CN111233863A - Hydroxyl purine compound and application thereof - Google Patents

Hydroxyl purine compound and application thereof Download PDF

Info

Publication number
CN111233863A
CN111233863A CN202010154010.6A CN202010154010A CN111233863A CN 111233863 A CN111233863 A CN 111233863A CN 202010154010 A CN202010154010 A CN 202010154010A CN 111233863 A CN111233863 A CN 111233863A
Authority
CN
China
Prior art keywords
methyl
dione
purine
dimethyl
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202010154010.6A
Other languages
Chinese (zh)
Other versions
CN111233863B (en
Inventor
吴凌云
张鹏
张丽
黎健
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong Raynovent Biotech Co Ltd
Original Assignee
Guangdong Raynovent Biotech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong Raynovent Biotech Co Ltd filed Critical Guangdong Raynovent Biotech Co Ltd
Priority to CN202010154010.6A priority Critical patent/CN111233863B/en
Publication of CN111233863A publication Critical patent/CN111233863A/en
Application granted granted Critical
Publication of CN111233863B publication Critical patent/CN111233863B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention discloses a series of hydroxyl purine compounds and application thereof as PDE2 or TNFa inhibitors, and particularly discloses a compound shown as a formula (I), a tautomer thereof or pharmaceutically acceptable salts thereof.

Description

Hydroxyl purine compound and application thereof
Technical Field
The invention relates to a series of hydroxyl purine compounds and application thereof as PDE2 or TNFa inhibitors, in particular to compounds shown in a formula (I), tautomers thereof or pharmaceutically acceptable salts thereof.
Background
Phosphodiesterases (PDEs) catalyze the hydrolysis of the cyclic nucleotides cGMP and cAMP, which regulate a variety of physiological responses by controlling the intramolecular concentration of these two important secondary signaling factors. Abnormal regulation of the cyclic nucleotides cGMP and cAMP within the molecule is responsible for a number of diseases and there are several drugs that ameliorate and treat diseases by inhibiting PDE activity, such as PDE5 inhibitors for pulmonary hypertension and PDE4 inhibitors for psoriasis-induced arthritis. The phosphodiesterase genes known at present have eleven major classes, each of which can express several subtypes, and there are more than 100 PDE subtypes in total. Different subtypes have different structures and different tissue distributions, so that the activities of cyclic nucleotides cGMP and cAMP are greatly different, and the physiological functions of regulation are also different.
PDE2 phosphodiesterase catalyzes the hydrolysis of the cyclic nucleotides cGMP and cAMP, while cAMP activity is regulated by cGMP and plays a key role in the intracellular functional balance of cGMP and cAMP. PDE2 is widely expressed in human tissues and is distributed primarily in the heart, central nervous system, liver, adrenal glands, endothelial cells, platelets, and the like. PDE2 is involved in regulating physiological activities such as central learning, memory and cognition, maintaining the basic rhythm of heart, smooth muscle and endothelial cells, endothelial cell permeability, and regulating inflammatory responses. PDE2 gene knock-out mice directly caused embryonic death. By inhibiting PDE2 activity, it is possible to treat a variety of central, cardiovascular diseases, and to control inflammatory responses.
The non-selective PDE inhibitory activity of a variety of natural and synthetic purines has long been discovered, such as caffeine, theophylline, pentoxifylline, and the like. Pentoxifylline (PDE2 activity) is clinically approved for lower limb claudication caused by peripheral vascular plugs, and has the main effects of reducing blood viscosity, increasing erythrocyte deformation, inhibiting platelet aggregation, etc. Novel highly selective PDE2 inhibitors have also been reported to control endothelial cell division and angiogenesis, and to improve central cognitive disorders. However, the development and application of the overall novel selective PDE2 inhibitor are very limited, and the discovery and application of the novel PDE2 inhibitor have wide prospects.
TNF α is mainly produced by monocytes and macrophage lines and is involved in immune regulation and cytokine network coordination of the body, TNF α plays an important role in immune defense and immune supervision under normal conditions, but has adverse effects under certain conditions, TNF α over-expression can induce expression of proinflammatory cytokines such AS interleukin 1 (IL 1), IL 6 and the like, increase endothelial cell permeability, up-regulation of adhesion molecules, activation of neutrophils and 865cells, and induce bone synoviocytes and chondrocytes to secrete acute phase substances and tissue degrading enzymes to promote inflammation development, which plays a very important role in the development of a number of immune-mediated inflammatory diseases (inflammatory bowel disease, arthritis) such AS inflammatory diseases (inflammatory bowel disease, arthritis) and rheumatoid arthritis (inflammatory arthritis), thus the inflammatory diseases can be effectively controlled by using various biological active cytokines such AS TNF 2 (TNF kinase), TNF α (TNF kinase), TNF kinase inhibitor, TNF α (TNF kinase inhibitor) and other drugs, so that the inflammatory diseases can be controlled by chronic inflammatory diseases such AS chronic arthritis, TNF kinase (IBD) and inflammatory arthritis (IBD) and inflammatory diseases (inflammatory arthritis).
Disclosure of Invention
The invention provides a compound shown in a formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof,
Figure BDA0002403430430000021
wherein the content of the first and second substances,
can form a structural unit
Figure BDA0002403430430000022
Is replaced by
Figure BDA0002403430430000023
Is concretely replaced by
Figure BDA0002403430430000024
L11Selected from the group consisting of null, C (R) (R');
r, R' are each independently selected from H, halogen, OH, NH2CN, optionally substituted 1-to 6-membered alkyl or heteroalkyl;
optionally, R, R' may be cyclized to form a 3-6 membered cycloalkyl, heterocycloalkyl;
a is empty, or is selected from optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
L12selected from optionally substituted 1-to 6-membered alkyl or heteroalkyl;
R1selected from optionally substituted 1-to 6-membered alkyl or heteroalkyl;
"hetero" stands for N, O, S, C (═ O), S (═ O)2The number of heteroatoms per group is selected from 1,2,3 or 4;
in some embodiments of the invention, the R, R', A, L12、R1Wherein the substituents are respectively and independently selected from halogen, OH and NH2CN, optionally substituted 1-6 membered alkyl or heteroalkyl, each independently selected from 1,2 or 3. In some embodiments of the invention, the R, R', A, L12、R1Wherein the substituents are independently selected from halogen and CF3CN, OH, Me, Et, n-propyl, isopropyl, cyclopropyl,
Figure BDA0002403430430000025
In some embodiments of the present invention, each of the R, R's is independently selected from H, Me, CF3、Et。
In some embodiments of the invention, L is11Is selected from
Figure BDA0002403430430000026
Figure BDA0002403430430000027
In some embodiments of the invention, a is selected from optionally substituted: 3-12 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl.
In some embodiments of the invention, a is selected from optionally substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypentyl, phenyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, or selected from the group consisting of bicyclic, spiro or fused rings of any two of the foregoing groups.
In some embodiments of the invention, a is selected from optionally substituted:
Figure BDA0002403430430000031
Figure BDA0002403430430000032
in some embodiments of the invention, A is selected from
Figure BDA0002403430430000033
Figure BDA0002403430430000034
In some embodiments of the invention, L is12Selected from methylene, methyl, ethyl, propyl, butyl,
Figure BDA0002403430430000035
Figure BDA0002403430430000041
in some embodiments of the invention, R is as defined above1Selected from Me and CHF2、CF3、Et、CH2CF3An isopropyl group,
Figure BDA0002403430430000042
A cyclopropyl group,
Figure BDA0002403430430000043
The present invention is selected from compounds of the formula:
Figure BDA0002403430430000044
Figure BDA0002403430430000051
further, the present invention is selected from compounds of the formula:
Figure BDA0002403430430000052
Figure BDA0002403430430000061
the invention also provides the application of the compound, the tautomer thereof or the chemically acceptable salt thereof in preparing a PDE2 inhibitor and a TNFa inhibitor.
Correlation definition
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical salts," Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.
Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form.
Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
The illustrations of enantiomers, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J.chem.Ed.1985,62: 114-120. In 1985,62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomer unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers by fractional crystallization or chromatography, as is well known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C3H) Iodine-125 (125I) Or C-14(14C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent, and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on The vector, reference may be made to Remington, The Science and Practice of Pharmacy,21st Ed., Lippincott, Williams & Wilkins (2005), The contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including deuterium and hydrogen variants, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., ═ O), it means that two hydrogen atoms are substituted. The keto substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
When a substituent's bond can cross-link two atoms on a ring, such substituent can be bonded to any atom on the ring. When no atom is indicated in the listed substituents for connecting to a compound included in the general chemical structure but not specifically mentioned, such substituent may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit
Figure BDA0002403430430000081
Meaning that it may be in cyclohexyl or ringSubstitution occurs at any position on the alkadiene.
Substituents for alkyl and heteroalkyl radicals are generally referred to as "alkyl substituents" and may be selected from, but are not limited to, one or more of the following groups: -R ', -OR', -O, ═ NR ', -N-OR', -NR 'R ", -SR', halogen, -SiR 'R" R' ", oc (O) R ', -c (O) R', -CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2And fluoro (C)1-C4) Alkyl, the number of substituents being 0 to (2m '+ 1), where m' is the total number of carbon atoms in such radicals. R ', R ", R'", R "" and R "" each independently preferably is hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy, thioalkoxy, or aralkyl. When a compound of the invention includes more than one R group, for example, each R group is independently selected, as are each of these groups when more than one R ', R ", R'", R "" and R "" groups are present. When R' and R "are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 5-, 6-or 7-membered ring. For example, -NR' R "is intended to include, but not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will appreciate that the term "alkyl" is intended to include groups consisting of carbon atoms bonded to non-hydrogen groups, such as haloalkyl (e.g., -CF)3、-CH2CF3) And acyl (e.g., -C (O) CH)3、-C(O)CF3、-C(O)CH2OCH3Etc.).
Similar to the substituents described for the alkyl radicals, the aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" and are selected from, for example, -R ', -OR', -NR 'R ", -SR', -halogen, -SiR 'R" R "'、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2Fluorine (C)1-C4) Alkoxy and fluorine (C)1-C4) Alkyl, etc., the number of substituents being between 0 and the total number of open valences on the aromatic ring; wherein R ', R ", R'", R "" and R "" are independently preferably selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each R group is independently selected, as are each of these groups when more than one R ', R ", R'", R "" and R "" groups are present.
Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by a substituent of the formula-T-C (O) - (CRR ') q-U-, wherein T and U are independently selected from-NR-, -O-, CRR' -or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula-A (CH2) r B-, wherein A and B are independently selected from-CRR' -, -O-, -NR-, -S (O) -, S (O)2-、-S(O)2NR' -or a single bond, and r is an integer of 1 to 4. Optionally, one single bond on the new ring thus formed may be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula-A (CH2) r B-, wherein S and d are each independently an integer selected from 0 to 3, and X is-O-, -NR', -S-, -S (O)2-or-S (O)2NR' -. The substituents R, R ', R "and R'" are each independently preferably selected from hydrogen and substituted or unsubstituted (C)1-C6) An alkyl group.
Unless otherwise specified, the term "halogen"Or "halogen" by itself or as part of another substituent denotes a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C)1-C4) Alkyl "is intended to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, and the like.
Examples of haloalkyl groups include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "alkoxy" represents the above alkyl group having the specified number of carbon atoms attached through an oxygen bridge. C1-6Alkoxy radicals comprising C1、C2、C3、C4、C5And C6Alkoxy group of (2). Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy. "cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-7 cycloalkyl radicals including C3、C4、C5、C6And C7A cycloalkyl group. "alkenyl" includes hydrocarbon chains in either a straight or branched configuration, wherein one or more carbon-carbon double bonds, such as ethenyl and propenyl, are present at any stable site along the chain.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
Unless otherwise specified, the term "hetero" denotes a heteroatom or a heteroatom group (i.e., a heteroatom-containing radical) including atoms other than carbon (C) and hydrogen (H) and radicals containing such heteroatoms, including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)2-, and optionally substituted-C (═ O) n (h) -, -C (═ NH) -, -S (═ O)2N (h) -or-S (═ O) n (h) -.
Unless otherwise specified, "cyclic" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term "ring" includes monocyclic, bicyclic, spiro, fused or bridged rings. The number of atoms in the ring is generally defined as the number of ring members, for example, "5 to 7 membered ring" means 5 to 7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1-3 heteroatoms. Thus, "5 to 7 membered ring" includes, for example, phenylpyridine and piperidinyl; in another aspect, the term "5-to 7-membered heterocycloalkyl ring" includes pyridyl and piperidyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.
Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable heteroatom or heteroatom group containing monocyclic, bicyclic, or tricyclic ring which may be saturated, partially unsaturated, or unsaturated (aromatic), which contains carbon atoms and 1,2,3, or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p). The nitrogen atom may be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituents already defined herein). The heterocyclic ring may be attached to any heteroatom or carbon pendant group to form a stable structure. The heterocyclic rings described herein may be substituted at the carbon or nitrogen position if the resulting compound is stable. The nitrogen atoms in the heterocycle are optionally quaternized. In a preferred embodiment, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. In another preferred embodiment, the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" means a stable 5,6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic group aromatic ring comprising carbon atoms and 1,2,3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituents already defined herein). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p). It is noted that the total number of S and O atoms on the heteroaromatic ring does not exceed 1. Bridged rings are also included in the definition of heterocyclic. Bridged rings are formed when one or more atoms (i.e., C, O, N or S) connect two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In bridged rings, ring substituents may also be present on the bridge.
Examples of heterocyclic compounds include, but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H,6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatino, isobenzofuranyl, pyran, isoindolyl, indolyl, etc, Isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthine, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, Pyrazolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, isothiazolylthiothienyl, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, and xanthenyl. Fused ring and spiro compounds are also included.
Unless otherwise specified, the term "hydrocarbyl" or its derivatives (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent, mean a straight, branched, or cyclic hydrocarbon radical or combination thereof, which may be fully saturated, mono-or poly-unsaturated, mono-, di-, or poly-substituted, may be mono-or di-or poly-valent (such as methine), may include di-or poly-valent radicals, having the specified number of carbon atoms (such as C)1-C10Representing 1 to 10 carbons). "hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl including linear and cyclic, specifically including, but not limited to, alkyl, alkenyl, alkynyl, and aromatic hydrocarbyl including, but not limited to, 6-12 membered aromatic hydrocarbyl such as benzene, naphthalene, and the like. In some embodiments, the term "alkyl" denotes a straight or branched chain radical or a combination thereof, which may be fully saturated, mono or polyunsaturated, and may include divalent and polyvalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and homologs or isomers of radicals such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups have one or more double or triple bonds, examples of which include, but are not limited to, ethenyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers.
Unless otherwise specified, the term "heterocarbyl" or subset thereof (e.g., heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means a stable straight, branched, or cyclic hydrocarbon radical or combination thereofConsisting of a certain number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl," by itself or in combination with another term, means a stable straight-chain, branched-chain hydrocarbon radical, or combination thereof, having a number of carbon atoms and at least one heteroatom constituent. In one exemplary embodiment, the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including the position where the hydrocarbyl group is attached to the remainder of the molecule). Examples include, but are not limited to-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3and-CH ═ CH-N (CH)3)-CH3. Up to two heteroatoms may be consecutive, e.g. -CH2-NH-OCH3。
The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in the conventional sense to refer to those alkyl groups attached to the rest of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
Unless otherwise specified, the terms "cycloalkyl", "heterocycloalkyl", or a subset thereof (e.g., aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, etc.) by themselves or in combination with other terms, mean cyclized "alkyl", "heteroalkyl", respectively. Furthermore, in the case of a heterohydrocarbyl or heterocycloalkyi (e.g., heteroalkyl, heterocycloalkyl), a heteroatom may occupy the position of the heterocycle attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclyl groups include 1- (1,2,5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran indol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl.
Unless otherwise specified, the term "aryl" denotes a polyunsaturated aromatic hydrocarbon substituent which may be mono-, di-or poly-substituted, and may be mono-, di-or polyvalent, and which may be monocyclic or polycyclic (preferably 1 to 3 rings) which are fused together or linked covalently. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In one illustrative example, the heteroatom is selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-oxazolyl, 2-thiazolyl, 2-pyridyl, 4-pyridyl, and the like, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolyl, and 6-quinolyl. The substituents for any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
For simplicity, aryl when used in combination with other terms (e.g., aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like), including those alkyl groups in which a carbon atom (e.g., methylene) has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl 3- (1-naphthyloxy) propyl and the like.
The term "leaving group" refers to a functional group or atom that can be substituted by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetyloxy, and the like.
The term "protecting group" includes, but is not limited to, "amino protecting group," hydroxyl protecting group, "or" thiol protecting group. The term "amino protecting group" refers to a protecting group suitable for use in preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl, for example alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups, such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
All solvents used in the present invention are commercially available and can be used without further purification. The invention employs the following abbreviations: aq represents water; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC stands for N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq representsEquivalent and equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH stands for ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents tert-butylcarbonyl as an amine protecting group; HOAc represents acetic acid; NaCNBH3Represents sodium cyanoborohydride; r.t. represents room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl2Represents thionyl chloride; CS2Represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N- (phenylsulfonyl) benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-dione; n-Bu4NF represents tetrabutyl ammonium fluoride; iPrOH represents 2-propanol; mp represents melting point; LDA represents lithium diisopropylamide; TMSCF3Represents trifluoromethyl trimethylsilane; ti (Oi-Pr)4Represents tetraisopropyl titanate; MSCl represents methanesulfonyl chloride; DMAP for N, N-dimethyl-4-aminopyridine; TEA for triethylamine; BnBr represents benzyl bromide; DIEA for diisopropylethylamine; BH3DMS represents borane dimethylsulfide; DMP stands for desmesartan periodinane; TBAF stands for tetrabutylammonium fluoride; HOBT represents 1-hydroxybenzotriazole; AIBN stands for azobisisobutyronitrile; NBS stands for N-bromosuccinimide.
The compound is made by hand or
Figure BDA0002403430430000132
The software names, and the commercial compounds are under the supplier catalog name.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention.
Example 1
3, 7-dimethyl-1- (6, 6, 6-trifluoro-5-hydroxy-5-methylhexyl) -1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000131
First step of
3, 7-dimethyl-1- (6, 6, 6-trifluoro-5-methyl-5- (trimethylsiloxy) hexyl) -1H-purine-2, 6(3H, 7H) -dione
3, 7-dimethyl-1- (5-oxohexyl) -1H-purine-2, 6(3H, 7H) -dione (200mg, 0.719mmol), cesium fluoride (10.9mg, 0.0719mmol) was dissolved in tetrahydrofuran (2mL), and trimethylsilyl trifluoromethanesulfonate (153mg, 1.08mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at 20 ℃ for 2 hours, and then saturated brine (50mL) was added to quench the reaction, followed by extraction with ethyl acetate (100 mL. times.3). The organic phase was washed with saturated brine (100 mL. times.3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Vacuum drying afforded 3, 7-dimethyl-1- (6, 6, 6-trifluoro-5-methyl-5- (trimethylsiloxy) hexyl) -1H-purine-2, 6(3H, 7H) -dione (200mg, white solid), yield: 66 percent. MS-ESI calculated value [ M + H%]+421, measured value 421.
Second step of
3, 7-dimethyl-1- (6, 6, 6-trifluoro-5-hydroxy-5-methylhexyl) -1H-purine-2, 6(3H, 7H) -dione
3, 7-dimethyl-1- (6, 6, 6-trifluoro-5-methyl-5- (trimethylsiloxy) hexyl) -1H-purine-2, 6(3H, 7H) -dione (200mg, 0.476mmol) was dissolved in tetrahydrofuran (2mL), and 1M hydrochloric acid (0.5mL) was added dropwise at 0 ℃ and stirred at 20 ℃ for 1 hour. The mixture was cooled to 0 ℃ and quenched by the addition of sodium bicarbonate solution (30 mL). The mixture was extracted with ethyl acetate (100mL x 3). The organic phase was washed with saturated brine (100 mL. times.3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Separation and purification by preparative high performance liquid chromatography gave 3, 7-dimethyl-1- (6, 6, 6-trifluoro-5-hydroxy-5-methylhexyl) -1H-purine-2, 6(3H, 7H) -dione (50.0mg, white solid) in yield: 30 percent.1H NMR:(400MHz，Methonal-d4) δ 7.85(s, 1H), 4.02-3.98(m, 2H), 3.96(s, 3H), 3.52(s, 3H), 1.69-1.64(m, 4H), 1.52-1.48(m, 2H), 1.28(s, 3H). MS-ESI calculated value [ M + H%]+349, found 349.
Example 2
1- (5-hydroxy-5-methylheptyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000141
First step of
Ethyl 5- (3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate
3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (5.00g, 28.0mmol), ethyl bromovalerate (7.51g, 33.4mmol), potassium carbonate (7.73g, 56.0mmol) and potassium iodide (500mg, 2.80mmol) were dissolved in N, N-dimethylformamide (62 mL). The reaction solution was heated to 110 ℃ and stirred for two hours. The reaction was poured into water and extracted with ethyl acetate (20mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give ethyl 5- (3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate (5.00g, yellow solid), yield: 50 percent.1H NMR：(400MHz，CDCl3)δ7.51(s，1H)，4.14-4.09(m，2H)，4.04-4.01(m，2H)，3.97(s，3H)，3.57(s，3H)，2.37-2.33(m，2H)，1.72-1.69(m，4H)，1.25(t，J＝7.2Hz，3H)。
Second step of
1- (5-Ethyl-5-hydroxyheptyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Ethyl 5- (3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate (0.500g, 1.62mmol) was dissolved in anhydrous tetrahydrofuran (5mL) and ethyl magnesium bromide (3M in diethyl ether, 3.42mL, 9.72mmol) was slowly added dropwise at-78 ℃ under nitrogen protection. The reaction mixture was stirred at-78 ℃ for 0.5 hour, slowly raised to 0 ℃ and reacted for 0.5 hour. The reaction was poured into water and extracted with ethyl acetate (30mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1- (5-ethyl-5-hydroxyheptyl-3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (0.300g, colorless oil) in 57% yield.1H NMR：(400MHz，CDCl3)δ7.50(s，1H)，4.05-4.01(m，2H)，3.99(s，3H)，3.57(s，3H)，170-1.37(m, 10H), 0.86(t, J ═ 7.6Hz, 6H). MS-ESI calculated value [ M + H%]+323, found value 323.
