,m,1H;4.06,m,1H;3.65-3.61,m,1H;3.43-3.40,m,1H;2.94,m,1H;2.15-1.93,m,2H;1.26,m,1H;0.88,s,9H;0.02-0.04,d,6H.
M/Z:348.21。
Step 2g:
Figure BDA00002105900400293
Step 2f products therefrom (1.2eq.) is dissolved in to tetrahydrofuran (THF) or DMF (10 times of volumes) and to adding triphenyl the see chloro-2-of (1.2eq.) 6-(t-Boc)-aminopurine (1.2eq) and diethyl azodiformate (1.2eq.) in this solution.Reaction solution at room temperature stirs evaporate to dryness organic solvent after 16 hours, and raffinate is dissolved in trifluoroacetic acid (8mL) and water (2mL) again.The all solvents of evaporate to dryness after 8 hours are at room temperature stirred in reaction, and resistates obtains required product white solid yield 45-62% after silicagel column purifying.
1H?NMR(300MHz,CDCl3):δ8.04(s,1H),7.43(s,NH),7.37-7.35(m,5H),5.87(m,1H),
5.25(d,1H),4.82(d,1H),4.56(s,2H),4.20(m,1H),3.87(m,2H),2.92(m,1H),2.53(m,2H),1.73(m,1H),1.55(s,9H),0.92(s,9H),0.1(s,6H)。
Step 2h:
Figure BDA00002105900400301
Step 2g products therefrom (1.2eq.) is dissolved in to tetrahydrofuran (THF) or DMF (10 times of volumes) and adds 1M HCl (10 volume) in this solution. reaction mixture is heated to 50 ° of C and stirs 36 hours; Be as cold as room temperature, with the 50%NaOH aqueous solution, adjust reaction mixture pH value to neutrality, filter, obtain light yellow solid.With this solid of ether, and water recrystallization obtains white solid product 40-65%.
H?NMR(300MHz,DMSOd 6):δ8.82(s,2H),8.08(s,1H),7.38-7.14(m,5H),5.28(m,1H),4.90(m,1H),4.57(s,2H),4.18(m,1H),3.75(m,2H),2.52(m,1H),2.28-2.09(m,2H).
Step 2i.:
Figure BDA00002105900400302
Product at step 2h adds 5 volume methylsulfonic acids and stirs 5 hours at 35 ° of C; In room temperature and under stirring, add methyl alcohol and the KOH aqueous solution to form suspension; Filter, by washed with methanol, filter institute's gained solid, all liquid is merged, evaporate to dryness, and be dissolved in acetic acid, then use KOH (50%) tone pitch neutral, concentrated; Utilize SP207 resin (Mitsubishi chemistry) desalination, obtain crude product.After recrystallization is dry, obtain required product white solid, yield 60-90%.
1H?NMR(DMSO-d 6)：δ10.71(br?s,1H),7.88(s,1H),6.52(br?s,2H),5.37(m,1H),5.11(m,1H),4.60(m,1H),4.22(m,1H),3.53(m,2H),2.52(m,1H),2.21(m,1H),2.04(m,1H).