Example 3
1- (4- (1-hydroxycyclopropyl) butyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000151
Ethyl magnesium bromide (3M ethereal solvent, 1.1mL, 3.24mmol) was added to a solution of ethyl 5- (3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate (500mg, 1.62mmol) and tetraisopropyl titanate (461mg, 1.62mmol) in tetrahydrofuran (10mL) at-35 ℃ under nitrogen. The reaction solution was slowly heated to 25 ℃ and stirred for 2 hours. The reaction was quenched by addition of water (10mL), insoluble material was removed by filtration, and the filtrate was extracted with ethyl acetate (20 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography to give 1- (4- (1-hydroxycyclopropyl) butyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (90.0mg, white solid) in yield: 19 percent.1HNMR：(400MHz，Methonal-d4) Δ 7.86(s, 1H), 4.03-3.90(m, 5H), 3.51(s, 3H), 1.72-1.53(m, 6H), 0.68-0.59(m, 2H), 0.46-0.38(m, 2H). MS-ESI calculated value [ M + H%]+293, found 293.
Example 4
3, 7-dimethyl-1- ((1- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) cyclopropyl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000152
Figure BDA0002403430430000161
First step of
Ethyl-1-acetylcyclopropane
Ethyl-3-oxobutanoic acid (10.0g, 76.8mmol) and 1,2Dibromoethane (21.7g, 115mmol) was dissolved in dimethyl sulfoxide (300mL) and potassium carbonate (42.5g, 307mmol) was added portionwise under nitrogen. The reaction solution was stirred at 25 ℃ for 24 hours. Water (500mL) was added, the reaction was extracted with ethyl acetate (300mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10: 1 petroleum ether/ethyl acetate, Rf ═ 0.4) to give ethyl 1-acetylcyclopropane (6.00g, white oil) in yield: 50 percent.1H NMR：(400MHz，Methonal-d4)δ4.25-4.20(m，2H)，2.44(s，3H)，1.47-1.42(m，4H)，1.32-1.28(m，3H)。
Second step of
1- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) cyclopropanecarboxylic acid
Ethyl 1-acetylcyclopropane (2.00g, 12.8mmol), cesium fluoride (195mg, 1.28mmol) were dissolved in tetrahydrofuran (30mL), and trimethylsilyltrifluoromethyl (3.64g, 25.6mmol) was added at 0 ℃. The reaction solution was reacted at 20 ℃ under nitrogen for 6 hours. Then 4N diluted hydrochloric acid (7mL) was added. The mixture was reacted at room temperature under nitrogen for 6 hours. The reaction was quenched by addition of saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (100mL x3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10: 1 petroleum ether/ethyl acetate, Rf ═ 0.4) to give 1- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) cyclopropanecarboxylic acid (1.70g, white oil), yield: 59 percent.1H NMR：(400MHz，Methonal-d4)δ4.14-4.10(m，2H)，1.64(s，3H)，1.29-1.24(m，3H)，1.23-1.22(m，2H)，0.92-0.90(m，2H)。
The third step
1,1, 1-trifluoro-2- (1- (hydroxymethyl) cyclopropyl) propan-2-ol
1- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) cyclopropanecarboxylic acid (400mg, 1.77mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and lithium aluminum hydride (81.0mg, 2.12mmol) was added at 0 ℃. The reaction solution was heated to 25 ℃ and stirred for 1 hour. Quenching with water (10mL), extracting with ethyl acetate (50mL x3), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by silica gel column chromatography (1:1 petroleum ether)Ethyl acetate, Rf ═ 0.2) to give 1,1, 1-trifluoro-2- (1- (hydroxymethyl) cyclopropyl) propan-2-ol (200mg, yellow oil), yield: 61 percent.1H NMR：(400MHz，DMSO-d6)δ5.64(s，1H)，4.63-4.60(m，1H)，3.64-3.60(m，1H)，3.23-3.17(m，1H)，1.36(s，3H)，0.83-0.91(m，1H)，0.56-0.55(m，1H)，0.39-0.35(m，2H)。
The fourth step
(1- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) cyclopropyl) methyl methanesulfonate
1,1, 1-trifluoro-2- (1- (hydroxymethyl) cyclopropyl) propan-2-ol (100mg, 0.543mmol) was dissolved in dichloromethane (5mL) and triethylamine (110mg, 1.08mmol) and methanesulfonyl chloride (62.2mg, 0.543mmol) were added at 0 ℃. The reaction mixture was reacted at 0 ℃ for 2 hours. Quenched by addition of saturated aqueous sodium bicarbonate (10mL), extracted with dichloromethane (10mL x3), the organic phases were combined, washed with saturated sodium chloride solution (10mL x3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (1- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) cyclopropyl) methyl methanesulfonate (80.0mg, yellow oil), yield: 56 percent.
The fifth step
3, 7-dimethyl-1- ((1- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) cyclopropyl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
(1- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) cyclopropyl) methyl methanesulfonate (80.0mg, 0.305mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (54.9mg, 0.305mmol), potassium iodide (5.10mg, 0.0305mmol) and potassium carbonate (126mg, 0.915mmol) were dissolved in anhydrous N, N-dimethylformamide (5 mL). The reaction solution was heated to 120 ℃ and reacted for 2 hours. The reaction was cooled to 20 ℃, filtered and purified by preparative high performance liquid chromatography to give 3, 7-dimethyl-1- ((1- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) cyclopropyl) methyl) -1H-purine-2, 6- (3H, 7H) -dione (40.0mg, white solid), yield: 38 percent.1H NMR：(400MHz，Methonal-d4)δ7.88(s，1H)，4.45(d，J＝6.8Hz，1H)，4.24(d，J＝6.8Hz，1H)，3.97(s，3H)，3.53(s，3H)，1.53(s，3H)，0.92-0.88(m，1H)，0.64-0.63(m，1H)，0.41-0.38(m，1H)，0.15-0.12(m，1H)。
MS-ESI calculated value [ M + H%]+347, found 347.
Example 51- ((3-hydroxy-3- (trifluoromethyl) cyclobutyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -Di
Ketones
Figure BDA0002403430430000171
Figure BDA0002403430430000181
First step of
3-Oxocyclobutanecarboxylic acid methyl ester
3-Oxocyclobutanecarboxylic acid (25.0g, 0.220mmol), methanol (14mL) and N, N-dimethyl-4-aminopyridine (3.00g, 353mmol) were dissolved in dichloromethane (500mL) and stirred at 25 deg.C, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (64.0g, 340mmol) was slowly added dropwise and stirred overnight. The reaction solution was washed successively with aqueous hydrochloric acid (1.5N, 72mL), water (150 mL. times. 2) and saturated brine (75 mL. times.2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product methyl 3-oxocyclobutanecarboxylate (25g, yellow liquid) in yield: 89 percent.
Second step of
5, 8-Dioxaspiro [3, 4] octane-2-carboxylic acid methyl ester
Methyl-3-oxocyclobutanecarboxylic acid (25.0g, 195mmol), ethylene glycol (35.0g, 564mmol) and p-toluenesulfonic acid (3.50g, 20.0mmol) were dissolved in toluene (250mL), added to a water separator and heated under reflux overnight. The reaction was cooled to 25 ℃ and washed successively with water (300 mL. times.2) and saturated sodium bicarbonate (500 mL. times.2). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product methyl 5, 8-dioxaspiro [3, 4] octane-2-carboxylate (22.5g, yellow liquid), yield: 90 percent.
The third step
5, 8-dioxaspiro [3, 4] octane-2-methanol
Under the protection of nitrogen at 0 DEG CNext, lithium aluminum hydride (5.20g, 136mmol) was slowly dissolved in tetrahydrofuran (240mL), followed by dropwise addition of 5, 8-dioxaspiro [3, 4] dissolved in tetrahydrofuran (60mL)]Octane-2-carboxylic acid methyl ester (19.5g, 113 mmol). The reaction was slowly warmed to 25 ℃ and stirred for 3.5 hours. The reaction mixture was cooled to 0 ℃ and water (5.20g, 289mmol), 15% sodium hydroxide (5.20g, 19.5mmol) and water (15.6g, 867mmol) were added slowly in that order. Filtration, washing of the filter cake with tetrahydrofuran (10mL x3), concentration of the filtrate under reduced pressure and purification by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.4) gave the product 5, 8-dioxaspiro [3, 4]]Octane-2-methanol (10.0g, yellow liquid), yield: 62 percent.1H NMR：(400MHz，CDCl3)δ3.90-3.87(m，4H)，3.67(d，J＝6.4Hz，2H)，2.45-2.40(m，2H)，2.38-2.26(m，1H)，2.13-2.08(m，2H)。
The fourth step
5, 8-dioxaspiro [3, 4] octan-2-ylmethyl methanesulfonate
5, 8-dioxaspiro [3, 4] octane-2-methanol (500mg, 53.1mmol) and diisopropylethylamine (896mg, 6.90mmol) were dissolved in dichloromethane (23mL), and methanesulfonyl chloride (1.40g, 12.6mmol) was slowly added at 0 ℃. The reaction was brought to 25 ℃ and stirred overnight. The reaction was quenched by addition of water (50mL) and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the product 5, 8-dioxaspiro [3, 4] octan-2-ylmethyl methanesulfonate (2.30g, yellow liquid).
MS-ESI calculated value [ M + H%]+223, measured value 223.
The fifth step
(1- (5, 8-dioxaspiro [3, 4] octan-2-ylmethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Mixing 5, 8-dioxaspiro [3, 4]]Octane-2-ylmethyl methanesulfonate (1.00g, 4.50mmol), 3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (810mg, 4.50mmol), potassium carbonate (1.20g, 13.5mmol) and potassium iodide (75.0mg, 0.45mmol) were dissolved in N, N-dimethylformamide (20 mL). The reaction was heated to 130 ℃ and stirred for 3.5 hours. Filtering the reaction solution, and concentrating the filtrate under reduced pressure to obtain 1- (5, 8-dioxaspiro [3, 4]]Octane-2-ylmethyl) -3,7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (1.50g, brown liquid), yield: 93 percent. MS-ESI calculated value [ M + H%]+307, found 307.
The sixth step
3, 7-dimethyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione
1- (5, 8-dioxaspiro [3, 4] octan-2-ylmethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (1.50g, 5.00mmol) was dissolved in acetone (18mL), and aqueous hydrochloric acid (4N, 3mL) was added. The reaction was heated to 30 ℃ and stirred overnight. Dilute with water, adjust the pH to neutral with saturated aqueous sodium bicarbonate (20mL), and extract with ethyl acetate (150mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting product was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.2) to give the product 3, 7-dimethyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (180mg, white solid) in yield: 14 percent.
1H NMR：(400MHz，CDCl3) δ 7.49(s, 1H), 4.25(d, J ═ 7.6Hz, 2H), 3.95(s, 3H), 3.55(s, 3H), 3.13-2.96(m, 4H), 2.95-2.84(m, 1H). MS-ESI calculated value [ M + H%]+263, found 263.
Seventh step
1- ((3-hydroxy-3- (trifluoromethyl) cyclopentyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
3, 7-dimethyl-1- ((3-oxocyclopentyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (100mg, 0.382mmol) and cesium fluoride (11.5mg, 0.0763mmol) were dissolved in anhydrous tetrahydrofuran (3mL) and trifluoromethyltrimethylsilane (95.0mg, 0.640mmol) was added under nitrogen. The reaction mixture was slowly heated to 30 ℃ and stirred for 12 hours. Aqueous hydrochloric acid (1N, 5mL) was then added to the reaction and stirring was continued for 0.5 h. The reaction was diluted with water (50mL), adjusted to pH 7 with saturated aqueous sodium bicarbonate (10mL), concentrated under reduced pressure, and purified by preparative high performance liquid chromatography to give 1- ((3-hydroxy-3- (trifluoromethyl) cyclopentyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (80.0mg, white solid) in yield: and 64 percent. 1H NMR：(400MHz，Mehonal-d4) Delta.8.54 (s, 1H), 4.13-4.07(m, 5H), 3.56(s, 3H), 2.58-2.48(m, 3H), 2.14-2.10(m, 2H). MS-ESI calculated value [ M + H%]+333, found value 333.
Example 6
1- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) -3-hydroxycyclobutyronitrile
Figure BDA0002403430430000201
First step of
((1, 3-dibromopropan-2-yl) oxy) methyl) benzene
2- (bromomethyl) oxirane (8.40g, 61.3mmol) was added to benzyl bromide (8.74g, 51.1mmol) with cuprous chloride (6.87g, 51.1mmol) dissolved therein at room temperature. The reaction was stirred at 150 ℃ for 11 hours. The reaction was cooled to room temperature, water (100mL) was slowly added and extracted with ethyl acetate (100 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained product was purified by silica gel column chromatography (petroleum ether, Rf ═ 0.6) to obtain a product (((1, 3-dibromopropan-2-yl) oxy) methyl) benzene (8.60g, yellow oil), yield: 44 percent.1H NMR：(400MHz，CDCl3)δ7.39-7.31(m，5H)，4.67(s，2H)，3.82-3.78(m，1H)，3.58(d，J＝5.2Hz，4H)。
Second step of
Ethyl 3- (benzyloxy) -1-cyanocyclobutanecarboxylic acid ethyl ester
Ethyl cyanoacetate (2.76g, 24.3mmol) was slowly added to N, N-dimethylformamide (35mL) dissolved with (((1, 3-dibromopropan-2-yl) oxy) methyl) benzene (7.00g, 18.2mmol) and potassium carbonate (10.0g, 72.7mmol) at room temperature. The reaction was stirred at 90 ℃ for 4 hours. Cooled to room temperature, filtered and the solid washed with ethyl acetate (20 mL). The resulting organic phase was washed with saturated aqueous ammonium chloride (20mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained product was purified by silica gel column chromatography (30: 1 petroleum ether/ethyl acetate, Rf ═ 0.4) to give ethyl 3- (benzyloxy) -1-cyanocyclobutanecarboxylate (3.80g, colorless oil) as a productForm), yield: 81 percent.1H NMR：(400MHz，Methonal-d4)δ7.40-7.28(m，5H)，4.48-4.44(m，2H)，4.37-4.31(m，1H)，4.30-4.24(m，2H)，2.97-2.80(m，2H)，2.73-2.65(m，2H)，1.37-1.30(m，3H)。
The third step
3- (benzyloxy) -1- (hydroxymethyl) cyclobutyronitrile
Sodium borohydride (1.39g, 36.6mmol) was dissolved in tetrahydrofuran and water (20 mL: 2mL) and a solution of ethyl 3- (benzyloxy) -1-cyanocyclobutanecarboxylate (3.80g, 14.6mmol) in tetrahydrofuran (22mL) was slowly added dropwise over 20 minutes at 0 ℃. The reaction was stirred at room temperature for 2 hours. Ethyl acetate (50mL) was added for dilution, and the organic phase was washed with water (30mL) and saturated brine (30mL), respectively, and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, 3- (benzyloxy) -1- (hydroxymethyl) cyclobutyronitrile (3.70g, colorless oil).1H NMR：(400MHz，DMSO-d6)δ7.38-7.25(m，5H)，5.57-5.52(m，1H)，4.39-4.36(m，2H)，4.13-4.04(m，1H)，3.57-3.51(m，2H)，2.58-2.51(m，1H)，2.49-2.45(m，1H)，2.31-2.09(m，2H)。
The fourth step
(3- (benzyloxy) -1-cyanocyclobutyl) methyl methanesulfonate
3- (benzyloxy) -1- (hydroxymethyl) cyclobutyronitrile (3.70g, 15.3mmol), triethylamine (3.10g, 30.6mmol) were dissolved in dichloromethane (35mL) and methanesulfonyl chloride (3.29g, 28.7mmol) was added slowly at 0 ℃. The reaction was stirred at rt for 4h, saturated ammonium chloride (30mL) was added, extracted with ethyl acetate (50mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (3- (benzyloxy) -1-cyanocyclobutyl) methyl methanesulfonate (4.56g, dark brown oil).1H NMR：(400MHz，Methonal-d4)δ7.36-7.26(m，5H)，4.47-4.45(m，2H)，4.44-4.38(m，2H)，3.21-3.18(m，1H)，3.17-3.14(m，3H)，2.81-2.60(m，2H)，2.53-2.26(m，2H)。
The fifth step
3- (benzyloxy) -1- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) cyclobutyronitrile
(3- (benzyloxy) -1-cyanocyclobutyl) methyl methanesulfonate (4.50g, 15.2mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (2.75g, 15.2mmol) and potassium iodide (1.26g, 7.62mmol) were dissolved in N, N-dimethylformamide (100mL), potassium carbonate (6.32g, 45.7mmol) was added, and the reaction was heated under reflux at 120 ℃ for 4 hours. The reaction was cooled to room temperature, filtered, the filtrate concentrated under reduced pressure, water (50mL) was added, and extracted with ethyl acetate (50mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the crude product 3- (benzyloxy) -1- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) cyclobutyronitrile (4.60g, yellow solid). MS-ESI calculated value [ M + H%]+380, found 380.
The sixth step
1- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) -3-hydroxycyclobutyronitrile
3- (benzyloxy) -1- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) cyclobutyronitrile (100mg, 0.263mmol) was dissolved in dichloromethane (10mL) and ferric chloride (128mg, 0.790mmol) was added. The reaction was stirred at room temperature for 12 hours. Water (10mL) was added and extracted with dichloromethane (40mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the product, 1- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) -3-hydroxycyclobutyronitrile (12.0mg, yellow solid), yield: 16 percent.1H NMR：(400MHz，CDCl3) δ 7.56(s, 1H), 4.66-4.49(m, 1H), 4.45-4.37(m, 2H), 4.01(s, 3H), 3.62(s, 3H), 2.96-2.85(m, 2H), 2.60-2.49(m, 2H). MS-ESI calculated value [ M + H%]+290, found value 290.
Example 7
Figure BDA0002403430430000211
Figure BDA0002403430430000221
First step of
Methyl 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester
Reacting 3- (methoxycarbonyl) bicyclo [1.1.1]Pentane-1-carboxylic acid (100mg, 0.587mmol) and triethylamine (71.0mg, 0.705mmol) were dissolved in tetrahydrofuran (20mL) and methyl chloroformate (56.0mg, 0.587mmol) was slowly added dropwise at-10 ℃. The reaction mixture was stirred at 0 ℃ for half an hour, then sodium borohydride (33.0mg, 0.881mmol) was added and the reaction was continued for 2 hours. Adding water (10mL) into the reaction solution, extracting with ethyl acetate (10mL x3), combining organic phases, washing with saturated sodium chloride (10mL x2), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain methyl 3- (hydroxymethyl) bicyclo [1.1.1]Pentane-1-carboxylic acid methyl ester (80.0mg, colorless oil), yield: 87 percent.1H NMR：(400MHz，CDCl3)δ3.65(s，3H)，3.60(s，2H)，2.00(s，6H)。
Second step of
Methyl 3- (((methylsulfonyl) oxy) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester
Methyl 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate (40.0mg, 0.256mmol) and triethylamine (39.0mg, 0.384mmol) were dissolved in dichloromethane (15mL) and methanesulfonyl chloride (35.0mg, 0.307mmol) was slowly added dropwise at 0 ℃. The reaction was stirred at 0 ℃ for 2 hours, dichloromethane (10mL) was added to dilute the reaction, the organic phase was washed with water (10mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl 3- (((methylsulfonyl) oxy) methyl) bicyclo [1.1.1] pentane-1-carboxylate (50.0mg, yellow oil), yield: 83 percent.
The third step
Methyl 3- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester
Reacting methyl 3- (((methylsulfonyl) oxy) methyl) bicyclo [1.1.1]Pentane-1-carboxylic acid methyl ester (100mg, 0.426mmol) and 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (77.0mg, 0.427mmol) were dissolved in N, N-dimethylformamide (20mL), and potassium carbonate (88.0mg, 0.640mmol) was added at room temperatureAnd potassium iodide (8.00mg, 0.0430 mmol). The reaction mixture was stirred at 100 ℃ for 2 hours, cooled to room temperature and concentrated, ethyl acetate (20mL) was added to dilute the reaction mixture, the organic phase was washed with water (20mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to separate and purify the organic phase by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.2) to obtain methyl 3- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) bicyclo [ 1.1.1)]Pentane-1-carboxylic acid methyl ester (100mg, yellow solid), yield: 73 percent.1H NMR：(400MHz，CDCl3) δ 7.50(s, 1H), 4.12(s, 2H), 3.95(s, 3H), 3.60(s, 3H), 3.53(s, 3H), 1.95(s, 6H). MS-ESI calculated value [ M + H%]+319, found 319.
The fourth step
3- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid
Methyl 3- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxylate (100mg, 0.314mmol) was dissolved in tetrahydrofuran (15mL) and water (5mL), and lithium hydroxide (26.0mg, 0.628mmol) was added at room temperature. After stirring at room temperature for 2 hours, the reaction was adjusted to PH 4 by the addition of 2N dilute hydrochloric acid (10mL), extracted with ethyl acetate (15mL x3), the combined organic phases were washed with saturated sodium chloride solution (20mL x2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to 3- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid (90.0mg, white solid), yield: 94 percent.
MS-ESI calculated value [ M + H%]+305, measured value 305.
The fifth step
3- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) -N-methoxy-N-methylbicyclo [1.1.1]
Pentane-1-carboxamides
3- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid (30.0mg, 0.0986mmol) and N, O-dimethylhydroxylamine (10.0mg, 0.0986mmol) were dissolved in dichloromethane (20mL) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (75.0mg, 0.197mmol) and diisopropylethylamine (19.0mg, 0.148mmol) were added at room temperature. After stirring at room temperature for 12 hours, the reaction was extracted with water (20mL), dichloromethane (20mL x2), and the combined organic phases were washed with saturated ammonium chloride solution (20mL x 2). Dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (1: 2 petroleum ether/ethyl acetate, Rf ═ 0.2) to give 3- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) -N-methoxy-N-methylbicyclo [1.1.1] pentane-1-amide (30.0mg, white solid) in yield: 88 percent.
MS-ESI calculated value [ M + H%]+348, found value 348.
The sixth step
1- ((3-acetylbicyclo [1.1.1] pentan-1-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
Mixing 3- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) -N-methoxy-N-methylbicyclo [1.1.1]Pentane-1-amide (20.0mg, 0.0575mmol) was dissolved in tetrahydrofuran (20mL), and methyl magnesium bromide (3M in diethyl ether, 0.040mL, 0.120mmol) was added to the reaction mixture at-78 deg.c, followed by stirring for 30 minutes and then warming to room temperature for 4 hours. The reaction solution was added with saturated ammonium chloride solution (10mL) at 0 ℃, extracted with ethyl acetate (15mL × 3), the combined organic phases were washed with saturated sodium chloride solution (20mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Separating and purifying with silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.5) to obtain 1- ((3-acetyl bicyclo [ 1.1.1)]Pentan-1-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (15.0mg, colorless oil), yield: 86 percent.1H NMR：(400MHz，CDCl3) δ 7.55(s, 1H), 4.17(s, 2H), 3.99(s, 3H), 3.59(s, 3H), 2.07(s, 3H), 1.97(s, 6H). MS-ESI calculated value [ M + H%]+303, found value 303.
Seventh step
3, 7-dimethyl-1- ((3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) bicyclo [1.1.1] pentan-1-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
1- ((3-acetyl bicyclo [ 1.1.1)]Pentane-1-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (20.0mg, 0.0660mmol) and trifluoromethyltrimethylchlorosilane (19.0mg, 0.132mmol) were dissolved in tetrahydrofuran (15mL), and cesium fluoride (10.0mg, 00660mmol) was added to the reaction mixture at room temperature, and the reaction was continued at room temperature for 12 hours. Adding 2N diluted hydrochloric acid (10mL) into the reaction solution, stirring for 30 min, extracting with ethyl acetate (20mL x2), combining organic phases, washing with saturated sodium bicarbonate solution (20mL x2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying with high performance liquid chromatography to obtain 3, 7-dimethyl-1- ((3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) bicyclo [ 1.1.1)]Pentan-1-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione (5.00mg, colorless oil), yield: 20 percent.1H NMR：(400MHz，CDCl3) δ 7.59(s, 1H), 4.20(s, 2H), 4.02(s, 3H), 3.59(s, 3H), 1.97(s, 6H), 1.79(s, 3H). MS-ESI calculated value [ M + H%]+373, found 373.
Example 8
3, 7-dimethyl-1- [ [ (1R, 3R) -3-3- [2, 2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl ] cyclobutyl ] methyl ] purine-2, 6-dione
3, 7-dimethyl-1- [ [ (1S, 3S) -3-3- [2, 2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl ] cyclobutyl ] methyl ] purine-2, 6-dione
Figure BDA0002403430430000241
First step of
3, 7-dimethyl-1- [ [3- [2, 2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl ] cyclobutyl ] methyl ] purine-2, 6-dione
3, 7-dimethyl-1- [ [3- (2, 2, 2-trifluoro-1, 1-dihydroxy-ethyl) cyclobutyl]Methyl radical]Purine-2, 6-dione (60.0mg, 0.165mmol), cesium fluoride (25.2mg, 0.165mmol) were dissolved in tetrahydrofuran (10mL), and trimethyl-trifluoromethyl-silane (70.6mg, 0.496mmol) was added at room temperature and stirred for 12 hours. The reaction was quenched by the addition of water (20 mL). Extract with ethyl acetate (10 mL. times.3). The organic phases are combined and saturatedWashing with brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. Purifying by preparative high performance liquid chromatography to obtain 3, 7-dimethyl-1- [ [ (1R, 3R) -3-3- [2, 2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl]Cyclobutyl radical]Methyl radical]Purine-2, 6-dione (8.00mg, yellow solid) (isomer 1, first peak), yield: 12 percent.1H NMR：(400MHz，Methonal-d4) δ 8.01(s, 1H), 4.22-4.17(m, 2H), 4.01(s, 3H), 3.54(s, 3H), 3.55-3.19(m, 1H), 2.63-2.56(m, 1H), 2.50-2.42(m, 2H), 1.82-1.78(m, 2H). MS-ESI calculated value [ M + H%]+415, found value 415.
And 3, 7-dimethyl-1- [ [ (1S, 3S) -3-3- [2, 2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl]Cyclobutyl radical]Methyl radical]Purine-2, 6-dione (4.00mg, yellow solid) (isomer 2, second peak), yield: 6 percent.1H NMR：(400MHz，Methonal-d4) Delta 8.20(s, 1H), 4.04-4.00(m, 5H), 3.55(s, 3H), 2.70-2.65(m, 1H), 2.55-2.53(m, 1H), 2.17-2.12(m, 2H), 2.02-1.98(m, 2H). MS-ESI calculated value [ M + H%]+415, found value 415.
Example 9
7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1S, 3S) -3- ((S) -1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione
7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1S, 3S) -3- ((R) -1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione
Figure BDA0002403430430000251
First step of
3-methylenecyclobutanecarboxylic acid
3-Methylenecyclobutyronitrile (10.0g, 107mmol) and potassium hydroxide (18.1g, 322mmol) were dissolved in ethanol (100mL) and water (50mL) and reacted at 100 ℃ for 2 hours. 1N hydrochloric acid (120mL) was added. Extraction with dichloromethane (30mL x3), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave 3-methylenecyclobutanecarboxylic acid (11.0g, yellow oil)Form), yield: 91 percent.1H NMR：(400MHz，Methonal-d4)δ4.83-4.76(m，2H)，3.15-2.96(m，1H)，2.95-2.92(m，4H)。
Second step of
Methyl-3-methylenecyclobutanecarboxylic acid
3-methylenecyclobutanecarboxylic acid (11.0g, 98.1mmol) and potassium carbonate (27.1g, 196mmol) were dissolved in acetone (100mL), dimethyl sulfate (14.8g, 117mmol) was added at 25 ℃ and reaction was carried out at 70 ℃ for 12 hours. The reaction was quenched by addition of water (20mL), extracted with dichloromethane (30mL x3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl-3-methylenecyclobutanecarboxylic acid (12.0g, yellow oil), yield: 97 percent.1H NMR：(400MHz，Methonal-d4)δ4.83-4.79(m，2H)，3.96(s，2H)，3.68(s，3H)，3.17-3.15(m，1H)，2.95-2.92(m，2H)。
The third step
Methyl 3- (hydroxymethyl) cyclobutanecarboxylic acid ethyl ester
Methyl-3-methylenecyclobutanecarboxylic acid (2.00g, 15.8mmol) was dissolved in tetrahydrofuran (30mL), borane dimethylsulfide (3.61g, 47.5mmol) was added dropwise at-10 ℃, then reaction was carried out at-10 ℃ for 3 hours, 3N aqueous sodium hydroxide solution (10mL) and hydrogen peroxide (5mL) were added, reaction was continued for 1 hour, the reaction was quenched by addition of saturated aqueous sodium thiosulfate solution (30mL), dichloromethane extraction (10mL × 3), anhydrous sodium sulfate was dried, filtration was carried out, and the filtrate was concentrated under reduced pressure to give ethyl methyl 3- (hydroxymethyl) cyclobutanecarboxylate (2.00g, yellow oil), yield: 87 percent.1H NMR：(400MHz，Methonal-d4)δ3.70(s，3H)，3.58(d，J＝6.8Hz，1H)，3.49(d，J＝6.8Hz，1H)，3.10-3.05(m，1H)，2.32-2.26(m，3H)，2.03-1.98(m，2H)。
The fourth step
3- (methylsulfonyloxymethyl) cyclobutanecarboxylic acid ethyl ester
Ethyl 3- (hydroxymethyl) cyclobutanecarboxylate (1.00g, 6.94mmol) and triethylamine (2.11g, 20.8mmol) were dissolved in dichloromethane (20mL) and methanesulfonyl chloride (1.59g, 13.9mmol) was added at 0 ℃. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of aqueous sodium bicarbonate (50 mL). Use twoExtraction with methyl chloride (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 3- (methylsulfonyloxymethyl) cyclobutanecarboxylate (1.40g, yellow oil), yield: 91 percent.1H NMR：(400MHz，Methonal-d4) δ 4.28(d, J ═ 6.8Hz, 1H), 4.19(d, J ═ 6.8Hz, 1H), 3.70(s, 3H), 3.20-3.08(m, 4H), 2.40-2.34(m, 3H), 2.13-2.09(m, 2H). MS-ESI calculated value [ M + H%]+223, measured value 223.
The fifth step
3- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl ] cyclobutanecarboxylic acid ethyl ester
Ethyl 3- (methylsulfonyloxymethyl) cyclobutanecarboxylate (1.40g, 6.30mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (1.13g, 6.30mmol), potassium iodide (209mg, 1.26mmol) and potassium carbonate (2.61g, 18.90mmol) were dissolved in N, N-dimethylformamide (100 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, water (100mL) was added and extracted with dichloromethane (10mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give ethyl 3- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl ] cyclobutanecarboxylate (1.50g, yellow solid) in yield: 78 percent.
1H NMR：(400MHz，Methonal-d4) δ 7.51(s, 1H), 4.18-4.10(m, 2H), 3.99(s, 3H), 3.67(s, 3H), 3.55(s, 3H), 3.26-2.65(m, 2H), 2.29-2.13(m, 4H). MS-ESI calculated value [ M + H%]+307, found 307.
The sixth step
3- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl ] cyclobutanecarboxylic acid
Reacting 3- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl]Ethyl cyclobutanecarboxylate (1.00g, 3.26mmol), potassium hydroxide (548mg, 9.78mmol) were dissolved in methanol (10mL) and water (5 mL). The reaction solution was heated to 90 ℃ and stirred for 3 hours. Cooled to room temperature, neutralized by addition of 1N hydrochloric acid (20mL), filtered, and extracted with dichloromethane (10 mL. times.3). The organic phases were combined, washed with saturated brine and anhydrous sulfuric acidSodium drying, filtering, concentrating the filtrate under reduced pressure to obtain 3- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl]Cyclobutanecarboxylic acid (800.00mg, yellow solid), yield: 84 percent. MS-ESI calculated value [ M + H%]+293, found 293.
Seventh step
3- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl ] -N-methoxy-N-methylcyclobutanecarboxamide
Reacting 3- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl]Cyclobutanecarboxylic acid (300mg, 1.03mmol), N, O-dimethylhydroxylamine hydrochloride (200mg, 2.05mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (394mg, 2.06mmol), 1-hydroxybenzotriazole (27.8mg, 0.206mmol) and triethylamine (312mg, 3.09mmol) were dissolved in dichloromethane (10 mL). Stirred at 25 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative TLC plate (ethyl acetate, Rf 0.3) to give 3- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl]-N-methoxy-N-methylcyclobutanecarboxamide (200mg, yellow solid), yield: 58 percent. MS-ESI calculated value [ M + H%]+336, measured value 336.
Eighth step
1- [ (3-Acetylcyclobutyl) methyl ] -3, 7-dimethylpurine-2, 6-dione
3- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl ] -N-methoxy-N-methylcyclobutanecarboxamide (300mg, 0.894mmol) was dissolved in tetrahydrofuran (10 mL). Methyl magnesium bromide (3M in ether, 1.49mL, 4.47mmol) was added dropwise at 0 deg.C and stirred for 3 hours. The reaction was quenched by addition of saturated ammonium chloride solution (20mL) and extracted with dichloromethane (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by preparative TLC plate separation (ethyl acetate, Rf 0.5) to give 1- [ (3-acetylcyclobutyl) methyl ] -3, 7-dimethylpurine-2, 6-dione (200mg, yellow solid) in yield: 77 percent.
MS-ESI calculated value [ M + H%]+291, found 291.
The ninth step
7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1S, 3S) -3- ((S) -1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione
7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1S, 3S) -3- ((R) -1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione
1- [ (3-acetylcyclobutyl) methyl group]-3, 7-dimethylpurine-2, 6-dione (250mg, 0.861mmol), cesium fluoride (130mg, 0.861mmol) were dissolved in tetrahydrofuran (10mL), and trimethyl-trifluoromethyl-silane (244mg, 1.72mmol) was added at room temperature and stirred for 12 hours. The reaction was quenched by the addition of water (20 mL). Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification by preparative high performance liquid chromatography gave 7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1S, 3S) -3- ((S) -1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione (65.0mg, yellow solid) (isomer 1, first peak), yield: 20 percent.1H NMR：(400MHz，Methonal-d4) δ 8.21(s, 1H), 4.23(d, J ═ 7.6Hz, 2H), 4.03(s, 3H), 3.55(s, 3H), 3.26 to 3.19(m, 2H), 2.63 to 2.56(m, 2H), 2.55 to 2.42(m, 2H), 1.82 to 1.78(m, 3H). MS-ESI calculated value [ M + H%]+361, found 361.
7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1S, 3S) -3- ((R) -1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione (80.0mg, yellow solid) (isomer 2, second peak), yield: 22 percent.1H NMR：(400MHz，Methonal-d4) Delta 8.05(s, 1H), 4.01-3.99(m, 5H), 4.03(s, 3H), 3.54(s, 3H), 2.71-2.66(m, 1H), 2.55-2.54(m, 1H), 2.17-2.12(m, 2H), 2.02-1.98(m, 2H). MS-ESI calculated value [ M + H%]+361, found 361.
Example 10
1,3 trans-1- ((3-hydroxy-3- (trifluoromethyl) cyclopentyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
1,3 cis-1- ((3-hydroxy-3- (trifluoromethyl) cyclopentyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000281
First step of
1, 4-Dioxaspiro [4.4] nonane-7-carboxylic acid methyl ester
Methyl 3-oxo-cyclopentanecarboxylate (16.0g, 110mmol), p-toluenesulfonic acid (14.0g, 220mmol) and ethylene glycol (969mg, 5.60mmol) were dissolved in dry toluene (160mL), heated to reflux for 4 hours after addition to a water separator. The reaction was quenched by addition of water (200mL), extracted with ethyl acetate, and the organic phases combined. The combined organic phases were washed successively with water (200 mL. times.2), saturated sodium chloride solution (200 mL. times.2), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting 1, 4-dioxaspiro [4.4] compound was purified by silica gel column chromatography (5: 1 petroleum ether/ethyl acetate, Rf ═ 0.3)]Nonane-7-carboxylic acid methyl ester (6.20g, yellow oil), yield: 29 percent.1H NMR：(400MHz，CDCl3) Delta 3.93-3.89(m, 4H), 3.69(s, 3H), 2.91-2.89(m, 1H), 2.11-1.82(m, 6H). MS-ESI calculated value [ M + H%]+187, found 187.
Second step of
(1, 4-dioxaspiro [4.4] nonan-7-yl) -methanol
1, 4-dioxaspiro [4.4]]Methyl nonane-7-carboxylate (1.00g, 10.7mmol) was dissolved in anhydrous tetrahydrofuran (30mL) under nitrogen and lithium aluminum hydride (531mg, 13.9mmol) was added slowly at-10 ℃. The reaction solution was slowly warmed to 25 ℃ and stirred for 3 hours. To the reaction mixture were added water (0.5mL), 15% sodium hydroxide solution (0.5mL), and water (1.5mL) in this order. Filtering to remove insoluble substances, and concentrating the filtrate under reduced pressure to obtain (1, 4-dioxaspiro [4.4]]Nonan-7-yl) -methanol (1.5mg, yellow oil), yield: 88 percent.1H NMR：(400MHz，CDCl3) Delta 3.94-3.89(m, 4H), 3.58-3.57(m, 2H), 2.31-1.48(m, 7H). MS-ESI calculated value [ M + H%]+159, found 159.
The third step
Methanesulfonic acid 1, 4-dioxaspiro [4.4] nonan-7-ylmethyl ester
Mixing (1, 4-dioxaspiro [4.4]]Nonane-7-yl) -methanol (500mg, 53.1mmol) and triethylamine (800mg, 7.92mmol) were dissolved in dry dichloromethane (5mL) under nitrogen and methanesulfonyl chloride (433mg, 3.80mmol) was added slowly at 0 ℃. The reaction was warmed to 25 ℃ and stirred for 2 hours. The reaction was quenched by addition of water (40mL) and extracted with ethyl acetate. The combined organic phases were washed successively with water (20mL x2), saturated sodium chloride solution (50mL x2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methanesulfonic acid 1, 4-dioxaspiro [4.4] spiro [ e]Nonan-7-ylmethyl ester (800mg, yellow oil). MS-ESI calculated value [ M + H%]+237, found 237.
The fourth step
(1, 4-dioxaspiro [4.4] nonan-7-ylmethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Methanesulfonic acid 1, 4-dioxaspiro [4.4]]Nonan-7-ylmethyl ester (300mg, 1.27mmol) was dissolved in dry N, N-dimethylformamide (10mL) under nitrogen, and potassium carbonate (350mg, 2.54mmol), potassium iodide (21.0mg, 0.130mmol), 2, 6-hydroxy-3, 7-dimethylpurine (275mg, 1.52mmol) were added at 25 ℃. The reaction solution was heated to 130 ℃ and stirred for 3 hours. The reaction was cooled to 25 ℃ and quenched by the addition of water (40mL) and extracted with ethyl acetate (30 mL. times.2). The combined organic phases were washed with saturated sodium chloride solution (100 mL. times.2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (1, 4-dioxaspiro [4.4] spiro]Nonan-7-ylmethyl) -3, 7-dimethyl 1H-purine-2, 6(3H, 7H) -dione (200mg, white solid), yield: 45 percent. MS-ESI calculated value [ M + H%]+321, found value 321.
The fifth step
3, 7-dimethyl-1- (3-oxo-cyclopentylmethyl) -1H-purine-2, 6(3H, 7H) -dione
Mixing (1, 4-dioxaspiro [4.4]]Nonan-7-ylmethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (200mg, 0.620mmol) was dissolved in anhydrous tetrahydrofuran (5mL) under nitrogen and concentrated hydrochloric acid (3mL) was added at 25 ℃. The reaction solution was stirred at 25 ℃ for 1 hour. Water (60mL) was added to dilute the reaction solution, and the reaction solution was extracted with ethyl acetate (20 mL. times.3). The combined organic phases were washed with saturated sodium chloride solution (100mL x2), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure,purification by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.3) gave 3, 7-dimethyl-1- (3-oxo-cyclopentylmethyl) -1H-purine-2, 6(3H, 7H) -dione (100mg, yellow oil) in yield: 57 percent. MS-ESI calculated value [ M + H%]+277, found 277.
The sixth step
1,3 trans-1- ((3-hydroxy-3- (trifluoromethyl) cyclopentyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
1,3 cis-1- ((3-hydroxy-3- (trifluoromethyl) cyclopentyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
3, 7-dimethyl-1- ((3-oxocyclopentyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (100mg, 0.362mmol) and cesium fluoride (11.0mg, 0.0725mmol) were dissolved in anhydrous tetrahydrofuran (3mL) and trifluoromethyltrimethylsilane (95.0mg, 0.640mmol) was added under nitrogen. The reaction solution was slowly heated to 30 ℃ and stirred for 12 hours. To the reaction mixture was added aqueous hydrochloric acid (1N, 5mL), and the mixture was further stirred at 30 ℃ for 0.5 hour. The reaction was diluted with water (50mL), adjusted to pH 7 with saturated aqueous sodium bicarbonate (10mL), and extracted with ethyl acetate (30 mL. times.2). The combined organic phases are dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain two cis-trans isomeric products.
1,3 trans-1- ((3-hydroxy-3- (trifluoromethyl) cyclopentyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (isomer 1, first peak) (40.0mg, white solid), yield: 32 percent.1H NMR：(400MHz，Methonal-d4) δ 7.68(s, 1H), 4.13-4.08(m, 2H), 4.05(s, 3H), 3.61(s, 3H), 2.80-2.78(m, 1H), 2.40-2.24(m, 1H), 2.04-2.03(m, 1H), 2.01-1.87(m, 2H), 1.84-1.76(m, 1H), 1.62-1.60(m, 1H). MS-ESI calculated value [ M + H%]+347, found 347.
1,3 cis-1- ((3-hydroxy-3- (trifluoromethyl) cyclopentyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (isomer 2, second peak) (20.0mg, white solid), yield: 16 percent.1H NMR：(400MHz，Methonal-d4)δ7.62(s，1H)，4.22-4.18(m，1H) 4.05-4.04(m, 1H), 4.00(s, 3H), 3.63(s, 3H), 2.65-2.63(m, 1H), 2.09-2.01(m, 4H), 1.70-1.68(m, 1H), 1.67-1.65(m, 1H). MS-ESI calculated value [ M + H%]+347, found 347.
Example 11
1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000301
Figure BDA0002403430430000311
First step of
Ethyl 1, 4-dioxaspiro [4, 5] decane-8-carboxylic acid ethyl ester
Ethyl 4-oxocyclohexanecarboxylic acid (30.0g, 176mmol), ethylene glycol (22.0g, 353mmol) and p-toluenesulfonic acid (304mg, 1.70mmol) were dissolved in toluene (315mL), and the reaction was heated under reflux overnight after addition to a water separator. The reaction was cooled to 25 ℃, washed with water (300mL x2) and saturated sodium bicarbonate (500mL x2) in that order, the organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give the product ethyl 1, 4-dioxaspiro [4, 5]]Ethyl decane-8-carboxylate (37.2g, yellow liquid), yield: 99 percent. MS-ESI calculated value [ M + H%]+215, measured value 215.
Second step of
1, 4-dioxaspiro [4, 5] decan-8-ylmethanol
Lithium aluminum hydride (2.30g, 61.0mmol) was slowly added to tetrahydrofuran (60mL) at 0 deg.C under nitrogen, and ethyl 1, 4-dioxaspiro [4, 5] spiro [ was added dropwise]A solution of ethyl decane-8-carboxylate (10.0g, 42.0mmol) in tetrahydrofuran (40 mL). The reaction was slowly warmed to 25 ℃ and stirred for 3.5 hours. The reaction mixture was cooled to 0 ℃ and water (2.3g, 127mmol), 15% sodium hydroxide (2.3g, 8.60mmol) and water (6.9g, 383mmol) were added slowly in that order. Filtration, cake washing with tetrahydrofuran (50mL x3), combining the organic phases, and application of anhydrous sulfurDrying sodium salt, filtering, and concentrating the filtrate under reduced pressure to obtain 1, 4-dioxaspiro [4, 5] product]Decan-8-ylmethanol (6.22g, yellow liquid), yield: 89 percent. MS-ESI calculated value [ M + H%]+173, found 173.
The third step
1, 4-dioxaspiro [4, 5] decan-8-ylmethylmethylmethanesulfonates
1, 4-dioxaspiro [4, 5]]Decan-8-ylmethanol (2.00g, 12.0mmol) and diisopropylethylamine (3.10g, 24.0mmol) were dissolved in dichloromethane (40mL) and methanesulfonyl chloride (3.90g, 30.0mmol) was added slowly at 0 ℃. The reaction was warmed to 25 ℃ and stirred overnight. The reaction was quenched by addition of saturated aqueous ammonium chloride (100mL) and extracted with ethyl acetate (200 mL. times.3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (3: 1 petroleum ether/ethyl acetate, Rf ═ 0.4) to give the product 1, 4-dioxaspiro [4, 5] spiro [4, 5]]Decan-8-ylmethyl mesylate (1.80g, yellow liquid), yield: 60 percent. MS-ESI calculated value [ M + H%]+251, found value 251.
The fourth step
1- (1, 4-dioxaspiro [4, 5] decan-8-ylmethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl methanesulfonate (1.50g, 6.00mmol), 3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (1.00g, 6.00mmol) and potassium carbonate (2.50g, 18.0mmol), potassium iodide (100mg, 0.600mmol) were dissolved in N, N-dimethylformamide (20mL), and the reaction mixture was heated to 130 ℃ and stirred for 3 hours. The reaction mixture was cooled to 25 ℃ and quenched with saturated brine (100mL) and extracted with ethyl acetate (500 mL. times.3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give the product 1- (1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (1.75g, white solid), yield: and 63 percent. MS-ESI calculated value [ M + H%]+335, measured value 335.