C-13NMR(DMSO-d 6)：δ153.6,151.5,116.2,156.9,136.1,55.2,39.4,70.4,54.1,151.3,109.4,63.1。

Claims (23)

1. suc as formula the preparation method of the purine derivative shown in IV or its hydrate, it comprises the following step: compound ii and compound III are carried out to coupling;
Wherein, R 1for H or R 1a; R 2for H or R 2a; R 3for halogen, OH or OR 3a; R 4for H or R 4a; R 5for H or R 5a;
Wherein, R 1afor CH 2oR 1a', C (O) R 1a', C (O) OR 1a', C (O) NHR 1a', CH 2r 1d', SiR 1a' R 1b' R 1c' or C (O) NR 1b' R 1c';
R 2afor CH 2oR 2a', C (O) R 2a', C (O) OR 2a', C (O) NHR 2a', CH 2r 2d', SiR 2a' R 2b' R 2c' or C (O) NR 2b' R 2c;
R 3afor CH 2oR 3a', C (O) R 3a', C (O) OR 3a', C (O) NHR 3a', CH 2r 3d', SiR 3a' R 3b' R 3c' or C (O) NR 3b' R 3c';
R 4afor CH 2oR 4a', C (O) R 4a', C (O) OR 4a', C (O) NHR 4a', CH 2r 4d', SiR 4a' R 4b' R 4c' or C (O) NR 4b' R 4c';
R 5afor OC (O) R 5a', C (O) R 5a', OC (O) OR 5a' or OSO 2r 5a';
Wherein, R 1a', R 2a', R 3a', R 4a', R 1b', R 2b', R 3b', R 4b', R 1c', R 2c', R 3c', R 4c' and R 5a' be independently:
(1) there is the alkyl of 1 ~ 8 carbon, there is the thiazolinyl of 2 to 8 carbon, the alkynyl that contains 2 to 8 carbon, the cycloalkyl that contains 3 to 8 carbon or containing the saturated heterocyclyl of 2 to 8 carbon;
(2) the substituted alkyl that contains 1 to 8 carbon, the substituted thiazolinyl that contains 2 to 8 carbon, the substituted alkynyl that contains 2 to 8 carbon, the substituted cycloalkyl that contains 3 to 8 carbon or the substituted saturated heterocyclyl that contains 2 to 8 carbon;
The aryl of (3) 6 to 12 carbon;
(4) aryl of substituted 6 to 12 carbon;
The heteroaryl of (5) 3 to 12 carbon; Or
(6) heteroaryl of substituted 3 to 12 carbon; Or
R 1b' and R 1c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings; R 2b' and R 2c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings; R 3b' and R 3c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings; R 4b' and R 4c' be connected, by nitrogen-atoms or Siliciumatom, form 3 to 12 yuan of saturated or unsaturated rings;
Wherein, R 1d', R 2d', R 3d' and R 4d' be independently:
(1) thiazolinyl that contains 2 to 8 carbon, the alkynyl that contains 2 to 8 carbon;
(2) the substituted thiazolinyl that contains 2 to 8 carbon, the substituted alkynyl that contains 2 to 8 carbon;
The aryl of (3) 6 to 12 carbon;
(4) aryl of substituted 6 to 12 carbon;
The heteroaryl of (5) 3 to 12 carbon; Or
(6) heteroaryl of substituted 3 to 12 carbon;