The fifth step
3, 7-dimethyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione
1- (1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (1.50g, 4.50mmol) was dissolved in acetone (15mL), and aqueous hydrochloric acid (2N, 2.5mL) was added. The reaction was stirred overnight at 25 deg.C, quenched by addition of water (50mL) and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (1: 3 petroleum ether/ethyl acetate, Rf ═ 0.4) to give the product 3, 7-dimethyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (1.02g, white solid) in yield: 78 percent. MS-ESI calculated value [ M + H%]+291, found 291.
The sixth step
1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
3, 7-dimethyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (100mg, 0.330mmol) and cesium fluoride (60.0mg, 0.350mmol) were dissolved in tetrahydrofuran (5mL) and trifluoromethyltrimethylsilane (75.0mg, 0.500mmol) was added slowly under nitrogen. The reaction solution was stirred at 30 ℃ for 3 hours. Cooled to 25 ℃, aqueous hydrochloric acid (4N, 3mL) was added, stirred at 25 ℃ for half an hour, the PH was adjusted to 7, diluted with water and extracted with ethyl acetate (20mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative high performance liquid chromatography to give the product 1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (24.0mg, white solid), yield: 39 percent.
1H NMR：(400MHz，Methonal-d4) δ 7.86(s, 1H), 4.04(d, J ═ 7.2Hz, 1H), 3.97(s, 3H), 3.89(d, J ═ 7.6Hz, 1H), 3.53(s, 3H), 2.06-1.97(m, 2H), 1.88-1.77(m, 3H), 1.62-1.43(m, 4H). MS-ESI calculated value [ M + H%]+361, found 361.
Example 12
Figure BDA0002403430430000321
Figure BDA0002403430430000331
First step of
4-hydroxy-4- (trifluoromethyl) cyclohexanecarboxylic acid ethyl ester
Ethyl 4-oxocyclohexanecarboxylate (10.0g, 58.7mmol) was dissolved in tetrahydrofuran (100mL), and trifluoromethyltrimethylsilane (12.5g, 88.1mmol) and cesium fluoride (8.92g, 58.7mmol) were added at room temperature. The reaction was stirred at rt for 12 h, tetrabutylammonium fluoride (9.27g, 29.4mmol) was added, after stirring at rt for 30 min, ethyl acetate (80mL) was added to dilute, the organic phase was washed with saturated sodium bicarbonate (50mL x2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (10: 1 petroleum ether/ethyl acetate, Rf ═ 0.5) to give ethyl 4-hydroxy-4- (trifluoromethyl) cyclohexanecarboxylate (12.0g, colorless oil) in yield: 85 percent.1H NMR:(400MHz，Methanol-d4)δ4.20-4.12(m，2H)，2.03-1.86(m，9H)，1.29-1.25(m，3H)。
MS-ESI calculated value [ M + H%]+241, measured value 241.
Second step of
4- (hydroxymethyl) -1- (trifluoromethyl) cyclohexanol
Ethyl 4-hydroxy-4- (trifluoromethyl) cyclohexanecarboxylate (12.00g, 49.9mmol) was dissolved in tetrahydrofuran (20mL), and lithium aluminum hydride (3.79g, 100mmol) was added thereto at 0 ℃ to react for 2 hours. The reaction was quenched by the addition of water (30 mL). Extraction with ethyl acetate (50mL × 3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.2) gave (4- (hydroxymethyl) -1- (trifluoromethyl) cyclohexanol (9.00g, colorless oil) in 91% yield.1H NMR:(400MHz，Methanol-d4)δ3.58-3.40(m，2H)，1.90-1.40(m，9H)。
The third step
(4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl methanesulfonate
(4- (hydroxymethyl) -1- (trifluoromethyl) cyclohexanol (11).0g, 55.5mmol) and triethylamine (1.18g, 11.6mmol) were dissolved in dichloromethane (80mL) and methanesulfonyl chloride (14.4g, 125mmol) was added at 0 ℃. After the reaction mixture was stirred at room temperature for 2 hours, dichloromethane (60mL) was added to dilute the reaction mixture, and the mixture was washed with saturated sodium bicarbonate (50mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (4: 1 petroleum ether/ethyl acetate, Rf ═ 0.5) to give (4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl methanesulfonate (13.00g, colorless oil) in yield: 85 percent.1H NMR:(400MHz，Methanol-d4)δ4.25-4.01(m，2H)，3.10-3.07(m，3H)，2.03-1.24(m，9H)。
The fourth step
1- (((1S, 4S) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -
Diketones
(4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl methanesulfonate (10.0g, 36.2mmol) was dissolved in N, N-dimethylformamide (100mL), and 3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (6.52g, 36.2mmol), potassium carbonate (7.50g, 54.3mmol) and potassium iodide (184mg, 1.11mmol) were added to the reaction mixture at room temperature. The reaction was heated to 100 ℃ for 5 hours, concentrated, diluted with ethyl acetate (100mL), the organic phase washed with saturated sodium bicarbonate (50mL x2), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, separated by preparative SFC under separation conditions: a chromatographic column: chiralpak AD-3150 x 4.6mm i.d., 3um mobile phase: ethanol (0.05% diethylamine) in CO2from 5% to 40% at 2.5mL/min wavelength 220nm gave 1- (((1R, 4R) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (2.5g, white solid) (isomer 1, peak 1), yield: 19 percent.1HNMR：(400MHz，Methanol-d4) δ 7.88(s, 1H), 4.02(d, J ═ 7.6Hz, 2H), 3.98(s, 3H), 3.53(s, 3H), 2.16-2.02(m, 1H), 1.99-1.98(m, 2H), 1.87-1.80(m, 2H), 1.60-1.49(m, 2H), 1.48-1.46(m, 2H). MS-ESI calculated value [ M + H%]+361, found 361.
1- (((1S, 4S) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl)-3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (2.40g, white solid) (isomer 2, second peak), yield: 19 percent.1H NMR:(400MHz，CDCl3) δ 7.88(s, 1H), 3.99(s, 3H), 3.90(d, J ═ 7.6Hz, 2H), 3.54(s, 3H), 1.84-1.81(m, 3H), 1.58-1.46(m, 6H). MS-ESI calculated value [ M + H%]+361, found 361.
Example 13
1- ((4-hydroxy-4-methylcyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000341
3, 7-dimethyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (50.0mg, 0.170mmol) was dissolved in tetrahydrofuran (2 mL). Under nitrogen, methyl Grignard reagent (3M ether solvent, 0.4mL, 1.20mmol) was added slowly at-78 ℃. The reaction solution was stirred at-78 ℃ for 0.5 hour, slowly raised to 0 ℃ and stirred for 0.5 hour. Adding saturated ammonium chloride solution for quenching, and adjusting the pH value to 7. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give the product 1- ((4-hydroxy-4-methylcyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (8.0mg, white solid), yield: 16 percent.1H NMR：(400MHz，Methonal-d4) δ 7.86(s, 1H), 3.97(s, 3H), 3.88(d, J ═ 7.6Hz, 2H), 3.52(s, 3H), 1.85-1.78(m, 1H), 1.73-1.57(m, 3H), 1.46-1.33(m, 2H), 1.32-1.15(m, 6H). MS-ESI calculated value [ M + H-H2O]+289, found value 289.
Example 14
1- ((4-Ethyl-4-hydroxycyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000351
3, 7-dimethyl-1- ((4-Oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (50.0mg, 0.170mmol) was dissolved in tetraTetrahydrofuran (2 mL). Under nitrogen, ethyl Grignard reagent (3M in ether solvent, 0.4mL, 1.20mmol) was added slowly at-78 ℃. The reaction solution was stirred at-78 ℃ for 0.5 hour, slowly raised to 0 ℃ and stirred for 0.5 hour. Adding saturated ammonium chloride solution for quenching, and adjusting the pH value to 7. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give the product 1- ((4-ethyl-4-hydroxycyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (42.0mg, white solid), yield: 77 percent.1H NMR：(400MHz，Methonal-d4) δ 7.86(s, 1H), 3.97(s, 3H), 3.88(d, J ═ 7.6Hz, 2H), 3.54-3.50(m, 3H), 1.93-1.80(m, 1H), 1.76-1.72(m, 2H), 1.66-1.51(m, 3H), 1.38-1.28(m, 3H), 1.27-1.13(m, 2H), 0.89(t, J ═ 7.2Hz, 3H). MS-ESI calculated value [ M + H-H2O]+303, found value 303.
Example 15
1-2- (((1R, 4R) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
1- (2- ((1S, 4S) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000352
Figure BDA0002403430430000361
First step of
Ethyl 2- (1, 4-dioxaspiro [4.5] decan-8-ylidene) acetic acid methyl ester
Triethyl phosphonoacetate (12.2g, 54.4mmol) was dissolved in tetrahydrofuran (100mL), sodium hydride (1.92g, 48.0mmol) was added in portions at 0 deg.C, and the reaction was stirred for 30 minutes under nitrogen. A solution of 1, 4-cyclohexanedione monoethylene ketal (5.00g, 32.0mmol) in tetrahydrofuran (15mL) was added dropwise to the reaction mixture at 0 ℃ and the reaction mixture was stirred at 25 ℃ for 3 hours. The reaction was quenched by addition of water (25mL) and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5: 1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give ethyl 2- (1, 4-dioxaspiro [4.5] ethyl]Decane-8-ylidene) acetic acid methyl ester (6.30g, colorless oil), yield: 93 percent.1H NMR：(400MHz，CDCl3) δ 5.67(s, 1H), 4.15(q, J ═ 7.2Hz, 2H), 3.98(s, 4H), 3.00(t, J ═ 6.4Hz, 2H), 2.38(t, J ═ 6.4Hz, 2H), 1.84-1.68(m, 4H), 1.28(t, J ═ 7.2Hz, 3H). MS-ESI calculated value [ M + H%]+227, found 227.
Second step of
Ethyl 2- (1, 4-dioxaspiro [4.5] decan-8-yl) acetate
Methyl 2- (1, 4-dioxaspiro [4.5] decan-8-ylidene) acetate (3.80g, 17.9mmol) was dissolved in methanol (50mL), and dry palladium on carbon (palladium 10%, water 1%, 400mg) was added to react the reaction mixture at room temperature under hydrogen (50psi) for 18 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give ethyl methyl 2- (1, 4-dioxaspiro [4.5] decan-8-yl) acetate (3.50g, colorless oil), yield: 91 percent.
1H NMR：(400MHz，CDCl3) δ 4.12(q, J ═ 7.2Hz, 2H), 3.93(s, 4H), 2.22(d, J ═ 7.2Hz, 2H), 1.90-1.64(m, 5H), 1.63-1.48(m, 2H), 1.40-1.16(m, 5H). MS-ESI calculated value [ M + H%]+229, found 229.
The third step
2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethanol
Ethyl 2- (1, 4-dioxaspiro [4.5] decan-8-yl) acetate (1.00g, 4.38mmol) was dissolved in tetrahydrofuran (20mL), lithium aluminum hydride (216mg, 5.69mmol) was added in portions at 0 ℃ and the reaction was stirred under nitrogen for 18 hours. The reaction mixture was cooled to 0 ℃ and water (0.2mL), a 15% aqueous solution of sodium hydroxide (0.2mL) and water (0.6mL) were added slowly in this order. Filtration and concentration of the filtrate under reduced pressure gave the product 2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethanol (780mg, yellow oil) in yield: 96 percent.
1H NMR：(400MHz，CDCl3)δ3.94(s，4H)，3.69(t，J＝6.4Hz，2H) 1.79-1.65(m, 4H), 1.59-1.38(m, 5H), 1.34-1.17(m, 2H). MS-ESI calculated value [ M + H%]+187, found 187.
The fourth step
2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl methanesulfonate
2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethanol (400mg, 2.15mmol) and triethylamine (435mg, 4.30mmol) were dissolved in dichloromethane (10mL) and methanesulfonyl chloride (369mg, 3.23mmol) was added slowly at 0 ℃. The reaction mixture was stirred at 0 ℃ for 4 hours. The reaction was quenched with water (10mL) and extracted with dichloromethane (30 mL. times.2). The organic phases were combined, washed with saturated aqueous sodium bicarbonate (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl methanesulfonate (500mg crude, yellow oil).
1H NMR：(400MHz，CDCl3) δ 4.28(t, J ═ 6.4Hz, 2H), 3.94(s, 4H), 3.01(s, 3H), 1.76-1.63(m, 6H), 1.60-1.43(m, 3H), 1.37-1.21(m, 2H). MS-ESI calculated value [ M + H%]+265, found 265.
The fifth step
1- (2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (204mg, 1.13mmol) was dissolved in N, N-dimethylformamide (15mL), and 2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl methanesulfonate (300mg, 1.13mmol), potassium carbonate (312mg, 2.26mmol) and potassium iodide (225mg, 1.36mmol) were added. The reaction solution was heated to 120 ℃ and stirred for 3 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.2) to give 1- [2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl ] -3, 7-dimethylpurine-2, 6-dione (190mg, white solid), yield: 48 percent.
1H NMR：(400MHz，CDCl3) δ 7.50(s, 1H), 4.09-4.03(m, 2H), 4.02(s, 3H), 3.99(s, 4H), 3.57(s, 1H), 1.90-1.70(m, 5H), 1.68-1.47(m, 6H), 1.45-1.31(m, 2H). MS-ESI calculated value [ M + H%]+349, measured value349。
The sixth step
3, 7-dimethyl-1- (2- (4-oxocyclohexyl) ethyl) -1H-purine-2, 6- (3H, 7H) -dione
1- [2- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl ] -3, 7-dimethylpurine-2, 6-dione (190mg, 545. mu. mol) was dissolved in tetrahydrofuran (3mL) and concentrated hydrochloric acid (1mL) was added. The reaction was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure, the aqueous phase was neutralized to pH 7 with saturated sodium bicarbonate, extracted with ethyl acetate (20mL × 2), the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate, Rf ═ 0.3) to give 3, 7-dimethyl-1- (2- (4-oxocyclohexyl) ethyl) -1H-purine-2, 6- (3H, 7H) -dione (150mg, colorless oil), yield: 90 percent.
MS-ESI calculated value [ M + H%]+305, measured value 305.
Seventh step
3, 7-dimethyl-1- (2- (4- (trifluoromethyl) -4- ((trimethylsilyl) oxy) cyclohexyl) ethyl) -1-purine-2, 6- (3H, 7H) -dione
Mixing 3, 7-dimethyl-1- [2- (4-oxygen cyclohexyl) ethyl]Purine-2, 6-dione (145mg, 0.476mmol) and caesium fluoride (7.2mg, 0.0476mmol) were dissolved in tetrahydrofuran (10mL) and trifluoromethyl trimethylsilane was added slowly under nitrogen protection(203mg, 1.43 mmol). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction was diluted with water (20mL), extracted with ethyl acetate (15mL × 2), the organic phases combined, washed with brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 3, 7-dimethyl-1- (2- (4- (trifluoromethyl) -4- ((trimethylsilyl) oxy) cyclohexyl) ethyl) -1-purine-2, 6- (3H, 7H) -dione (170mg, colorless liquid), yield: 80 percent.
MS-ESI calculated value [ M + H%]+447, found 447.
Eighth step
1- (2- ((1R, 4R) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
1- (2- ((1S, 4S) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
3, 7-dimethyl-1- [2- [4- (trifluoromethyl) -4-trimethylsiloxy-cyclohexyl]Ethyl radical]Purine-2, 6-dione (160mg, 0.358mmol) was dissolved in tetrahydrofuran (3mL) and concentrated hydrochloric acid (12M, 0.107mL) was added. The reaction solution was stirred at 25 ℃ for 18 hours. Diluted with water, saturated sodium bicarbonate solution (10mL) adjusted pH to 7 and extracted with ethyl acetate (10mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative high performance liquid chromatography to give 1- (2- ((1R, 4R) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione hydrochloride (40.0mg, white solid) (isomer 1, first peak), yield: 27 percent.1H NMR：(400MHz，CDCl3) Δ 8.01(s, 1H), 4.09-3.94(m, 5H), 3.53(s, 3H), 1.97-1.79(m, 4H), 1.76-1.62(m, 3H), 1.61-1.45(m, 4H). MS-ESI calculated value [ M + H%]+375, found 375.
And 1- (2- ((1S, 4S) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione hydrochloride (15.0mg, white solid) (isomer 2, second peak), yield: 10 percent.1H NMR：(400MHz，CDCl3) δ 8.01(s, 1H), 4.09-3.95(m, 5H), 3.53(s, 3H), 1.87-1.68(m, 4H), 1.64-1.48(m, 4H), 1.46-1.25(m, 3H). MS-ESI calculated value [ M + H%]+375, found 375.
Example 16
1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000391
First step of
Ethyl-8-methyl-1, 4-dioxaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Reacting ethyl 1, 4-dioxaspiro [4.5]]Decane-8-carboxylic acid ethyl ester (5.00g, 23.3mmol) was dissolved in anhydrous tetrahydrofuran (100mL) and slowly cooled at-78 ℃ under nitrogenLithium diisopropylamide solution (2M tetrahydrofuran solution, 14.0mL, 28.0mmol) was slowly added dropwise and the reaction stirred at-78 deg.C for 1 h. Methyl iodide (6.62g, 46.7mmol) was added slowly and stirring continued for 1 hour. The reaction was quenched by the addition of water (100 mL). The reaction solution was extracted with ethyl acetate (100mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10: 1 petroleum ether/ethyl acetate, Rf ═ 0.4) to give ethyl-8-methyl-1, 4-dioxaspiro [4.5 ═ b]Tert-butyl decane-8-carboxylate (5.00g, yellow oil), yield: 94 percent.1H NMR：(400MHz，Methonal-d4)δ4.16-4.10(m，2H)，3.93-3.86(m，4H)，2.13-2.06(m，2H)，1.61-1.48(m，6H)，1.25-1.22(m，3H)，1.15(s，3H)。
Second step of
Ethyl-1-methyl-4-oxocyclohexanecarboxylic acid
Reacting ethyl-8-methyl-1, 4-dioxaspiro [4.5]]Tert-butyl decane-8-carboxylate (5.00g, 21.9mmol) was dissolved in tetrahydrofuran (50mL), and 1N aqueous hydrochloric acid (20mL) was added dropwise at 0 ℃ and then stirred at 20 ℃ for 1 hour. The mixture was cooled to 0 ℃ and quenched by the addition of sodium bicarbonate solution (50 mL). The mixture was extracted with ethyl acetate (100mL x 3). The organic phase was washed with saturated brine (100 mL. times.3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography (10: 1 petroleum ether/ethyl acetate, Rf ═ 0.4) gave ethyl-1-methyl-4-oxocyclohexanecarboxylic acid (3.00g, colorless oil) in: 74 percent.1H NMR：(400MHz，Methonal-d4)δ4.26-4.11(m，2H)，2.46-2.29(m，5H)，1.74-1.55(m，3H)，1.33-1.26(m，6H)。
The third step
Ethyl 4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexanecarboxylic acid
Ethyl-1-methyl-4-oxocyclohexanecarboxylic acid (3.00g, 16.3mmol), cesium fluoride (247mg, 1.63mmol) were dissolved in tetrahydrofuran (50mL), and trimethylsilyltrifluoromethyl (4.63g, 35.3mmol) was added at 0 ℃. The reaction solution was reacted at 20 ℃ under nitrogen for 6 hours. Then 4N aqueous hydrochloric acid (4mL) was added. The mixture was reacted at room temperature under nitrogen for 6 hours. The reaction was quenched by addition of saturated sodium bicarbonate solution (30mL) and quenched with ethyl acetateAcid ethyl ester extraction (100mL x3), organic phase dried over anhydrous sodium sulfate, filtered, filtrate concentrated under reduced pressure and purified by silica gel column chromatography (10: 1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give ethyl 4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexanecarboxylic acid (3.00g, colorless oil), yield: 73 percent.1HNMR:(400MHz，Methanol-d4)δ4.20-4.12(m，2H)，2.03-1.31(m，8H)，1.29-1.23(m，6H)。
The fourth step
4- (hydroxymethyl) -4-methyl-1- (trifluoromethyl) cyclohexanol
Ethyl 4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexanecarboxylic acid (3.00g, 11.8mmol) was dissolved in anhydrous tetrahydrofuran (50mL) and lithium aluminium hydride (896mg, 23.6mmol) was added at 0 ℃. The reaction solution was heated to 25 ℃ and stirred for 1 hour. Quenched with water (20mL), extracted with ethyl acetate (50mL x3), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and purified by silica gel column chromatography (3: 1 petroleum ether/ethyl acetate, Rf ═ 0.2) to give 4- (hydroxymethyl) -4-methyl-1- (trifluoromethyl) cyclohexanol (2.00g, colorless oil), yield: 80 percent.1H NMR:(400MHz，Methanol-d4)δ3.25(s，2H)，1.76-1.64(m，6H)，1.29-1.26(m，2H),0.93-0.91(m，3H)。
The fifth step
(4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl methanesulfonate
4- (hydroxymethyl) -4-methyl-1- (trifluoromethyl) cyclohexanol (2.00g, 9.42mmol) was dissolved in dichloromethane (30mL) and triethylamine (953mg, 9.42mmol) and methanesulfonyl chloride (1.08g, 9.42mmol) were added at 0 ℃. The reaction mixture was reacted at 0 ℃ for 2 hours. Quenched by addition of saturated aqueous sodium bicarbonate (10mL), extracted with dichloromethane (50mL x3), the organic phases combined, washed with saturated sodium chloride solution (50mL x3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give (4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl methanesulfonate (2.00g, yellow oil), yield: 73 percent.
The sixth step
1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
(4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methylmethanesulfonate (100mg, 0.344mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (62.1mg, 0.344mmol), potassium iodide (5.70mg, 0.0344mmol) and potassium carbonate (47.6mg, 0.344mmol) were dissolved in anhydrous N, N-dimethylformamide (5 mL). The reaction solution is heated to 150 ℃ by microwave and reacted for 4 hours. The reaction was cooled to 20 ℃, filtered and purified by preparative high performance liquid chromatography to give 1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (3.0mg, white solid), yield: 2 percent.1H NMR：(400MHz，Methonal-d4) δ 7.88(s, 1H), 3.98(s, 3H), 3.96(s, 2H), 3.54(s, 3H), 1.81-1.64(m, 6H), 1.63-1.34(m, 2H), 1.00(s, 3H). MS-ESI calculated value [ M + H%]+375, found 375.
Example 17
1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000411
First step of
Ethyl 8- (methoxymethyl) -1, 4-dioxaspiro [4.5] decane-8-carboxylic acid ethyl ester
Reacting ethyl 1, 4-dioxaspiro [4.5]]Ethyl decane-8-carboxylate (5.00g, 23.3mmol) was dissolved in anhydrous tetrahydrofuran (100mL), a lithium diisopropylamide solution (2M n-hexane solution, 14.0mL, 28.0mmol) was slowly added dropwise at-78 ℃ under nitrogen protection, and the reaction solution was stirred at-78 ℃ for 1 hour. Methoxybromomethane (5.83g, 46.7mmol) was added slowly and stirring continued for 1 h. The reaction was quenched by the addition of water (100 mL). The reaction solution was extracted with ethyl acetate (100mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10: 1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give ethyl 8- (methoxymethyl) -1, 4-dioxaspiro [4.5]]Ethyl decane-8-carboxylate (5.00g, yellow oil), yield: 83 percent.1H NMR:(400MHz，Methanol-d4)δ4.18(q，J＝6.8Hz，2H)，3.94(s，4H)，3.55(s，2H),3.33(s，3H)，2.14-2.12(m，2H)，1.65-1.57(m，6H),1.26(t，J＝6.8Hz，3H)。
Second step of
Ethyl-1- (methoxymethyl) -4-oxocyclohexanecarboxylic acid ethyl ester
Reacting ethyl 8- (methoxymethyl) -1, 4-dioxaspiro [4.5]]Ethyl decane-8-carboxylate (5.00g, 19.4mmol) was dissolved in tetrahydrofuran (50mL), and 1N diluted hydrochloric acid (10mL) was added dropwise at 0 ℃ and then stirred at 20 ℃ for 1 hour. The mixture was cooled to 0 ℃ and quenched by the addition of sodium bicarbonate solution (50 mL). The mixture was extracted with ethyl acetate (100mL x 3). The organic phase was washed with saturated brine (100 mL. times.3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography (10: 1 petroleum ether/ethyl acetate, Rf ═ 0.4) gave ethyl-1- (methoxymethyl) -4-oxocyclohexanecarboxylate (3.00g, white oil) in yield: 73 percent.1H NMR:(400MHz，Methanol-d4)δ4.25(q，J＝6.8Hz，2H)，3.52(s，2H)，3.34(s，3H)，2.52-2.30(m，6H)，1.82-1.78(m，2H),1.30(t，J＝6.8Hz，3H)。
The third step
4-hydroxy-1- (methoxymethyl) -4- (trifluoromethyl) cyclohexanecarboxylic acid ethyl ester
Ethyl-1- (methoxymethyl) -4-oxocyclohexanecarboxylate (3.00g, 14.0mmol), cesium fluoride (243mg, 1.40mmol) were dissolved in tetrahydrofuran (50mL), and trimethylsilyltrifluoromethyl (3.98g, 28.0mmol) was added at 0 ℃. The reaction solution was reacted at 20 ℃ under nitrogen for 6 hours. Then 4N diluted hydrochloric acid (7mL) was added. The mixture was reacted at room temperature under nitrogen for 6 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (100mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (10: 1 petroleum ether/ethyl acetate, Rf ═ 0.4) to give ethyl 4-hydroxy-1- (methoxymethyl) -4- (trifluoromethyl) cyclohexanecarboxylate (1.7g, colorless oil), yield: and 43 percent.1H NMR：(400MHz，Methonal-d4)4.18-4.09(m，2H)，3.61(s，2H)，3.33(s，3H)，1.84-1.71(m，8H)，1.28-1.25(m，3H)。
The fourth step
4- (hydroxymethyl) -4- (methoxymethyl) -1- (trifluoromethyl) cyclohexanol
Ethyl 4-hydroxy-1- (methoxymethyl) -4- (trifluoromethyl) cyclohexanecarboxylate (1.50g, 5.28mmol) was dissolved in anhydrous tetrahydrofuran (50mL), and lithium aluminum hydride (220mg, 5.81mmol) was added at 0 ℃. The reaction solution was heated to 25 ℃ and stirred for 1 hour. Quenched with water (20mL), extracted with ethyl acetate (50mL x3), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.2) to give 4- (hydroxymethyl) -4- (methoxymethyl) -1- (trifluoromethyl) cyclohexanol (1.20g, colorless oil) in yield: 84 percent.1H NMR:(400MHz，Methanol-d4)δ3.33-3.32(m，7H)，1.67-1.63(m，4H)，1.52-1.48(m，4H)。
The fifth step
(4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl methanesulfonate
4- (hydroxymethyl) -4- (methoxymethyl) -1- (trifluoromethyl) cyclohexanol (1.20g, 4.95mmol) was dissolved in dichloromethane (20mL), and triethylamine (851mg, 9.91mmol) and methanesulfonyl chloride (851mg, 7.43mmol) were added at 0 ℃. The reaction mixture was reacted at 0 ℃ for 2 hours. Quenched by addition of saturated aqueous sodium bicarbonate (10mL), extracted with dichloromethane (50mL x3), the organic phases were combined, washed with saturated sodium chloride solution (50mL x3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl methanesulfonate (1.30g, yellow oil), yield: 92 percent.
The sixth step
1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
(4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methylmethanesulfonate (300mg, 1.05mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (189mg, 1.05mmol), potassium iodide (17.4mg, 0.105mmol) and potassium carbonate (435mg, 3.15mmol) were dissolved in anhydrous N, N-dimethylformamide (5 mL). The reaction solution is heated to 150 ℃ by microwave and reacts for 2 hours. The reaction solution was cooled to 20 c,filtration and purification by preparative high performance liquid chromatography gave 1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (12.0mg, white solid), yield: 3 percent.1H NMR：(400MHz，Methonal-d4) δ 7.87(s, 1H), 4.06(s, 2H), 3.83(s, 3H), 3.98(s, 3H), 3.53(s, 2H), 3.42(s, 3H), 1.69-1.58(m, 8H). MS-ESI calculated value [ M + H%]+405, found value 405.
Example 18
1- ((4- (3-hydroxypentan-3-yl) -cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000431
First step of
4-Hydroxymethylcyclohexanecarboxylic acid methyl ester
Methyl 1, 4-cyclohexanecarboxylate (1.20g, 6.45mmol) was dissolved in anhydrous tetrahydrofuran (20mL), borane dimethylsulfide (10M, 1.0mL, 10.3mmol) was slowly added dropwise at 0 ℃ under nitrogen protection, the reaction was stirred at 0 ℃ for 0.5 h, slowly warmed to 25 ℃ and stirred for 1 h. The reaction was quenched by the addition of water (40mL) and the reaction was extracted with ethyl acetate. The combined organic phases were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl 4-hydroxymethylcyclohexanecarboxylate (1.00g, white solid) in yield: 91 percent.1H NMR：(400MHz，CDCl3) δ 3.67(s, 3H), 3.48-3.46(m, 2H), 2.26-2.25(m, 1H), 2.05-2.01(m, 2H), 1.89-1.85(m, 2H), 1.47-1.43(m, 2H), 1.31(s, 1H), 1.01-0.98(m, 2H). MS-ESI calculated value [ M + H%]+173, found 173.
Second step of
4-Methanesulfonyloxymethyl-cyclohexanecarboxylic acid methyl ester
Methyl 4-hydroxymethylcyclohexanecarboxylate (900mg, 5.20mmol) and triethylamine (1.58g, 15.6mmol) were dissolved in dry dichloromethane (5mL) under nitrogen and methanesulfonyl chloride (720mg, 6.30mmol) was added at 0 ℃. The reaction solution was warmed to 25 ℃ and stirred for 2 hours. Adding waterThe reaction was quenched (60mL) and the reaction was extracted with ethyl acetate. The combined organic phases were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by preparative TLC plates (3: 1 petroleum ether/ethyl acetate, Rf ═ 0.5) to give the product methyl 4-methanesulfonyloxymethyl-cyclohexanecarboxylate (1.00g, white solid) in yield: 91 percent.1H NMR：(400MHz，CDCl3) δ 3.67(s, 3H), 3.48-3.46(m, 2H), 3.01(s, 3H), 2.26-2.25(m, 1H), 2.05-2.01(m, 2H), 1.89-1.85(m, 2H), 1.47-1.43(m, 2H), 1.31(s, 1H), 1.01-0.98(m, 2H). MS-ESI calculated value [ M + H%]+251, found value 251.
The third step
4- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) -cyclohexanecarboxylic acid methyl ester
Methyl 4-methanesulfonyloxymethyl-cyclohexanecarboxylate (580mg, 2.32mmol) was dissolved in 5mL of anhydrous N, N-dimethylformamide, and potassium carbonate (640mg, 4.64mmol), potassium iodide (38.0mg, 0.230mmol), 2, 6-hydroxy-3, 7-dimethylpurine (501mg, 2.80mmol) were added under nitrogen atmosphere at 25 ℃. The reaction solution was stirred at 130 ℃ for 3 hours. 40mL of water was added to the reaction and extracted with ethyl acetate, the organic phases combined, washed sequentially with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, the filtrate concentrated under reduced pressure, and purified using a high performance prep. plate to give the product methyl 4- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) -cyclohexanecarboxylate (400mg, white solid), yield: 52 percent. MS-ESI calculated value [ M + H%]+335, measured value 335.
The fourth step
1- ((4- (3-hydroxypentan-3-yl) -cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Methyl 4- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) -cyclohexanecarboxylic acid (100mg, 0.30mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, ethyl magnesium bromide solution (3M diethyl ether solution, 1mL, 3.00mmol) was slowly added dropwise at-65 ℃ under nitrogen protection, the reaction was stirred at-65 ℃ for 2 hours, water (40mL) was added to the reaction, and ethyl acetate was usedExtraction and combination of the organic phases were washed with saturated sodium chloride solution (50mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give the product 1- ((4- (3-hydroxypentan-3-yl) -cyclohexyl) methyl) -3, 7-dimethyl 1H-purine-2, 6(3H, 7H) -dione (20.0mg, white solid) in yield: 19 percent.1H NMR：(400MHz，CDCl3) δ 7.52(s, 1H), 4.00(s, 3H), 3.90-3.88(m, 2H), 3.59(s, 3H), 1.80-1.74(m, 6H), 1.50-1.45(m, 4H), 1.11-1.10(m, 4H), 0.86-0.82(m, 6H). MS ESI calculated value [ M + H [ ]]+363, measured value 363.
Example 19
3, 7-dimethyl-1- [ [4- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) cyclohexyl ] methyl ] purine-2, 6-dione
Figure BDA0002403430430000441
Figure BDA0002403430430000451
First step of
4-Hydroxymethylcyclohexanecarboxylic acid methyl ester
Trans-cyclohexane-1, 4-dicarboxylic acid monomethyl ester (5.00g, 26.8mmol) was dissolved in tetrahydrofuran (100mL), borane dimethylsulfide (3.06g, 40.3mmol) was added at 0 ℃ and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by the addition of saturated methanol (50 mL). After concentration, water (50mL) was added and extracted with ethyl acetate (10mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl 4-hydroxymethylcyclohexanecarboxylate (4.00g, yellow oil), yield: 87 percent.1H NMR:(400MHz，Methonal-d4) δ 3.67(s, 3H), 3.43-3.38(m, 2H), 2.31-2.54(m, 1H), 2.03-1.98(m, 2H), 1.90-1.82(m, 2H), 1.45-1.38(m, 3H), 1.03-0.99(m, 2H). MS-ESI calculated value [ M + H%]+173, found 173.
Second step of
4-Methanesulfonyloxymethyl-cyclohexanecarboxylic acid methyl ester
Methyl 4-hydroxymethylcyclohexanecarboxylate (4).00g, 23.2mmol) and triethylamine (7.05g, 69.6mmol) were dissolved in dichloromethane (50mL) and methanesulfonyl chloride (7.98g, 69.6mmol) was added at 0 ℃. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of aqueous sodium bicarbonate (50 mL). Extract with dichloromethane (20 mL. times.3). The organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-methanesulfonyloxymethyl-cyclohexanecarboxylic acid methyl ester (5.80g, yellow oil), yield: 99 percent.1H NMR:(400MHz，Methonal-d4) δ 4.10-4.03(m, 2H), 3.65(s, 3H), 3.07(s, 3H), 2.42-2.31(m, 1H), 2.10-2.03(m, 2H), 1.90-1.82(m, 2H), 1.75-1.66(m, 1H), 1.48-1.42(m, 2H), 1.21-1.10(m, 2H). MS-ESI calculated value [ M + H%]+251, found value 251.
The third step
Methyl 4- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl ] cyclohexanecarboxylic acid
4-Methanesulfonyloxymethyl-cyclohexanecarboxylic acid methyl ester (1.00g, 4.00mmol), 3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (719mg, 4.00mmol), potassium iodide (66.0mg, 0.397mmol) and potassium carbonate (1.10g, 7.96mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooling to room temperature, filtering, and concentrating the filtrate under reduced pressure. Separating and purifying with silica gel column chromatography (ethyl acetate, Rf 0.1) to obtain methyl 4- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl]Cyclohexanecarboxylic acid (800mg, yellow solid), yield: 60 percent.1H NMR:(400MHz，Methonal-d4) δ 7.88(s, 1H), 3.98(s, 3H), 3.90-3.82(m, 2H), 3.72(s, 3H), 3.51(s, 3H), 2.33-2.25(m, 1H), 2.03-1.98(m, 2H), 1.80-1.74(m, 3H), 1.42-1.36(m, 2H), 1.21-1.10(m, 2H). MS-ESI calculated value [ M + H%]+335, measured value 335.
The fourth step
1- (4-Acetylcyclohexylmethyl) -3, 7-dimethyl-3, 7-dihydro-purine-2, 6-dione
Methyl 4- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl]Cyclohexanecarboxylic acid (300mg, 0.897mmol) and O, N-dimethylhydroxylamine hydrochloride(114mg, 1.17mmol) was dissolved in tetrahydrofuran (25mL) and methylmagnesium bromide (3M in ether, 1.50mL, 4.50mmol) was added at 0 ℃. The reaction solution was slowly warmed to room temperature and stirred for 12 hours. The reaction was quenched by the addition of saturated ammonium chloride (10 mL). Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification on preparative TLC plates (ethyl acetate, Rf ═ 0.4) gave 1- (4-acetylcyclohexylmethyl) -3, 7-dimethyl-3, 7-dihydro-purine-2, 6-dione (80.0mg, yellow oil) in yield: 29 percent.1H NMR:(400MHz，Methonal-d4) δ 7.88(s, 1H), 3.98(s, 3H), 3.92-3.84(m, 2H), 3.55(s, 3H), 2.42-2.33(m, 1H), 2.15(s, 3H), 1.98-1.88(m, 2H), 1.85-1.75(m, 3H), 1.32-1.10(m, 4H). MS-ESI calculated value [ M + H%]+319, found 319.
The fifth step
3, 7-dimethyl-1- [ [4- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) cyclohexyl ] methyl ] purine-2, 6-dione
1- (4-Acetylcyclohexylmethyl) -3, 7-dimethyl-3, 7-dihydro-purine-2, 6-dione (80.0mg, 0.251mmol) and cesium fluoride (11.5mg, 0.753mmol) were dissolved in tetrahydrofuran (10mL), and trimethyl-trifluoromethyl-silane (71.6mg, 0.502mmol) was added at room temperature and stirred for 12 hours. 1N hydrochloric acid (10mL) was added and the mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate (50mL) was added to quench the reaction. Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purifying by preparative high performance liquid chromatography to obtain 3, 7-dimethyl-1- [ [4- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) cyclohexyl]Methyl radical]Purine-2, 6-dione (35.0mg, yellow solid), yield: 70 percent.1H NMR:(400MHz，Methonal-d4) δ 7.88(s, 1H), 3.98(s, 3H), 3.88(d, J ═ 6.8Hz, 2H), 3.53(s, 3H), 1.96-1.67 (m, 6H), 1.22(s, 3H), 1.15-1.06(m, 4H). MS-ESI calculated value [ M + H%]+389, found 389.
Example 20
3, 7-dimethyl-1- [4- (2, 2, 2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) -cyclohexylmethyl ] -3, 7-dihydro-purine-2, 6-dione
Figure BDA0002403430430000461
Figure BDA0002403430430000471
First step of
3, 7-dimethyl-1- [4- (2, 2, 2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) -cyclohexylmethyl ] -3, 7-dihydro-purine-2, 6-dione
Methyl 4- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl ] cyclohexanecarboxylic acid (200mg, 0.598mmol), cesium fluoride (45.4mg, 0.299mmol) were dissolved in tetrahydrofuran (10mL), and trimethyl-trifluoromethyl-silane (340mg, 2.39mmol) was added at room temperature and stirred for 12 hours. 1N hydrochloric acid (10mL) was added and the mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate (50mL) was added to quench the reaction. Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification by preparative high performance liquid chromatography was added to give 3, 7-dimethyl-1- [4- (2, 2, 2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) -cyclohexylmethyl ] -3, 7-dihydro-purine-2, 6-dione (35.0mg, yellow solid), yield: 41 percent.
1H NMR:(400MHz，Methonal-d4) δ 7.88(s, 1H), 3.98(s, 3H), 3.88(d, J ═ 6.8Hz, 2H), 3.53(s, 3H), 2.08-1.79(m, 6H), 1.30-1.24(m, 2H), 1.11-1.08(m, 2H). MS-ESI calculated value [ M + H%]+443, found 443.
Example 21
1- [ [4- (1-hydroxycyclopropyl) cyclohexyl ] methyl ] -3, 7-dimethylpurine-2, 6-dione
Figure BDA0002403430430000472
First step of
1- [ [4- (1-hydroxycyclopropyl) cyclohexyl ] methyl ] -3, 7-dimethylpurine-2, 6-dione
Methyl 4- [ (3, 7-dimethyl-2, 6-dioxo-purin-1-yl) methyl ] cyclohexanecarboxylic acid (200mg, 0.598mmol), tetraisopropyltitanium oxide (340mg, 1.20mmol) were dissolved in tetrahydrofuran (10mL), and ethylmagnesium bromide (3M in diethyl ether, 0.39mL, 1.17mmol) was added thereto at room temperature, followed by stirring for 12 hours. The reaction was quenched by the addition of saturated ammonium chloride (50 mL). Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 1- [ [4- (1-hydroxycyclopropyl) cyclohexyl ] methyl ] -3, 7-dimethylpurine-2, 6-dione (70.0mg, yellow solid) in yield: 35 percent.
1H NMR:(400MHz，Methonal-d4) δ 7.87(s, 1H), 3.98(s, 3H), 3.88(d, J ═ 6.8Hz, 2H), 3.53(s, 3H), 1.79-1.71(m, 5H), 1.29-1.07(m, 5H), 0.60-0.57(m, 2H), 0.42-0.39(m, 2H). MS-ESI calculated value [ M + H%]+333, found value 333.
Example 22
1- (2- (3-Ethyl-3-hydroxycyclohexyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000481
First step of
2- (3-Ethyl-3-hydroxycyclohexyl) ethyl methanesulfonate
1-Ethyl-3- (2-hydroxyethyl) cyclohexanol (450mg, 2.61mmol) and diisopropylethylamine (500mg, 3.92mmol) were dissolved in dichloromethane (10mL) and methanesulfonyl chloride (600mg, 5.40mmol) was added slowly at 0 ℃. The reaction mixture was stirred at 0 ℃ for 0.5 hour. The reaction was quenched with water and extracted with ethyl acetate (20 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (10: 1 petroleum ether/ethyl acetate, Rf ═ 0.4) to give the product 2- (3-ethyl-3-hydroxycyclohexyl) ethyl methanesulfonate (450mg, yellow oil) in yield: and 69 percent. MS-ESI calculated value [ M + H%]+251, actual measurementA value 251.
Second step of
1- (2- (3-Ethyl-3-hydroxycyclohexyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
2- (3-Ethyl-3-hydroxycyclohexyl) ethyl methanesulfonate (200mg, 0.790mmol), 3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (144mg, 0.790mmol) and potassium carbonate (220mg, 1.60mmol), potassium iodide (13.1mg, 0.0790mmol) were dissolved in N, N-dimethylformamide (3 mL). The reaction solution was heated to 130 ℃ and stirred for 3 hours. The reaction mixture was cooled to 25 ℃, and saturated brine was added thereto, followed by extraction with ethyl acetate (40mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give the product 1- (2- (3-ethyl-3-hydroxycyclohexyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (70.0mg, white solid) in yield: 26 percent.1H NMR：(400MHz，Methonal-d4) δ 7.86(s, 1H), 4.09-3.94(m, 5H), 3.52(s, 3H), 1.88-1.84(m, 1H), 1.80-1.40(m, 10H), 1.26-1.16(m, 1H), 1.02-0.95(m, 1H), 0.91(t, J ═ 7.2Hz, 3H). MS-ESI calculated value [ M + H-18 ]]+317, measured value 317.
Example 23
1- [ [ (1R, 3R) -3-hydroxy-3- (trifluoromethyl) cyclohexyl ] methyl ] -3, 7-dimethylpurine-2, 6-dione
1- [ [ (1R, 3S) -3-hydroxy-3- (trifluoromethyl) cyclohexyl ] methyl ] -3, 7-dimethylpurine-2, 6-dione
Figure BDA0002403430430000491
First step of
3-trifluoromethyl-3-trimethylsilyloxy-cyclohexanecarboxylic acid ethyl ester
Ethyl-3-oxocyclohexanecarboxylic acid (1.00g, 5.88mmol), cesium fluoride (446mg, 2.94mmol) were dissolved in tetrahydrofuran (30mL), and trimethyl-trifluoromethyl-silane (1.67g, 11.7mmol) was added at room temperature and stirred for 12 hours. The reaction was quenched by the addition of water (20 mL). Extract with ethyl acetate (20 mL. times.3). Mixing the organic phases, adding saturated saline solution(60mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give ethyl 3-trifluoromethyl-3-trimethylsiloxy-cyclohexanecarboxylate (1.40g, yellow oil), yield: 76 percent. MS-ESI calculated value [ M + H%]+313, found 313.
Second step of
(3-trifluoromethyl-3-trimethylsilyloxycyclohexyl) methanol
3-trifluoromethyl-3-trimethylsiloxy-cyclohexanecarboxylic acid ethyl ester (1.00g, 3.20mmol) was dissolved in tetrahydrofuran (10mL), and lithium aluminum hydride (243mg, 6.40mmol) was added thereto at 0 ℃ to react for 1 hour. The reaction was quenched by the addition of water (10 mL). Extraction with ethyl acetate (20mL x3), drying over anhydrous sodium sulfate, filtration and concentration of the filtrate under reduced pressure gave (3-trifluoromethyl-3-trimethylsiloxy cyclohexyl) methanol (800mg, colorless oil) in yield: 92 percent. MS-ESI calculated value [ M + H%]+271, found value 271.