Wherein, described " substituted " refers to one, two, more than three or three, hydrogen atom is replaced by one or more following group independently: the amino of the hydroxyl of fluorine, chlorine, bromine, iodine, hydroxyl, protection, nitro, cyano group, amino, protection, carbonyl, thiocarbonyl ,-NH-(C 1-C 12Alkyl) ,-NH-(C 2-C 8Thiazolinyl) ,-NH-(C 2-C 8Alkynyl) ,-NH-(C 3-C 12Cycloalkyl) ,-NH-(C 6-C 12Aryl) ,-NH-(C 3-C 12Heteroaryl) ,-NH-(C 3-C 12Saturated heterocyclyl) ,-NH-(C 3-C 12Unsaturated heterocycle base), two (C 1-C 12Alkyl) replace amino, two (C 6-C 12Aryl) replace amino, two (C 3-C 12Heteroaryl) replace amino ,-O-(C 1-C 12Alkyl) ,-O-(C 2-C 8Thiazolinyl) ,-O-(C 2-C 8Alkynyl) ,-O-(C 3-C 12Cycloalkyl) ,-O-(C 6-C 12Aryl) ,-O-(C 3-C 12Heteroaryl) ,-O-(C 3-C 12Saturated heterocyclyl) ,-O-(C 3-C 12Unsaturated heterocycle base) ,-C (O)-(C 1-C 12Alkyl) ,-C (O)-(C 2-C 8Thiazolinyl) ,-C (O)-(C 2-C 8Alkynyl) ,-C (O)-(C 3-C 12Cycloalkyl) ,-C (O)-(C 6-C 12Aryl) ,-C (O)-(C 3-C 12Heteroaryl) ,-C (O)-(C 3-C 12Saturated heterocyclyl) ,-C (O)-(C 3-C 12Unsaturated heterocycle base) ,-CONH 2,-CONH-(C 1-C 12Alkyl) ,-CONH-(C 2-C 8Thiazolinyl) ,-CONH-(C 2-C 8Alkynyl) ,-CONH-(C 3-C 12Cycloalkyl) ,-CONH-(C 6-C 12Aryl) ,-CONH-(C 3-C 12Heteroaryl) ,-CONH-(C 3-C 12Saturated heterocyclyl) ,-CONH-(C 3-C 12Unsaturated heterocycle base) ,-OCO 2-(C 1-C 12Alkyl) ,-OCO 2-(C 2-C 8Thiazolinyl) ,-OCO 2-(C 2-C 8Alkynyl) ,-OCO 2-(C 3-C 12Cycloalkyl) ,-OCO 2-(C 6-C 12Aryl),-OCO 2-(C 3-C 12Heteroaryl) ,-OCO 2-(C 3-C 12Saturated heterocyclyl) ,-OCO 2-(C 3-C 12Unsaturated heterocycle base) ,-OCONH 2,-OCONH-(C 1-C 12Alkyl) ,-OCONH-(C 2-C 8Thiazolinyl) ,-OCONH-(C 2-C 8Alkynyl) ,-OCONH-(C 3-C 12Cycloalkyl) ,-OCONH-(C 6-C 12Aryl) ,-OCONH-(C 3-C 12Heteroaryl) ,-OCONH-(C 3-C 12Saturated heterocyclyl) ,-OCONH-(C 3-C 12Unsaturated heterocycle base) ,-NHC (O)-(C 1-C 12Alkyl) ,-NHC (O)-(C 2-C 8Thiazolinyl) ,-NHC (O)-(C 2-C 8Alkynyl) ,-NHC (O)-(C 3-C 12Cycloalkyl) ,-NHC (O)-(C 6-C 12Aryl) ,-NHC (O)-(C 3-C 12Heteroaryl) ,-NHC (O)-(C 3-C 12Saturated heterocyclyl) ,-NHC (O)-(C 3-C 12Unsaturated heterocycle base) ,-NHCO 2-(C 1-C 12Alkyl) ,-NHCO 2-(C 2-C 8Thiazolinyl) ,-NHCO 2-(C 2-C 8Alkynyl) ,-NHCO 2-(C 3-C 12Cycloalkyl) ,-NHCO 2-(C 6-C 12Aryl) ,-NHCO 2-(C 3-C 12Heteroaryl) ,-NHCO 2-(C 3-C 12Saturated heterocyclyl) ,-NHCO 2-(C 3-C 12Unsaturated heterocycle base) ,-NHC (O) NH 2,-NHC (O) NH-(C 1-C 12Alkyl) ,-NHC (O) NH-(C 2-C 8Thiazolinyl) ,-NHC (O) NH-(C 2-C 8Alkynyl) ,-NHC (O) NH-(C 3-C 12Cycloalkyl) ,-NHC (O) NH-(C 6-C 12Aryl) ,-NHC (O) NH-(C 3-C 12Heteroaryl) ,-NHC (O) NH-(C 3-C 12Saturated heterocyclyl) ,-NHC (O) NH-(C 3-C 12Unsaturated heterocycle base) ,-NHC (S) NH 2,-NHC (S) NH-(C 1-C 12Alkyl) ,-NHC (S) NH-(C 2-C 8Thiazolinyl) ,-NHC (S) NH-(C 2-C 8Alkynyl) ,-NHC (S) NH-(C 3-C 12Cycloalkyl) ,-NHC (S) NH-(C 6-C 12Aryl) ,-NHC (S) NH-(C 3-C 12Heteroaryl) ,-NHC (S) NH-(C 3-C 12Saturated heterocyclyl) ,-NHC (S) NH-(C 3-C 12Unsaturated heterocycle base) ,-NHC (NH) NH 2,-NHC (NH) NH-(C 1-C 12Alkyl) ,-NHC (NH) NH-(C 2-C 8Thiazolinyl) ,-NHC (NH) NH-(C 2-C 8Alkynyl) ,-NHC (NH) NH-(C 3-C 12Cycloalkyl) ,-NHC (NH) NH-(C 6-C 12Aryl) ,-NHC (NH) NH-(C 3-C 12Heteroaryl) ,-NHC (NH) NH-(C 3-C 12Saturated heterocyclyl) ,-NHC (NH) NH-(C 3-C 12Unsaturated heterocycle base) ,-NHC (NH)-(C 1-C 12Alkyl) ,-NHC (NH)-(C 2-C 8Thiazolinyl) ,-NHC (NH)-(C 2-C 8Alkynyl) ,-NHC (NH)-(C 3-C 12Cycloalkyl) ,-NHC (NH)-(C 6-C 12Aryl) ,-NHC (NH)-(C 3-C 12Heteroaryl) ,-NHC (NH)-(C 3-C 12Saturated heterocyclyl) ,-NHC (NH)-(C 4-C 12Unsaturated heterocycle base) ,-C (NH) NH-(C 1-C 12Alkyl) ,-C (NH) NH-(C 2-C 8Thiazolinyl) ,-C (NH) NH-(C 2-C 8Alkynyl) ,-C (NH) NH-(C 3-C 12Cycloalkyl) ,-C (NH) NH-(C 6-C 12Aryl) ,-C (NH) NH-(C 3-C 12Heteroaryl) ,-C (NH) NH-(C 3-C 12Saturated heterocyclyl) ,-C (NH) NH-(C 3-C 12Unsaturated heterocycle base) ,-S (O)-(C 1-C 12Alkyl) ,-S (O)-(C 2-C 8Thiazolinyl) ,-S (O)-(C 2-C 8Alkynyl) ,-S (O)-(C 3-C 12Cycloalkyl) ,-S (O)-(C 6-C 12Aryl) ,-S (O)-(C 3-C 12Heteroaryl) ,-S (O)-(C 3-C 12Saturated heterocyclyl) ,-S (O)-(C 3-C 12Unsaturated heterocycle base) ,-SO 2NH 2,-SO 2NH-(C 1-C 12Alkyl) ,-SO 2NH-(C 2-C 8Thiazolinyl) ,-SO 2NH-(C 2-C 8Alkynyl) ,-SO 2NH-(C 3-C 12Cycloalkyl) ,-SO 2NH-(C 6-C 12Aryl) ,-SO 2NH-(C 3-C 12Heteroaryl) ,-SO 2NH-(C 3-C 12Saturated heterocyclyl) ,-SO 2NH-(C 3-C 12Unsaturated heterocycle base) ,-NHSO 2-(C 1-C 12Alkyl) ,-NHSO 2-(C 2-C 8Thiazolinyl) ,-NHSO 2-(C 2-C 8Alkynyl) ,-NHSO 2-(C 3-C 12Cycloalkyl) ,-NHSO 2-(C 6-C 12Aryl) ,-NHSO 2-(C 3-C 12Heteroaryl) ,-NHSO 2-(C 3-C 12Saturated heterocyclyl) ,-NHSO 2-(C 3-C 12Unsaturated heterocycle base) ,-CH 2NH 2,-CH 2SO 2CH 3, C 6-C 12Aryl, C 6-C 12The C that aryl replaces 1-C 12Alkyl, C 3-C 12Heteroaryl, C 3-C 12The C that heteroaryl replaces 1-C 12Alkyl, C 3-C 12Saturated heterocyclyl, C 3-C 12Unsaturated heterocycle base, C 3-C 12Cycloalkyl, 1 C that alkoxyl replaces 1-C 12Alkyl, methoxymethoxy, methoxy ethoxy, sulfydryl ,-S-(C 1-C 12Alkyl) ,-S-(C 2-C 8Thiazolinyl) ,-S-(C 2-C 8Alkynyl) ,-S-(C 3-C 12Cycloalkyl) ,-S-(C 6-C 12Aryl) ,-S-(C 3-C 12Heteroaryl) ,-S-(C 3-C 12Saturated heterocyclyl) ,-S-(C 3-C 12Unsaturated heterocycle base) or methylthiomethyl; Wherein said aryl, heteroaryl, saturated heterocyclyl, unsaturated heterocycle base, alkyl, thiazolinyl, alkynyl, cycloalkyl, alkoxyl are without replacement or by the one or more further replacement in above-mentioned substituting group.