The third step
[3- (trifluoromethyl) -3-trimethylsiloxy cyclohexyl ] methyl methanesulfonate
3-trifluoromethyl-3-trimethylsilyloxycyclohexyl) methanol (850mg, 3.14mmol) and triethylamine (953mg, 9.42mmol) were dissolved in dichloromethane (15mL) and methanesulfonyl chloride (719mg, 6.28mmol) was added at 0 ℃. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL). Extraction with dichloromethane (20ml x 3). The organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give [3- (trifluoromethyl) -3-trimethylsiloxy cyclohexyl]Methyl methanesulfonate (900mg, yellow oil), yield: 82 percent.1HNMR:(400MHz，Methonal-d4) δ 4.36-4.32(m, 1H), 4.17-4.13 (m, 1H), 3.08(s, 3H), 2.12-1.60(m, 9H), 0.16(s, 9H). MS-ESI calculated value [ M + H%]+349, found 349.
The fourth step
3, 7-dimethyl-1- [ [3- (trifluoromethyl) -3-trimethylsiloxy-cyclohexyl ] methyl ] purine-2, 6-dione
[3- (trifluoromethyl) -3-trimethylsiloxycyclohexyl ] methyl methanesulfonate (200mg, 0.573mmol), 3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (103mg, 0.574mmol), potassium iodide (28.6mg, 0.172mmol) and potassium carbonate (374mg, 1.15mmol) were dissolved in N, N-dimethylformamide (30 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give 3, 7-dimethyl-1- [ [3- (trifluoromethyl) -3-trimethylsiloxy-cyclohexyl ] methyl ] purine-2, 6-dione (150mg, yellow solid) in yield: 60 percent.
MS-ESI calculated value [ M + H%]+433, measured value 433.
The fifth step
1- [ [ (1R, 3R) -3-hydroxy-3- (trifluoromethyl) cyclohexyl ] methyl ] -3, 7-dimethylpurine-2, 6-dione
1- [ [ (1R, 3S) -3-hydroxy-3- (trifluoromethyl) cyclohexyl ] methyl ] -3, 7-dimethylpurine-2, 6-dione
3, 7-dimethyl-1- [ [3- (trifluoromethyl) -3-trimethylsiloxy-cyclohexyl ] is reacted with a catalyst]Methyl radical]Purine-2, 6-dione (200mg, 0.462mmol) was dissolved in tetrahydrofuran (10mL), 1N hydrochloric acid (10mL) was added, the mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate (50mL) was added to quench the reaction. Extract with ethyl acetate (20 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purifying with preparative high performance liquid chromatography to obtain 1- [ [ (1R, 3R) -3-hydroxy-3- (trifluoromethyl) cyclohexyl]Methyl radical]-3, 7-dimethylpurine-2, 6-dione (10.0mg, yellow solid) (isomer 1, first peak), yield: 6 percent.1H NMR:(400MHz，Methonal-d4) δ 7.87(s, 1H), 3.97(s, 3H), 3.89-3.83(m, 2H), 3.52(s, 3H), 2.23-2.22(m, 1H), 1.76-1.07(m, 8H). MS-ESI calculated value [ M + H%]+361, found 361.
1- [ [ (1R, 3S) -3-hydroxy-3- (trifluoromethyl) cyclohexyl]Methyl radical]-3, 7-dimethylpurine-2, 6-dione (85.0mg yellow solid) (isomer 2, second peak), yield: 51 percent.1H NMR:(400MHz，Methonal-d4) δ 7.87(s, 1H), 4.31-4.26(m, 1H), 3.99-3.95(m, 4H), 3.55(s, 3H), 2.26-1.88(m, 3H), 1.79-1.47(m, 6H). MS-ESI calculated value [ M + H%]+361，Found 361.
Example 24
1- ((5-hydroxy-5- (trifluoromethyl) tetrahydro-2H-pyran-2-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000511
First step of
(3, 4-dihydro-2H-pyran-2-yl) -methanol
3, 4-dihydro-2H-pyran-2-carbaldehyde (3.00g, 26.7mmol) was dissolved in methanol (20mL), and sodium borohydride (2.02g, 53.5mmol) was added thereto at 0 ℃ to react for 2 hours. The reaction was quenched by the addition of saturated ammonium chloride (30 mL). Extraction with dichloromethane (20mL x3), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave (3, 4-dihydro-2H-pyran-2-yl) methanol (1.50g, yellow oil) in yield: 49 percent.1H NMR：(400MHz，Methonal-d4)δ6.40(d，J＝6.0Hz，1H)，4.71-4.68(m，1H)，3.86-3.83(m，1H)，3.82-3.61(m，2H)，2.13-2.12(m，1H)，2.10-2.08(m，1H)，2.02-2.01(m，1H)，1.68-1.63(m，1H)。
Second step of
(3, 4-dihydro-2H-pyran-2-yl) -methyl methanesulfonate
(3, 4-dihydro-2H-pyran-2-yl) -methanol (1.50g, 13.1mmol) and triethylamine (2.66g, 26.3mmol) were dissolved in dichloromethane (20mL) and methanesulfonyl chloride (3.01g, 26.3mmol) was added at 0 ℃. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL). Extract with dichloromethane (20 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (3, 4-dihydro-2H-pyran-2-yl) methyl methanesulfonate (1.70g, yellow oil), yield: 67%. MS-ESI calculated value [ M + H%]+193, measured value 193.
The third step
1- ((3, 4-dihydro-2H-pyran-2-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
The (3, 4-dihydro-2H-pyran-2-yl) methyl is substitutedThe sulfonate (1.70g, 8.84mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (1.59g, 8.84mmol), potassium iodide (146mg, 0.884mmol) and potassium carbonate (2.44g, 17.7mmol) were dissolved in N, N-dimethylformamide (50 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate, Rf ═ 0.4) to give 1- ((3, 4-dihydro-2H-pyran-2-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (1.30g, yellow solid) in yield: 53 percent. MS-ESI calculated value [ M + H%]+277, found 277.
The fourth step
1- ((5-Hydroxytetrahydro-2H-pyran-2-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
1- (3, 4-dihydro-2H-pyran-2-ylmethyl) -3, 7-dimethylpurine-2, 6-dione (600mg, 2.17mmol) was dissolved in tetrahydrofuran (30mL), and borane dimethylsulfide (825mg, 10.7mmol) was added at 0 ℃. The reaction solution was slowly warmed to room temperature and stirred for 12 hours. 3N aqueous sodium hydroxide (30mL) and hydrogen peroxide (10mL) were added to continue the reaction for 1 hour. The reaction was quenched by the addition of methanol (10mL), washed with sodium thiosulfate solution (30mL) and extracted with dichloromethane (10mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification by preparative TLC plate separation (20:1 dichloromethane/methanol, Rf ═ 0.3) gave 1- ((5-hydroxytetrahydro-2H-pyran-2-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (130mg, yellow oil) in yield: 20 percent.1H NMR：(400MHz，Methonal-d4) δ 7.88(s, 1H), 4.25-4.23(m, 1H), 4.20(s, 3H), 3.98-3.67(m, 5H), 3.54(s, 3H), 2.10-1.77(m, 2H), 1.49-1.31(m, 2H). MS-ESI calculated value [ M + H%]+295, found 295.
The fifth step
3, 7-dimethyl-1- ((5-oxotetrahydro-2H-pyran-2-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
1- ((5-Hydroxytetrahydro-2H-pyran-2-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (130mg, 0.441mmol) was dissolved in dichloromethane (10mL) and dessimutan was addedPeriodoalkane (138mg, 1.33mmol) was reacted at 25 ℃ for 3 hours. The reaction was quenched by addition of saturated sodium thiosulfate solution (20mL), extracted with dichloromethane (10mL x3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by preparative TLC plate (20:1 dichloromethane/methanol, Rf ═ 0.4) gave 3, 7-dimethyl-1- ((5-oxotetrahydro-2H-pyran-2-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione (60.0mg, yellow solid) yield: and 47 percent. MS-ESI calculated value [ M + H%]+293, found 293.
The sixth step
1- ((5-hydroxy-5- (trifluoromethyl) tetrahydro-2H-pyran-2-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H)
-diketones
3, 7-dimethyl-1- ((5-oxotetrahydro-2H-pyran-2-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione (60.0mg, 0.205mmol), cesium fluoride (6.24mg, 0.0411mmol) was dissolved in tetrahydrofuran (10mL), trimethyltrifluoromethylsilane (87.5mg, 0.615mmol) was added at room temperature, and stirred for 5 hours. 1N hydrochloric acid (10mL) was added and the mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate (50mL) was added to quench the reaction. Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification by preparative high performance liquid chromatography gave 1- ((5-hydroxy-5- (trifluoromethyl) tetrahydro-2H-pyran-2-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (15.0mg, yellow solid), yield: 30 percent.1H NMR：(400MHz，Methonal-d4) Δ 8.28(s, 1H), 4.39-4.10(m, 2H), 4.05(s, 3H), 3.93-3.89(m, 2H), 3.55(s, 3H), 3.32-3.27(m, 1H), 1.89-1.65(m, 4H). MS-ESI calculated value [ M + H%]+363, measured value 363.
Example 25
1- (4- (3-hydroxypentan-3-yl) benzyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000531
First step of
4- ((3, 7-dimethyl-2, 6-oxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) benzoic acid methyl ester
3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (180mg, 1.00mmol), methyl 4- (bromomethyl) benzoate (251mg, 1.10mmol) and potassium carbonate (179mg, 1.30mmol) were dissolved in anhydrous N, N-dimethylformamide (4mL) at 25 ℃ under nitrogen blanket, heated to 110 ℃ and stirred for 3 hours. After cooling to 25 ℃, water was added for dilution and extraction with ethyl acetate (30mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified with a chromatographic silica gel column (1:1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give methyl 4- ((3, 7-dimethyl-2, 6-oxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) benzoate (300mg, white solid) in yield: 91 percent. MS-ESI calculated value [ M + H%]+329 found, value 329.
Second step of
1- (4- (3-hydroxypentan-3-yl) benzyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Methyl 4- ((3, 7-dimethyl-2, 6-oxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) benzoate (200mg, 0.610mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). Ethyl magnesium bromide (3M in ether, 1.2mL, 3.60mmol) was added dropwise at-78 ℃ under nitrogen. The reaction solution was stirred at this temperature for 0.5 hour, and naturally warmed to 25 ℃ to continue the reaction for 1 hour. Quench with saturated aqueous ammonium chloride (5mL) and extract with ethyl acetate (30 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on preparative TLC plates (1: 3 petroleum ether/ethyl acetate, Rf ═ 0.3) to give 1- (4- (3-hydroxypentan-3-yl) benzyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (190mg, white solid) in yield: 87 percent.1H NMR：(400MHz，Methonal-d4) δ 7.85(s, 1H), 7.32(d, J ═ 8.0Hz, 2H), 7.28(d, J ═ 8.0Hz, 2H), 5.25(s, 2H), 3.96(s, 3H), 3.52(s, 3H), 1.82-1.72(m, 4H), 0.69(t, J ═ 7.2Hz, 6H). MS-ESI calculated value [ M + H%]+357, found value 357.
Example 26
3, 7-dimethyl-1- (3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzyl) -1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000541
First step of
3-Acetylbenzoic acid ethyl ester
After 3-acetylbenzoic acid (500mg, 3.05mmol) was dissolved in N, N-dimethylformamide (20mL), iodoethane (475mg, 3.05mmol) and potassium carbonate (632mg, 4.57mmol) were added at room temperature, and stirred at room temperature for 2 hours, the reaction solution was concentrated, ethyl acetate (30mL) was added for dilution, the organic phase was washed with water (20mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated and purified by silica gel column chromatography (5: 1 petroleum ether/ethyl acetate, Rf ═ 0.5) to obtain ethyl 3-acetylbenzoate (530mg, white solid) in yield: 90 percent.1H NMR：(400MHz，CDCl3) δ 8.60(s, 1H), 8.24(d, J ═ 7.6Hz, 1H), 8.15(d, J ═ 7.6Hz, 1H), 7.56(t, J ═ 7.6Hz, 1H), 4.41(q, J ═ 7.2Hz, 2H), 2.66(s, 3H), 1.42(t, J ═ 7.2Hz, 3H). MS-ESI calculated value [ M + H%]+193, measured value 193.
Second step of
Ethyl 3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzoate
Ethyl 3-acetylbenzoate (500mg, 2.60mmol) was dissolved in tetrahydrofuran (20mL), and trifluoromethyltrimethylsilane (370mg, 2.60mmol) and cesium fluoride (79.0mg, 0.520mmol) were added at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was diluted with ethyl acetate (30mL), the organic phase was washed with water (20mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (2: 1 petroleum ether/ethyl acetate, Rf ═ 0.5) to give ethyl 3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzoate (600mg, yellow solid), yield: 88 percent.1H NMR：(400MHz，CDCl3) δ 8.26(s, 1H), 8.05(d, J ═ 7.6Hz, 1H), 7.80(d, J ═ 7.6Hz, 1H), 7.48(t, J ═ 7.6Hz, 1H), 4.39(q, J ═ 7.2Hz, 2H), 1.82(s, 3H), 1.40(t, J ═ 7.2Hz, 3H). MS-ESI meterCalculated value of [ M + H]+263, found 263.
The third step
1,1, 1-trifluoro-2- (3-hydroxymethyl) phenyl) propan-2-ol
Ethyl 3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzoate (500mg, 1.91mmol) was dissolved in tetrahydrofuran (20mL), and the reaction mixture was stirred at 0 ℃ for 2 hours at room temperature with addition of lithium aluminum hydride (108mg, 2.87mmol), water (0.1mL), 15% sodium hydroxide (0.1mL) and water (0.3mL), respectively, and stirred for 20 minutes. The reaction was diluted with ethyl acetate (30mL), the organic phase washed with water (20mL x2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 1,1, 1-trifluoro-2- (3-hydroxymethyl) phenyl) propan-2-ol (400mg, yellow solid) in yield: 95 percent.
1H NMR：(400MHz，CDCl3) δ 7.62(s, 1H), 8.05(d, J ═ 7.6Hz, 1H), 7.41-7.37(m, 2H), 4.73(s, 2H), 1.80(s, 3H). MS-ESI calculated value [ M + H%]+221, found 221.
The fourth step
3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzyl methanesulfonate
1,1, 1-trifluoro-2- (3-hydroxymethyl) phenyl) propan-2-ol (400mg, 1.82mmol) and triethylamine (275mg, 2.72mmol) were dissolved in dichloromethane (20mL), the reaction was stirred at 0 deg.C with the addition of methanesulfonyl chloride (250mg, 2.18mmol), stirred for 2 hours, diluted with dichloromethane (30mL), the organic phase was washed with water (20mL x2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzyl methanesulfonate (500mg, yellow oil) as a yield: 92 percent.
MS-ESI calculated value [ M + H%]+299, measured value 299.
The fifth step
3, 7-dimethyl-1- (3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzyl) -1H-purine-2, 6- (3H, 7H) -dione
3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzyl methanesulfonate (100mg, 0.335mmol) and 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (60.0mg, 0.335mmol) were dissolved in NN-dimethylformamide (20mL), potassium carbonate (70.0mg, 0.502mmol) and potassium iodide (6.00mg, 0.0335mmol) were added at room temperature, the mixture was stirred at 100 ℃ for 2 hours, the reaction solution was cooled and concentrated, ethyl acetate (30mL) was added for dilution, the organic phase was washed with water (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by high performance liquid chromatography gave 3, 7-dimethyl-1- (3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzyl) -1H-purine-2, 6- (3H, 7H) -dione (30.0mg, white solid), yield: 23 percent.1HNMR：(400MHz，CDCl3) δ 7.90(s, 1H), 7.70(s, 1H), 7.49(d, J ═ 7.6Hz, 1H), 7.38-7.32(m, 2H), 5.21(s, 2H), 4.00(s, 3H), 3.55(s, 3H), 1.71(s, 3H). MS-ESI calculated value [ M + H%]+383, found 383.
Example 27
3, 7-dimethyl-1- (4- (1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) phenyl) -1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000551
Figure BDA0002403430430000561
First step of
4- (1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) benzoic acid methyl ester
Methyl 4-acetylbenzoate (10.0g, 56.1mmol) and trimethyl (trifluoromethyl) silane (16.0g, 112mmol) were dissolved in anhydrous tetrahydrofuran (150mL) at 0 ℃ under nitrogen blanket, and tetrabutylammonium fluoride (22.0g, 84.2mmol) was slowly added dropwise. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched by the addition of water (50 mL). Extraction with ethyl acetate (50mLx 3). The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product methyl 4- (1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) benzoate (7.00g, yellow liquid), yield: 50 percent.1H NMR:(400MHz，CDCl3)δ8.04(d，J＝8.0Hz，2H)，7.68(d，J＝8.0Hz, 2H), 3.92(s, 3H), 3.27(s, 1H), 1.80(s, 3H). MS-ESI calculated value [ M + H%]+249, found 249.
Second step of
1,1, 1-trifluoro-2- (4- (hydroxymethyl) phenyl) propyl-2-ol
Lithium aluminum hydride (1.61g, 42.3mmol) was slowly added to a solution of methyl 4- (1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) benzoate (7.00g, 28.2mmol) in tetrahydrofuran (150mL) at 0 ℃ under nitrogen. The reaction solution was stirred at 0 ℃ for 3 hours. Water (1.60mL), 15% sodium hydroxide solution (1.60mL) and water (4.80mL) were added slowly in that order at 0 ℃. Filtration and concentration of the filtrate under reduced pressure gave the product 1,1, 1-trifluoro-2- (4- (hydroxymethyl) phenyl) propyl-2-ol (2.40g, yellow liquid) in yield: 93 percent.1H NMR:(400MHz，CDCl3) δ 7.55(d, J ═ 8.0Hz, 2H), 7.34(d, J ═ 8.0Hz, 2H), 4.66(s, 2H), 3.37(s, 1H), 2.39(s, 1H), 1.75(s, 3H). MS-ESI calculated value [ M + H%]+221, found 221.
The third step
4- (1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) phenylmethanesulfonate
1,1, 1-trifluoro-2- (4- (hydroxymethyl) phenyl) propyl-2-ol (5.80g, 26.3mmol) and diisopropylethylamine (10.2g, 79.0mmol) were dissolved in dichloromethane (80mL) and methanesulfonyl chloride (4.53g, 39.5mmol) was added slowly at 0 ℃. The reaction mixture was stirred at 0 ℃ for 0.5 hour. The reaction was quenched by addition of saturated aqueous ammonium chloride (50mL) and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, washed with saturated aqueous sodium bicarbonate (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and purified by silica gel column chromatography (5: 1 petroleum ether/ethyl acetate, Rf ═ 0.4) to give the product 4- (1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) phenylmethanesulfonate (3.45g, yellow oil) in yield: 44 percent.1H NMR:(400MHz，CDCl3) δ 7.66(d, J ═ 8.0Hz, 2H), 7.46(d, J ═ 8.0Hz, 2H), 5.26(s, 2H), 2.96(s, 3H), 2.84(s, 1H), 1.80(s, 3H). MS-ESI calculated value [ M + H%]+299, measured value 299.
The fourth step
3, 7-dimethyl-1- (4- (1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) phenyl) -1H-purine-2, 6(3H, 7H) -dione
4- (1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) phenylmethanesulfonate (1.95g, 10.8mmol), 3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (652mg, 3.62mmol), potassium carbonate (2.99g, 21.6mmol) and potassium iodide (180mg, 1.08mmol) were dissolved in N, N-dimethylformamide (30 mL). The reaction solution was heated to 130 ℃ and stirred for 3 hours. The reaction mixture was cooled to room temperature, saturated brine (20mL) was added, and the mixture was extracted with ethyl acetate (100 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (1: 2 petroleum ether/ethyl acetate, Rf ═ 0.3) to give the product 3, 7-dimethyl-1- (4- (1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) phenyl) -1H-purine-2, 6(3H, 7H) -dione (1.27g, white solid) in yield: 31 percent.1H NMR:(400MHz，CDCl3) δ 7.57-7.55(m, 5H), 5.20(s, 2H), 3.99(s, 3H), 3.58(s, 3H), 2.60(s, 1H), 1.74(s, 3H). MS-ESI calculated value [ M + H%]+383, found 383.
Example 28
Figure BDA0002403430430000571
First step of
6-Bromonicotinic acid methyl ester
6-Bromonicotinic acid (1.00g, 4.95mmol) was dissolved in N, N-dimethylformamide (30mL), and methyl iodide (0.703g, 4.95mmol) and potassium carbonate (1.03g, 7.43mmol) were added. The reaction solution was stirred at 20 ℃ for 12 hours. The reaction was diluted with water (100mL), extracted with ethyl acetate (30mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (2: 1 petroleum ether/ethyl acetate, Rf ═ 0.5) to give methyl 6-bromonicotinate (1.00g, white solid) in yield: 94 percent. MS-ESI calculated value [ M + H%]+216 and 218, found values 216 and 218.
Second step of
(6-Bromopyridin-3-yl) methanol
Methyl 6-bromonicotinate (1.00g, 4.63mmol) was dissolved in tetraTetrahydrofuran (20mL) was added with lithium aluminum hydride (351mg, 9.26mmol) at 0 ℃ and reacted for 1 hour. The reaction was quenched by the addition of water (10 mL). Extraction with ethyl acetate (20mL x3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure and purification by column chromatography on silica gel (1:1 petroleum ether/ethyl acetate, Rf ═ 0.3) gave (6-bromopyridin-3-yl) methanol (600mg, yellow oil) in yield: and 69 percent. MS-ESI calculated value [ M + H%]+188 and 190, found 188 and 190.
The third step
(6-Bromopyridin-3-yl) methyl methanesulfonate
(6-Bromopyridin-3-yl) methanol (1.00g, 5.32mmol) and triethylamine (1.18g, 11.6mmol) were dissolved in dichloromethane (20mL) and methanesulfonyl chloride (1.38g, 12.0mmol) was added at 0 ℃. After the reaction mixture was stirred at room temperature for 2 hours, dichloromethane (20mL) was added to dilute the reaction mixture, and the mixture was washed with saturated sodium bicarbonate (30mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (4: 1 petroleum ether/ethyl acetate, Rf ═ 0.5) to give (6-bromopyridin-3-yl) methyl methanesulfonate (1.20g, colorless oil) in yield: 85 percent. MS-ESI calculated value [ M + H%]+266 and 268, found 266 and 268.
The fourth step
1- ((6-Bromopyridin-3-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
(6-Bromopyridin-3-yl) methyl methanesulfonate (500mg, 1.88mmol) was dissolved in N, N-dimethylformamide (20mL), and 3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (338mg, 1.88mmol), potassium carbonate (389mg, 2.82mmol) and potassium iodide (184mg, 1.11mmol) were added to the reaction mixture at room temperature. The reaction was heated to 100 ℃ for 2 hours, diluted with ethyl acetate (20mL), the organic phase was washed with saturated sodium bicarbonate (20mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give 1- ((6-bromopyridin-3-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (300mg, yellow solid) in yield: 46 percent. MS-ESI calculated value [ M + H%]+350 and 352, found 350 and 352.
The fifth step
1- ((6-acetylpyridin-3-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
1- ((6-Bromopyridin-3-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (2.00g, 5.71mmol) was dissolved in 1, 4-dioxane (50mL), and tributyl (1-ethoxyvinyl) stannane (8.25g, 22.8mmol) and palladium tetratriphenylphosphine (329mg, 0.285mmol) were added to the reaction mixture at room temperature. The reaction was heated to 120 ℃ and stirred for 2 hours, cooled to room temperature, diluted with ethyl acetate (70mL), washed with saturated sodium bicarbonate (20mL) (30mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (3: 1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give 1- ((6-acetylpyridin-3-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (1.00g, yellow solid), yield: 56 percent.1H NMR:(400MHz，CDCl3) δ 8.83(s, 1H), 8.00-7.98(m, 1H), 7.95-7.93(m, 1H), 7.54(s, 1H), 5.27(s, 2H), 4.01(s, 3H), 3.59(s, 3H), 2.71(s, 3H). MS-ESI calculated value [ M + H%]+314, measured value 314.
The sixth step
3, 7-dimethyl-1- ((6- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) pyridin-3-yl) methyl) -1H-purine-2, 6(3H, 7H) -dione
1- ((6-acetylpyridin-3-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (150mg, 0.478mmol) was dissolved in tetrahydrofuran (30mL), and trifluoromethyltrimethylsilane (102mg, 0.718mmol) and cesium fluoride (73.0mg, 0.478mmol) were added at room temperature. The reaction was stirred at rt for 12H, tetrabutylammonium fluoride (50.0mg, 0.207mmol) was added, stirring at rt for 30 min was then followed by ethyl acetate (20mL) dilution, the organic phase was washed with saturated sodium bicarbonate (20mL x2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography to give 3, 7-dimethyl-1- ((6- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) pyridin-3-yl) methyl) -1H-purine-2, 6(3H, 7H) -dione (50mg, white solid), yield: 27 percent.1H NMR:(400MHz，CDCl3)δ8.76(s，1H)，7.99(d，J＝8.0Hz，1H)，7.53(s，1H) 7.44(d, J ═ 8.0Hz, 1H), 5.23(s, 2H), 3.99(s, 3H), 3.58(s, 3H), 1.68(s, 3H). MS-ESI calculated value [ M + H%]+384, found 384.
Example 29
3, 7-dimethyl-1- [ [5- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) -2-pyridinyl ] methyl ] purine-2, 6-dione
Figure BDA0002403430430000591
First step of
1- [6- (bromomethyl) -3-pyridyl ] ethanone
1- (6-methyl-3-pyridyl) ethanone (500mg, 3.70mmol), N-bromosuccinimide (658mg, 3.70mmol), azobisisobutyronitrile (182mg, 1.11mmol) were dissolved in carbon tetrachloride (20mL) and reacted at 90 ℃ for 12 hours. The reaction was quenched by the addition of saturated sodium thiosulfate solution (30 mL). Extraction with dichloromethane (10mL x3), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave 1- [6- (bromomethyl) -3-pyridinyl]Ethanone (125mg, yellow oil), yield: 16 percent. MS-ESI calculated value [ M + H%]+214, 216, measured values 214, 216.
Second step of
1- [ (5-acetyl-2-pyridyl) methyl ] -3, 7-dimethylpurine-2, 6-dione
1- [6- (bromomethyl) -3-pyridyl]Ethanone (100mg, 0.467mmol), 3, 7-dimethylpurine-2, 6-dione (84.2mg, 0.467mmol), potassium iodide (7.70mg, 0.0467mmol) and potassium carbonate (194mg, 1.40mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative TLC plate separation (ethyl acetate, Rf 0.3) to give 1- [ (5-acetyl-2-pyridyl) methyl group]-3, 7-dimethylpurine-2, 6-dione (50.0mg, yellow solid), yield: 34 percent. MS-ESI calculated value [ M + H%]+314, measured value 314.
The third step
3, 7-dimethyl-1- [ [5- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) -2-pyridinyl ] methyl ] purine-2, 6-dione
1- [ (5-acetyl-2-pyridyl) methyl group]-3, 7-dimethylpurine-2, 6-dione (50.0mg, 0.159mmol), cesium fluoride (24.2mg, 0.159mmol) was dissolved in tetrahydrofuran (10mL), and trimethyl-trifluoromethyl-silane (113mg, 0.798mmol) was added at room temperature and stirred for 12 hours. The reaction was quenched by the addition of water (20 mL). Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purifying by preparative high performance liquid chromatography to obtain 3, 7-dimethyl-1- [ [5- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) -2-pyridyl]Methyl radical]Purine-2, 6-dione (10.0mg, yellow solid), yield: 16 percent.1H NMR：(400MHz，Methonal-d4) δ 8.96(s, 1H), 8.75(d, J ═ 8.0Hz, 1H), 8.06(d, J ═ 8.0Hz, 1H), 7.97(s, 1H), 5.55(s, 2H), 4.00(s, 3H), 3.57(s, 3H), 1.86(s, 3H). MS-ESI calculated value [ M + H%]+384, found 384.
Example 30
3, 7-dimethyl-1- ((5(1, 1, 1-trifluoro-2-hydroxypropan-2-yl) pyrazin-2-yl) methyl) -purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000601
First step of
N-methoxy-N, 5-dimethylpyrazine-2-carboxamide
5-methylpyrazine-2-carboxylic acid (2.00g, 14.5mmol), 1-hydroxybenzotriazole (391mg, 2.90mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.69g, 17.4mmol) were dissolved in anhydrous dichloromethane (10mL) and chloroform (30mL), triethylamine (1.76g, 17.4mmol) was slowly added under nitrogen at 0 ℃ and the reaction mixture was stirred at 25 ℃ for 12 hours. The reaction was quenched by the addition of water (50 mL). The reaction was extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate, Rf ═ 0.1) to give N-methoxy-N, 5-dimethylpyrazine-2-carboxamide (2.00g, yellow oil), yield: 76 percent.1H NMR:(400MHz，CDCl3)δ8.80(s，1H)，8.45(s，1H)，3.73(s，3H)，3.40(s，3H)，2.61(s，3H)。
Second step of
1- (5-methylpyrazin-2-yl) ethanones
N-methoxy-N, 5-dimethylpyrazine-2-carboxamide (1.50g, 8.28mmol) was dissolved in tetrahydrofuran (30mL), and methyl magnesium bromide (3M in diethyl ether, 13.3mL, 39.9mmol) was added dropwise at 0 ℃ and stirred at 25 ℃ for 1 hour. The mixture was cooled to 0 ℃ and water (10mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30mL x3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate, Rf ═ 0.2) to give 1- (5-methylpyrazin-2-yl) ethyl (700mg, yellow oil) in yield: 62 percent. MS-ESI calculated value [ M + H%]+137, found 137.
The third step
1- (5 (bromomethyl) pyrazin-2-yl) ethanones
1- (5-methylpyrazin-2-yl) ethane (700mg, 5.14mmol) was dissolved in carbon tetrachloride (20mL), followed by the addition of azobisisobutyronitrile (169mg, 1.03mmol) and N-bromosuccinimide (1.14g, 6.43 mmol). The reaction solution was reacted at 100 ℃ for 5 hours under nitrogen protection. The reaction was directly filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate, Rf ═ 0.5) to give 1- (5 (bromomethyl) pyrazin-2-yl) ethyl (300mg, yellow oil), yield: 27 percent. MS-ESI calculated value [ M + H%]+215 and 217, found values 215 and 217.
The fourth step
1- ((5-acetylpyrazin-2-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
1- (5 (bromomethyl) pyrazin-2-yl) ethane (300mg, 1.40mmol), 3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (251mg, 1.40mmol), potassium iodide (23.2mg, 0.140mmol) and potassium carbonate (578mg, 4.19mmol) were dissolved in anhydrous N, N-dimethylformamide (20 mL). The reaction solution was heated to 120 ℃ and reacted for 3 hours. The reaction mixture was cooled to 20 ℃, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate, Rf ═ 0.3) to give 1- ((5-acetylpyrazin-2-yl) methyl)-3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (300mg, yellow solid), yield: 68 percent. MSESI calculated value [ M + H [ ]]+315, measured value 315.
The fifth step
3, 7-dimethyl-1- ((5(1, 1, 1-trifluoro-2-hydroxypropan-2-yl) pyrazin-2-yl) methyl) -purine-2, 6(3H, 7H) -dione
1- ((5-acetylpyrazin-2-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (300mg, 0.954mmol), cesium fluoride (14.5mg, 0.0954mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and trimethylsilyltrifluoromethyl (407mg, 2.86mmol) was added. The reaction solution was reacted at 25 ℃ for 2 hours under nitrogen protection. Hydrochloric acid (4N, 4mL) was then added. The mixture was reacted at room temperature under nitrogen for 1 hour. The reaction was quenched by addition of saturated solution of sodium bicarbonate (10mL), extracted with ethyl acetate (10 × 3mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give 3, 7-dimethyl-1- ((5(1, 1, 1-trifluoro-2-hydroxypropan-2-yl) pyrazin-2-yl) methyl) -purine-2, 6(3H, 7H) -dione (100mg, white solid), yield: 40 percent.1HNMR:(400MHz，Methonal-d4) δ 8.85(s, 1H), 8.65(s, 1H), 7.92(s, 1H), 5.40(s, 2H), 3.99(s, 3H), 3.56(s, 3H), 1.78(s, 3H). MS ESI calculated value [ M + H [ ]]+385, measured value 385.
Example 31
1- ((3- (1, 1,1, 3, 3, 3-hexafluoro-2-hydroxypropan-2-yl) isoxazol-5-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000621
First step of
Methyl 5- (bromomethyl) isoxazole-3-carboxylic acid ethyl ester
Methyl 5-methylisoxazole-3-carboxylic acid ethyl ester (5.00g, 35.4mmol), N-bromosuccinimide (6.31g, 35.4mmol), benzoyl peroxide (858mg, 3.54mmol) were dissolved in carbon tetrachloride (20mL) and reacted at 80 ℃ for 12 hours. The reaction was quenched by the addition of saturated sodium thiosulfate solution (30 mL). Extraction with dichloromethane (20mL × 3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography (3: 1 petroleum ether/ethyl acetate, Rf value ═ 0.5) gave methyl 5- (bromomethyl) isoxazole-3-carboxylic acid ethyl ester (2.00g, yellow oil), yield: 26 percent.1H NMR：(400MHz，Methonal-d4) δ 6.88(s, 1H), 4.73(s, 2H), 3.97(s, 3H). MS-ESI calculated value [ M + H%]+220, 222, measured values 220, 222.
Second step of
Ethyl methyl 5- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) isoxazole-3-carboxylate Ethyl 5- (bromomethyl) isoxazole-3-carboxylate (2.00g, 9.09mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (1.64g, 9.09mmol), potassium iodide (151mg, 0.909mmol) and potassium carbonate (2.51g, 18.2mmol) were dissolved in N, N-dimethylformamide (50 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to isolate and purify (ethyl acetate, Rf value ═ 0.4) methyl 5- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) isoxazole-3-carboxylic acid ethyl ester (1.70g, yellow solid), yield: 59 percent.1H NMR：(400MHz，Methonal-d4) δ 8.06(s, 1H), 6.82(s, 1H), 5.22(s, 2H), 3.87(s, 3H), 3.83(s, 3H), 3.45(s, 3H). MS-ESI calculated value [ M + H%]+320, measured value 320.
The third step
1- ((3- (1, 1,1, 3, 3, 3-hexafluoro-2-hydroxypropan-2-yl) isoxazol-5-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
Ethyl methyl 5- ((3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) isoxazole-3-carboxylate (200mg, 0.626mmol), cesium fluoride (95.0mg, 0.626mmol) were dissolved in tetrahydrofuran (10mL), trimethyltrifluoromethylsilane (445mg, 3.13mmol) was added at room temperature, and stirring was carried out for 12 hours. 1N hydrochloric acid (10mL) was added and the mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate (50mL) was added to quench the reaction. Extract with ethyl acetate (10 mL. times.3). Combination of Chinese herbsThe organic phase was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by preparative high performance liquid chromatography gave 1- ((3- (1, 1,1, 3, 3, 3-hexafluoro-2-hydroxypropan-2-yl) isoxazol-5-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (10.0mg, yellow solid), yield: 4 percent.1H NMR：(400MHz，Methonal-d4) δ 7.95(s, 1H), 6.52(s, 1H), 5.37(s, 2H), 4.00(s, 3H), 3.57(s, 3H). MS-ESI calculated value [ M + H%]+428, found value 428.
Example 32
3, 7-dimethyl-1- ((3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) isoxazol-5-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000631
First step of
1- (5-methylisoxazol-3-yl) ethanone
Methyl 5-methylisoxazole-3-carboxylic acid ethyl ester (5.00g, 35.4mmol) and triethylamine (21.5g, 213mmol) were dissolved in tetrahydrofuran (80mL), and methylmagnesium bromide (3M in ether, 35mL, 105mmol) was added at 0 ℃ to react for 3 hours. The reaction was quenched by the addition of saturated ammonium chloride (30 mL). Extraction with ethyl acetate (30mL x3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography (3: 1 petroleum ether/ethyl acetate, Rf 0.7) gave 1- (5-methylisoxazol-3-yl) ethanone (1.00g, yellow oil) in yield: 23 percent.1H NMR：(400MHz，Methonal-d4) δ 6.39(s, 1H), 2.58(s, 3H), 2.49(s, 3H). MS-ESI calculated value [ M + H%]+126, found value 126.
Second step of
1- (5- (bromomethyl) isoxazol-3-yl) ethanones
1- (5-methylisoxazol-3-yl) ethanone (100mg, 0.799mmol), N-bromosuccinimide (142mg, 0.799mmol), benzoyl peroxide (19.3mg, 0.0800mmol) were dissolved in carbon tetrachloride (10mL) and reacted at 90 ℃ for 12 hours. Adding saturated sodium thiosulfate solution (30mL) to quenchAnd (5) carrying out a killing reaction. Extraction with dichloromethane (10mL x3), drying over anhydrous sodium sulfate, filtration and concentration of the filtrate under reduced pressure gave 1- (5- (bromomethyl) isoxazol-3-yl) ethanone (150mg, yellow oil), yield: 93 percent. MS-ESI calculated value [ M + H%]+204 and 206, measured values 204 and 206.
The third step
1- ((3-Acetylisoxazol-5-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
1- (5- (bromomethyl) isoxazol-3-yl) ethanone (150mg, 0.735mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (132mg, 0.735mmol), potassium iodide (61.0mg, 0.367mmol) and potassium carbonate (305mg, 2.21mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure and purified by preparative TLC plate separation (ethyl acetate, Rf 0.3) to give 1- ((3-acetylisoxazol-5-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (50.0mg, yellow solid) in yield: 22 percent. MS-ESI calculated value [ M + H%]+304, measured value 304.
The fourth step
3, 7-dimethyl-1- ((3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) isoxazol-5-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
Reacting 1- [ (3-acetylisoxazol-5-yl) methyl group]-3, 7-dimethylpurine-2, 6-dione (50.0mg, 0.164mmol), cesium fluoride (25.0mg, 0.164mmol) was dissolved in tetrahydrofuran (10mL), and trimethyltrifluoromethylsilane (70.3mg, 0.494mmol) was added at room temperature, followed by stirring for 12 hours. 1N hydrochloric acid (10mL) was added and the mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate (50mL) was added to quench the reaction. Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification by preparative high performance liquid chromatography gave 3, 7-dimethyl-1- ((3- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) isoxazol-5-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione (22.0mg, yellow solid), yield: 36 percent.1H NMR：(400MHz，Methonal-d4)δ7.98(s，1H)，6.48(s，1H)，5.33(s，2H)，4.01(s，3H)，3.57(s，3H) 1.71(s, 3H). MS-ESI calculated value [ M + H%]+374, found value 374.
Example 33
3, 7-dimethyl-1- ((2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000641
Figure BDA0002403430430000651
First step of
1- (4- (bromomethyl) thiazol-2-yl) ethanones
1- (4-Methylthiazol-2-yl) ethanone (200mg, 1.42mmol), N-bromosuccinimide (252mg, 1.42mmol), azobisisobutyronitrile (46.6mg, 0.284mmol) were dissolved in carbon tetrachloride (20mL) and reacted at 80 ℃ for 12 hours. The reaction was quenched by the addition of saturated sodium thiosulfate solution (30 mL). Extraction with dichloromethane (10mL x3), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave 1- (4- (bromomethyl) thiazol-2-yl) ethanone (200mg, yellow oil), yield: and 64 percent.1H NMR：(400MHz，Methonal-d4) δ 7.97(s, 1H), 4.73(s, 2H), 2.66(s, 3H). MS-ESI calculated value [ M + H%]+220, 222, measured values 220, 222.
Second step of
1- ((2-acetylthiazol-4-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
1- (4- (bromomethyl) thiazol-2-yl) ethanone (100mg, 0.454mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (81.9mg, 0.454mmol), potassium iodide (7.50mg, 0.0454mmol) and potassium carbonate (125mg, 0.908mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure and purified by preparative TLC plate separation (ethyl acetate, Rf value ═ 0.3) to give 1- ((2-acetylthiazol-4-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (80.0mg, yellow solid), yield: and 55 percent.1HNMR：(400MHz，Methonal-d4) δ 7.92(s, 1H), 7.73(s, 1H), 5.38(s, 2H), 4.00(s, 3H), 3.57(s, 3H), 2.64(s, 3H). MS-ESI calculated value [ M + H%]+320, measured value 320.
The third step
3, 7-dimethyl-1- ((2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
1- ((2-acetylthiazol-4-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (200mg, 0.626mmol), cesium fluoride (95.0mg, 0.626mmol) was dissolved in tetrahydrofuran (10mL), and trimethyl-trifluoromethyl-silane (267mg, 1.88mmol) was added at room temperature and stirred for 12 hours. The reaction was quenched by the addition of water (20 mL). Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification by preparative high performance liquid chromatography gave 3, 7-dimethyl-1- ((2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione (100mg, yellow solid), yield: 41 percent.1H NMR：(400MHz，Methonal-d4) δ 8.10(s, 1H), 7.33(s, 1H), 5.32(s, 2H), 4.03(s, 3H), 3.57(s, 3H), 1.80(s, 3H). MS-ESI calculated value [ M + H%]+390, found 390.
Example 34
3, 7-dimethyl-1- ((5-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000661
First step of
1- (4- (bromomethyl) -5-methylthiazol-2-yl) ethanone
1- (4, 5-dimethylpyridin-2-yl) ethanone (200mg, 1.29mmol), N-bromosuccinimide (229mg, 1.29mmol), azobisisobutyronitrile (21.1mg, 0.129mmol) were dissolved in carbon tetrachloride (10mL) and reacted at 80 ℃ for 12 hours. The reaction was quenched by the addition of saturated sodium thiosulfate solution (30 mL). Extraction with dichloromethane (10)mL x3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 1- (4- (bromomethyl) -5-methylthiazol-2-yl) ethanone (200mg, yellow oil), yield: 66 percent.1H NMR：(400MHz，Methonal-d4) δ 4.88(s, 2H), 2.65(s, 3H), 2.47(s, 3H). MS-ESI calculated value [ M + H%]+234, 236, found 234, 236.
Second step of
1- ((2-acetyl-5-methylthiazol-4-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
1- (4- (bromomethyl) -5-methylthiazol-2-yl) ethanone (200mg, 0.854mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (154mg, 0.854mmol), potassium iodide (14.0mg, 0.0854mmol) and potassium carbonate (354mg, 2.56mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure and purified by preparative TLC plates (ethyl acetate, Rf value ═ 0.3) to give 1- ((2-acetyl-5-methylthiazol-4-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (200mg, yellow solid) in yield: 70 percent.1H NMR：(400MHz，Methonal-d4) δ 7.90(s, 1H), 5.35(s, 2H), 4.00(s, 3H), 3.55(s, 3H), 2.66(s, 3H), 2.61(s, 3H). MS-ESI calculated value [ M + H%]+334, measured value 334.
The third step
3, 7-dimethyl-1- ((5-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
1- ((2-acetyl-5-methylthiazol-4-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (80.0mg, 0.240mmol), cesium fluoride (18.2mg, 0.120mmol) was dissolved in tetrahydrofuran (10mL), and trimethyl-trifluoromethyl-silane (102mg, 0.720mmol) was added at room temperature and stirred for 12 hours. The reaction was quenched by the addition of water (20 mL). Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purifying by preparative high performance liquid chromatography to obtain 3, 7-dimethyl-1- ((5-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropane-2-yl) thiazole-4-yl) methylYl) -1H-purine-2, 6- (3H, 7H) -dione (35.0mg, yellow solid), yield: 36 percent.1H NMR：(400MHz，Methonal-d4) δ 8.27(s, 1H), 5.36(s, 2H), 4.06(s, 3H), 3.57(s, 3H), 2.73(s, 3H), 1.90(s, 3H). MS-ESI calculated value [ M + H%]+404, measured value 404.
Example 35
3, 7-dimethyl-1- ((2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-5-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000671
First step of
1- (5-methylthiazol-2-yl) ethylcyclohexanone
5-Methylthiazole (2.00g, 20.2mmol) was dissolved in tetrahydrofuran (50mL) and n-butyllithium (2.5M in tetrahydrofuran, 9.68mL, 24.2mmol) was slowly added dropwise under nitrogen protection at-78 ℃. The reaction mixture was stirred at-78 ℃ for 0.5 h, and N-methoxy-N-methylacetamide (2.50g, 24.2mmol) dissolved in tetrahydrofuran (1mL) was slowly added dropwise. The reaction mixture was heated to 0 ℃ and stirred for 1.5 hours. Water (10mL) was slowly added to the reaction solution at 0 ℃ and extracted with ethyl acetate (30 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure and the resulting product was purified on a high performance preparative plate (1:1 petroleum ether/ethyl acetate, Rf ═ 0.7) to give the product 1- (5-methylthiazol-2-yl) ethylcyclohexanone (1.45g, yellow solid) in yield: 51 percent.1H NMR：(400MHz，Methonal-d4) δ 7.73(s, 1H), 2.61(s, 3H), 2.57(s, 3H). MS-ESI calculated value [ M + H%]+142, measured value 142.