2. preparation method as claimed in claim 1, is characterized in that, described linked reaction is prolonged and reacted by light.
3. preparation method as claimed in claim 1 or 2, is characterized in that, described R 1and R 2independently selected from H or hydroxyl protecting group; R 3hydroxyl or O-basic metal for F, Cl, Br, I, OH, protection; R 4for H or amino protecting group.
4. preparation method as claimed in claim 3, is characterized in that, described R 1for benzyl or tertiary butyl dimethyl-silicon; R 2for benzyl; R 3for F, Cl, Br or I; R 4for H or tertbutyloxycarbonyl.
5. preparation method as claimed in claim 3, is characterized in that, described R 1for H; R 2for H; R 3for OH; R 4for H.
6. the preparation method as described in any one in aforementioned claim, is characterized in that, described Compound I I is made by following either method:
(1) work as R 2for R 2atime, compound ii is made by following reaction:
Wherein, radicals R 1, R 2aand R 5definition as described in one of claim 1 ~ 5; Or
(2) work as R 2during for H, compound ii is made by compound V:
Figure FDA00002105900300042
Wherein, radicals R 1and R 5definition as described in one of claim 1 ~ 5.
7. preparation method as claimed in claim 6, is characterized in that, the R in formula II and V 1for hydroxyl protecting group; R 5for H or R 5a, R 5afor C (O) R 5a', and R 5a' be selected from the alkyl with 1 ~ 8 carbon of optional replacement, the optional thiazolinyl with 2 ~ 8 carbon replacing, the optional alkynyl that contains 2 ~ 8 carbon replacing, the optional cycloalkyl that contains 3 ~ 8 carbon replacing or the optional saturated heterocyclyl containing 2 ~ 8 carbon replacing.
8. the preparation method as described in claim 6 or 7, is characterized in that, the R in formula II and V 1for TBS or Bn; R 5for H or R 5a, R 5afor ethanoyl.
9. the preparation method as described in any one in claim 6 ~ 8, is characterized in that, described method (1) is following either method:
(i) under the existence of alkali, incite somebody to action wherein R 2compound ii and R for H 2aoTf, R 2acl or R 2abr reacts, and wherein, OTf is trifluoro-methanesulfonyl oxy; Or
(ii) under sour existence, incite somebody to action wherein R 2compound ii and R for H 2ac (NH) CCl 3or 1-methyl-2-R 2ayl pyridines salt reacts.
10. the preparation method as described in any one in claim 6 ~ 9, is characterized in that, described method (2) is that compound V is reacted and makes Compound I I under the effect of tiron and reducing metal.
11. preparation methods as claimed in claim 10, it is characterized in that: described tiron is selected from one or more in cyclopentadienyl titanium dichloride (IV), the luxuriant titanium of a chlorine two (III), tetraisopropoxy titanium (IV) and titanium tetrachloride (IV), and/or described reducing metal is selected from one or more in zinc, iron and magnesium.
12. preparation methods as described in any one in claim 6 ~ 11, is characterized in that: the reaction of described method (2) is to carry out under protonated ammonium salt exists.
13. preparation methods as described in any one in claim 6 ~ 12, is characterized in that: described compound V is made by following method:
Formula VI compound epoxidation is obtained to formula V compound:
Figure FDA00002105900300051
Wherein, R 1and R 5definition as described in one of in claim 1 ~ 5 and 7 ~ 8.
14. preparation methods as claimed in claim 13, is characterized in that: described compound VI is made by following either method:
(1) work as R 5for R 5atime, compound VI is made by following reaction:
Figure FDA00002105900300052
Wherein, radicals R 1and R 5adefinition as described in one of in claim 1 ~ 5 and 7 ~ 8; Or
(2) work as R 5during for H, compound VI is made by compound VI I:
Figure FDA00002105900300061
Wherein, radicals R 1definition as described in one of in claim 1 ~ 5 and 7 ~ 8.
15. preparation methods as claimed in claim 14, is characterized in that: in method (1), compound VI is made by following either method: under the existence of alkali, incite somebody to action wherein R (i) 5compound VI and R for H 5aoTf, R 5acl or R 5abr reaction;
(ii) under sour existence, incite somebody to action wherein R 5compound VI and R for H 5ac (NH) CCl 3or 1-methyl-2-R 5ayl pyridines reactant salt; Or, (iii) by R 5for the R in the compound VI of H 5for the hydroxyl of H carries out acidylate.
16. preparation methods as described in claims 14 or 15, is characterized in that, method (2) be selected from following any one:
By compound VII with
Figure FDA00002105900300062
reaction;
Wherein, radicals R 1definition as described in one of in claim 1 ~ 5 and 7 ~ 8; Or
By compound VII with reaction, obtains compound VII '; Again by compound VII ' remove the reaction of silicon protecting group;
Figure FDA00002105900300065
Wherein, radicals R 1definition as described in one of in claim 1 ~ 5 and 7 ~ 8.
17. preparation methods as described in any one in claim 14 ~ 16, is characterized in that: described compound VI I is made by formula IX compound:
Wherein, radicals R 1definition as described in one of in claim 1 ~ 5 and 7 ~ 8; R 6the same R of definition 1a', R 1a' definition as described in one of in claim 1 ~ 5; R 7it is halogen.
18. preparation methods as claimed in claim 17, is characterized in that: wherein, and R 1for Bn; R 6be selected from the alkyl with 1 ~ 6 carbon of optional replacement, as methyl; R 7i or Br.
19. preparation methods as claimed in claim 18, is characterized in that, described reaction is carried out under the existence of reductive agent and optional acid-salt.
20. preparation methods as claimed in claim 19, is characterized in that, described reductive agent is selected from zinc, iron, magnesium, chromium dioxide and/or samarium diodide; And/or described acid-salt is selected from ammonium chloride and/or pyridine hydrochloride.
21. preparation methods as described in any one in claim 17 ~ 20, is characterized in that, described Compound I X is made by compounds X:
Figure FDA00002105900300071
Wherein, radicals R 1definition as described in one of in claim 1 ~ 5 and 7 ~ 8; R 6definition as described in claim 17 or 18; R 7definition as described in claim 17 or 18.
22. suc as formula the compound shown in V or VI:
Figure FDA00002105900300072
Wherein, radicals R 1and R 5definition as described in one of in claim 1 ~ 5 and 7 ~ 8.
Compound described in 23. claims 22 is for the preparation of the formula IV compound described in any one in claim 1 ~ 5 or the application of its hydrate.
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