Second step of
1- (5- (bromomethyl) thiazol-2-yl) ethylcyclohexanone
1- (5-Methylthiazol-2-yl) ethylcyclohexanone (200mg, 1.42mmol) and azoisobutyronitrile (2.33mg, 0.0142mmol) were dissolved in chloroform (5mL), and bromosuccinimide (252mg, 1.42mmol) was added at room temperature. The reaction was heated to 78 ℃ and stirred for 16 hours. The reaction was cooled to room temperature and water (30mL) was slowly added) And extracted with chloroform (30mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, 1- (5- (bromomethyl) thiazol-2-yl) ethylcyclohexanone (290mg, yellow oil). MS-ESI calculated value [ M + H%]+220 and 222, and measured values 220 and 222.
The third step
1- ((2-acetylthiazol-5-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
1- (5- (bromomethyl) thiazol-2-yl) ethylcyclohexanone (290mg, 1.05mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (284mg, 1.58mmol) and potassium iodide (17.5mg, 0.105mmol) were dissolved in N, N-dimethylformamide (5mL), potassium carbonate (437mg, 3.16mmol) was added, and the reaction was carried out at 130 ℃ for 2.5 hours. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the product, 1- ((2-acetylthiazol-5-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (292mg, yellow solid), purified on a prep. plate (ethyl acetate, Rf ═ 0.4), yield: 87 percent. MS-ESI calculated value [ M + H%]+320, measured value 320.
The fourth step
3, 7-dimethyl-1- ((2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-5-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
1- ((2-acetylthiazol-5-yl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (280mg, 0.438mmol) and cesium fluoride (6.66mg, 0.0438mmol) were dissolved in tetrahydrofuran (6mL) and trifluoromethyltrimethylsilane (75.0mg, 0.500mmol) was added slowly under nitrogen. The reaction was stirred at 25 ℃ for 1.5 hours. After addition of 4N aqueous hydrochloric acid (0.2mL) and stirring at room temperature for half an hour, pH was adjusted to 7 with saturated sodium bicarbonate solution (10mL), water (20mL) was added and ethyl acetate (50mL x3) was used, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by preparative high performance liquid chromatography to give the product 3, 7-dimethyl-1- ((2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-5-yl) methyl) -1H-purine-2, 6- (3H, 7H) -dione (32.0mg, white solid), yield: 19 percent.1H NMR：(400MHz，Methonal-d4)δ7.89(s，1H)，7.82(s，1H) 5.35(s, 2H), 4.00(s, 3H), 3.56(s, 3H), 1.76(s, 3H). MS-ESI calculated value [ M + H%]+390, found 390.
Example 36
3, 7-dimethyl-1- (2- (4-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-5-yl) ethyl) -1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000681
Figure BDA0002403430430000691
First step of
1- (5- (2-hydroxyethyl) -4-methylthiazol-2-yl) ethanone
2- (4-Methylthiazol-5-yl) ethanol (500mg, 3.49mmol) was dissolved in tetrahydrofuran (100mL) and N-butyllithium (3M in N-hexane, 2.33mL, 6.98mmol) was added at-78 deg.C and after reaction for half an hour N-methoxy-N-methyl-acetamide (432mg, 4.19mmol) was added and stirring was continued for 3 hours. The reaction was quenched by the addition of saturated ammonium chloride (50 mL). Extraction with ethyl acetate (10mL × 3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and separation and purification by silica gel column chromatography (5: 1 petroleum ether/ethyl acetate, Rf value ═ 0.1) gave 1- (5- (2-hydroxyethyl) -4-methylthiazol-2-yl) ethanone (200mg, yellow oil), yield: 31 percent.1H NMR：(400MHz，CDCl3) δ 3.78(t, J ═ 6.4Hz, 2H), 3.18(t, J ═ 6.4Hz, 2H), 2.67(s, 3H), 2.47(s, 3H). MS-ESI calculated value [ M + H%]+186, found 186.
Second step of
2- (2-acetyl-4-methyl-thiazol-5-yl) ethyl methanesulfonate
1- (5- (2-hydroxyethyl) -4-methylthiazol-2-yl) ethanone (120mg, 0.647mmol) and triethylamine (196mg, 1.94mmol) were dissolved in dichloromethane (10mL) and methanesulfonyl chloride (148mg, 1.30mmol) was added at 0 ℃. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of aqueous sodium bicarbonate (50 mL). Extraction with dichloromethane (10ml x 3). Incorporating organic matterThe phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative TLC plate separation (1:1 petroleum ether/ethyl acetate, Rf ═ 0.5) to give 2- (2-acetyl-4-methyl-thiazol-5-yl) ethyl methanesulfonate (150mg, yellow oil) in yield: 88 percent.1H NMR: (400MHz, CDCl3) δ 4.41(t, J ═ 6.4Hz, 2H), 3.27(t, J ═ 6.4Hz, 2H), 3.01(s, 3H), 2.67(s, 3H), 2.46(s, 3H). MS-ESI calculated value [ M + H%]+264, found 264.
The third step
1- (2- (2-acetyl-4-methylthiazol-5-yl) ethyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
2- (2-acetyl-4-methyl-thiazol-5-yl) ethyl methanesulfonate (150mg, 0.569mmol), 3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (102mg, 0.569mmol), potassium iodide (18.9mg, 0.114mmol) and potassium carbonate (236mg, 1.71mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooling to room temperature, filtering, and concentrating the filtrate under reduced pressure. Purification by preparative TLC plate (ethyl acetate, Rf 0.5) gave 1- (2- (2-acetyl-4-methylthiazol-5-yl) ethyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (30.0mg, yellow solid) in yield: 15 percent. MS-ESI calculated value [ M + H%]+348, found value 348.
The fourth step
3, 7-dimethyl-1- (2- (4-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-5-yl) ethyl) -1H-purine-2, 6- (3H, 7H) -dione
1- (2- (2-acetyl-4-methylthiazol-5-yl) ethyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (40.0mg, 0.115mmol), cesium fluoride (17.5mg, 0.115mmol) was dissolved in tetrahydrofuran (10mL), trimethyltrifluoromethylsilane (49.0mg, 0.345mmol) was added at room temperature, and stirred for 12 hours. The reaction was quenched by the addition of water (20 mL). Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purifying by preparative high performance liquid chromatography to obtain 3, 7-dimethyl-1- (2- (4-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropane-2-yl) thiazole-5-yl) ethyl) -1H-purine-2, 6- (3H, 7H) -dione (15.0mg, yellow solid), yield: 31 percent.1H NMR：(400MHz，Methonal-d4) δ 8.37(s, 1H), 4.25(t, J ═ 6.4Hz, 2H), 4.01(s, 3H), 3.54(s, 3H), 3.26(t, J ═ 6.4Hz, 2H), 2.50(s, 3H), 1.90(s, 3H). MS-ESI calculated value [ M + H%]+418, found 418.
Example 37
1- (3-hydroxy-2- (hydroxymethyl) -2-methylpropyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000701
Reacting 3, 7-dimethyl-1- [ (3-methyloxetan-3-yl) methyl]Purine-2, 6-dione (20.0mg, 0.0757mmol) was dissolved in 0.16% hydrochloric acid (0.5mL), the reaction was stirred at room temperature for 6 hours, pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution, and purification was performed by high performance liquid chromatography to give 1- (3-hydroxy-2- (hydroxymethyl) -2-methylpropyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (12.0mg, white solid) in yield: 56 percent.1H NMR：(400MHz，CDCl3) δ 7.58(s, 1H), 4.25-3.94(m, 7H), 3.62(s, 3H), 3.35-3.26(m, 2H), 3.25-3.14(m, 2H), 1.01(s, 3H). MS-ESI calculated value [ M + H%]+283, found 283.
Example 38
1- (2- (2-hydroxy-2-methylcyclopropyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000702
Figure BDA0002403430430000711
First step of
2- (2- (3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-yl) ethoxy) acetate
To a solution of sodium hydride (21.0mg, 0.890mmol) in N, N-dimethylformamide (10mL) was added 1- (2-hydroxyethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (100mg, 0.446mmol) at room temperature, and the reaction mixture was stirred at 25 ℃ for 1 hour. Ethyl 2-bromoacetate (149mg, 0.890mmol) was added. The reaction solution was further stirred for 16 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give 2- (2- (3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-yl) ethoxy) acetate (60.0mg, white solid), yield: and 43 percent.
MS-ESI calculated value [ M + H%]+311, measured value 311.
Second step of
1- (2- (2-hydroxy-2-methylcyclopropyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
To a solution of 2- (2- (3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-yl) ethoxy) acetate (100mg, 0.322mmol) in tetrahydrofuran (5mL) was slowly added dropwise a solution of methylmagnesium bromide (3M in tetrahydrofuran, 0.43mL, 1.29mmol) at-78 ℃. The reaction solution was stirred at-78 ℃ for 2 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (20mL x 3). The organic phases were combined, concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give 1- (2- (2-hydroxy-2-methylcyclopropyl) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (40.0mg, colorless oil). Yield: 42 percent.1H NMR：(400MHz，Methonal-d4) δ 7.88(s, 1H), 4.23(t, J ═ 5.8Hz, 2H), 3.98(s, 3H), 3.72(t, J ═ 5.8Hz, 2H), 3.53(s, 3H), 3.32(s, 2H), 1.13(s, 6H). MS-ESI calculated value [ M + H%]+296, found 296.
Example 39
1- (2- ((1-hydroxycyclobutyl) methoxy) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000712
Figure BDA0002403430430000721
First step of
1- (hydroxymethyl) cyclobutanol
To a solution of lithium aluminum hydride (1.52g, 40.0mmol) in tetrahydrofuran (30mL) was added dropwise a solution of 1-hydroxycyclobutanoic acid (1.16g, 10.0mmol) in tetrahydrofuran (10mL) at 25 ℃. The reaction mixture was heated to reflux and reacted for 1 hour. The reaction was cooled to 25 ℃, quenched with water (20mL), extracted with ethyl acetate (50mL x3), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 1- (hydroxymethyl) cyclobutanol (0.800g, colorless oil) in yield: 80 percent.
Second step of
2- (3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) ethyl methanesulfonate
To a solution of 1- (2-hydroxyethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (448mg, 2.00mmol) in dichloromethane (25mL) was added triethylamine (600mg, 6.00mmol) and methanesulfonyl chloride (342mg, 3.00mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 0.5 hour. The reaction was quenched by the addition of saturated sodium bicarbonate solution (30mL) and extracted with dichloromethane (20mL x 3). The organic phase was washed with saturated brine (20mL x3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) ethyl methanesulfonate (650mg, yellow oil) in yield: 100 percent.
The third step
1- (2- ((1-hydroxycyclobutyl) methoxy) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
To a solution of the mixture of 1- (hydroxymethyl) cyclobutanol (102mg, 1.00mmol) and 2- (3, 7-dimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) ethyl methanesulfonate (450mg, 1.50mmol) in N, N-dimethylformamide (5mL) were added potassium carbonate (414mg, 3.00mmol) and potassium iodide (16.0mg, 0.100 mmol). The reaction was heated to 60 ℃ and stirred overnight. Then slowly cooled to room temperature and quenched by addition of water (20 mL). The mixture was extracted with ethyl acetate (20 mL. times.3), and the organic phase was washed with saturated brine (20 mL. times.3) and dried over anhydrous sodium sulfate.Filtration and concentration of the filtrate under reduced pressure followed by separation and purification by preparative high performance liquid chromatography gave 1- (2- ((1-hydroxycyclobutyl) methoxy) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (50.0mg, white solid) in yield: 16 percent.1H NMR：(400MHz，Methonal-d4) δ 7.88(s, 1H), 4.57-4.59(m, 2H), 4.21-4.24(m, 2H), 3.98(s, 3H), 3.80(s, 2H), 3.54(s, 3H), 2.07-1.95(m, 4H), 1.52-1.54(m, 2H). MS-ESI calculated value [ M + H%]+309, found value 309.
Example 40
(S) -1- (2- ((2-hydroxypropyl) amino) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000731
First step of
1- (3-chloropropyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (1.00g, 5.56mmol) was dissolved in methanol (20mL), 30% sodium methoxide (9.64g, 49.9mmol) was added, and the reaction mixture was refluxed for 1 hour. 1-bromo-2-chloroethane (47.2g, 299mmol) was added thereto, and the reaction mixture was stirred for further 16 hours. The reaction was quenched by addition of water (30mL), extracted with dichloromethane (20mL x3), the organic phase was washed with saturated brine (20mL x3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (1: 2 petroleum ether/ethyl acetate) to give 1- (3-chloropropyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (230mg, white solid) in yield: 17 percent.1H NMR：(400MHz，CDCl3)δ7.50(s，1H)，4.36(t，J＝6.4Hz，2H)，3.97(s，3H)，3.75(t，J＝6.4Hz，2H)，3.56(s，3H).
Second step of
(S) -1- (2- ((2-hydroxypropyl) amino) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione
To a mixture of 1- (3-chloropropyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (62.4mg, 0.826mmol) and (S) -1-aminopropan-2-ol (50.0mg, 0.2) at 25 deg.C07mmol) in acetonitrile (2mL) was added potassium carbonate (138mg, 1.03mmol) and potassium iodide (86.3mg, 0.517 mmol). The reaction solution was stirred at 90 ℃ for 4 hours. The reaction was quenched by addition of water (10mL) and extracted with ethyl acetate (20 mL. times.3). The organic phase was washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by preparative high performance liquid chromatography gave (S) -1- (2- ((2-hydroxypropyl) amino) ethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (10.0mg, white solid) in yield: 17 percent.1HNMR：(400MHz，Methonal-d4) δ 7.86(s, 1H), 4.16(t, J ═ 6.4Hz, 2H), 3.97(s, 3H), 3.84(m, 1H), 3.56(s, 3H), 2.93(m, 2H), 2.64(m, 2H), 1.14(d, J ═ 6.4Hz, 3H). MS-ESI calculated value [ M + H%]+282, measured value 282.
EXAMPLE 41
Figure BDA0002403430430000732
Figure BDA0002403430430000741
Figure BDA0002403430430000742
First step of
1- (1, 4-dioxaspiro [4.5] decan-8-ylmethyl) -7- (difluoromethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
1- (1, 4-dioxaspiro [4.5] decan-8-ylmethyl) -9- (difluoromethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
A mixture (200mg, 0.930mmol) of 7- (difluoromethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione and 9- (difluoromethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione was dissolved in N, N-dimethylformamide (20mL), and 1, 4-dioxaspiro [4.5] decan-8-ylmethylmethylsulfonate (245mg, 1.10mmol), potassium iodide (183mg, 1.10mmol) and potassium carbonate (303mg, 2.20mmol) were added to the reaction solution at room temperature. The reaction solution was heated to 100 ℃ and stirred for 2 hours. Ethyl acetate (30mL) was added to the reaction solution for dilution, and the organic phase was washed with water (20mL × 2), dried over anhydrous sodium sulfate, and concentrated to give a mixture of 1- (1, 4-dioxaspiro [4.5] decan-8-ylmethyl) -7- (difluoromethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione and 1- (1, 4-dioxaspiro [4.5] decan-8-ylmethyl) -9- (difluoromethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (234mg, yellow oil), yield: 68 percent.
MS-ESI calculated value [ M + H%]+371, found 371.
Second step of
7- (difluoromethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione
9- (difluoromethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione
A mixture of 1- (1, 4-dioxaspiro [4.5] decan-8-ylmethyl) -7- (difluoromethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione, 1- (1, 4-dioxaspiro [4.5] decan-8-ylmethyl) -9- (difluoromethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (230mg, 0.750mmol) was dissolved in tetrahydrofuran (15mL), 10% hydrochloric acid (5mL) was added thereto at room temperature, and the reaction mixture was heated to 50 ℃ and stirred for 1 hour. Cooling to room temperature, dilution with ethyl acetate (20mL), washing of the organic phase with saturated sodium bicarbonate (20mL × 2), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and separation and purification by silica gel column chromatography (2: 1 petroleum ether/ethyl acetate, Rf ═ 0.3) gave a mixture of 7- (difluoromethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione, 9- (difluoromethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (200mg, white solid), yield: 81 percent.
MS-ESI calculated value [ M + H%]+327, measured value 327.
The third step
7- (difluoromethyl) -1- (4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
9- (difluoromethyl) -1- (4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Reacting 7- (difluoromethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-A mixture of 2, 6(3H, 7H) -dione, 9- (difluoromethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (168mg, 0.515mmol) was dissolved in tetrahydrofuran (30mL), and trifluoromethyltrimethylsilane (109mg, 0.773mmol) and cesium fluoride (15.7mg, 0.103mmol) were added at room temperature. The reaction was stirred at rt for 12H, tetrabutylammonium fluoride (50.0mg, 0.207mmol) was added, stirring at rt for 30 min and then ethyl acetate (20mL) was added for dilution, the organic phase was washed with saturated sodium bicarbonate (20mL x2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography to give 7- (difluoromethyl) -1- (4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (54mg, white solid), yield: 23 percent of the total weight of the mixture,1H NMR:(400MHz，Methanol-d4) δ 8.46(s, 1H), 7.89-7.74(m, 1H), 4.06(d, J ═ 7.2Hz, 2H), 3.59(s, 3H), 2.19-2.17(m, 1H), 2.05-1.99(m, 2H), 1.88-1.81(m, 2H), 1.61-1.58(m, 2H), 1.51-1.47(m, 2H). MS-ESI calculated value [ M + H%]+397, found 397.
9- (difluoromethyl) -1- (4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (12mg, white solid), yield: 10 percent.1H NMR:(400MHz，Methanol-d4) δ 8.49(s, 1H), 7.93-7.89(m, 1H), 4.07(d, J ═ 7.2Hz, 2H), 3.59(s, 3H), 2.20-2.19(m, 1H), 2.05-1.99(m, 2H), 1.88-1.85(m, 2H), 1.61-1.58(m, 2H), 1.51-1.48(m, 2H). MS-ESI calculated value [ M + H%]+397, found 397.
Example 42
7-Ethyl-1- (5-ethyl-5-hydroxyheptyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000751
First step of
7-Ethyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione
3-methyl-1H-purine-2, 6(3H, 7H) -dione (500mg, 3.00mmol), potassium carbonate (414mg, 3.00mmol) and potassium iodide (4.0mg, 0.300mmol) were dissolvedDissolved in N, N-dimethylformamide (15 mL). The reaction solution is heated to 80 ℃ for half an hour. Iodothane (470mg, 4.50mmol) was added. The reaction was continued for 5 hours. The reaction was quenched by pouring the reaction solution into aqueous sodium hydroxide (50mL) and extracted with ethyl acetate (20 mL. times.3). The aqueous phase was adjusted to pH 7 with 1N dilute hydrochloric acid (10mL), filtered, and the filter cake dried to give 7-ethyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (500mg, light yellow solid), yield: 86 percent.1H NMR：(400MHz，DMSO-d6): δ 8.05(s, 1H), 4.25-4.19 (m, 2H), 3.34(s, 3H), 1.37(t, J ═ 7.2Hz, 3H). MS-ESI calculated value [ M + H%]+195, found value 195.
Second step of
Ethyl 5- (7-ethyl-3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate
7-Ethyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (0.300g, 1.55mmol), ethyl bromovalerate (480mg, 2.32mmol), potassium carbonate (430mg, 3.10mmol) and potassium iodide (26.0mg, 0.155mmol) were dissolved in N, N-dimethylformamide (4 mL). The reaction mixture was heated to 110 ℃ and reacted for 2 hours. The reaction was quenched by pouring the reaction into water (20mL) and extracted with ethyl acetate (20 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 5- (7-ethyl-3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate (320mg, yellow solid), yield: 62 percent. MS-ESI calculated value [ M + H%]+323, found value 323.
The third step
7-Ethyl-1- (5-ethyl-5-hydroxyheptyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Ethyl 5- (7-ethyl-3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate (0.100g, 0.310mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and ethylmagnesium bromide (3M tetrahydrofuran solution, 0.62mL, 1.86mmol) was slowly added dropwise at-78 ℃. The reaction mixture was reacted at-78 ℃ for 0.5 hour, and slowly raised to 0 ℃ for 0.5 hour. After completion of the reaction, the reaction mixture was poured into water (20mL) and extracted with ethyl acetate (30 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to give 7-ethyl-1- (5-ethyl-5-hydroxyheptyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (30.0mg, colorless oil), yield: 30 percent.
1H NMR：(400MHz，CDCl3): δ 7.56(s, 1H), 4.37-4.32 (m, 2H), 4.05(t, J ═ 7.2Hz, 2H), 3.60(s, 3H), 1.68-1.37 (m, 13H), 0.86(t, J ═ 7.2Hz, 6H). MS-ESI calculated value [ M + H%]+337, found 337.
Example 43
7-Ethyl-3-methyl-1- (6, 6, 6-trifluoro-5-hydroxy-5-methylhexyl) -1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000761
Figure BDA0002403430430000771
First step of
7-Ethyl-3-methyl-1- (5-oxohexyl) -1H-purine-2, 6(3H, 7H) -dione
7-Ethyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (0.100g, 0.515mmol), 6-chloro-2-pentanone (90.0mg, 0.670mmol), potassium carbonate (140mg, 1.03mmol) and potassium iodide (8.5mg, 0.0155mmol) were dissolved in DMF (2mL) and heated to 110 ℃ for two hours. The reaction was poured into water and extracted with ethyl acetate (20mL x 3). The combined organic phases were dried, filtered, concentrated and washed with tert-butyl methyl ether, and the solid was dried to give the title compound 7-ethyl-3-methyl-1- (5-oxohexyl) -1H-purine-2, 6(3H, 7H) -dione (100mg, white solid) in yield: 70 percent. MS-ESI calculated value [ M + H%]+293, found 293.
Second step of
7-Ethyl-3-methyl-1- (6, 6, 6-trifluoro-5-hydroxy-5-methylhexyl) -1H-purine-2, 6(3H, 7H) -dione
7-Ethyl-3-methyl-1- (5-oxohexyl) -1H-purine-2, 6(3H, 7H) -dione (100mg, 0.340mmol) was dissolved in 1ml of tetrahydrofuran, and trifluoromethyl trimethyl was added in that orderSilane (53.0mg, 0.370mmol) and cesium fluoride (10.0mg, 0.0340mmol) were reacted at 30 ℃ for 3 hours. The reaction solution was poured into dilute hydrochloric acid (10%, 10mL) and stirred for half an hour. Extract with ethyl acetate (20 mL. times.3). The organic phases were combined, dried and concentrated, and the residue was purified by preparative chromatography using the title compound 7-ethyl-3-methyl-1- (6, 6, 6-trifluoro-5-hydroxy-5-methylhexyl) -1H-purine-2, 6(3H, 7H) -dione (20.0mg, white solid), yield: 79 percent.1H NMR：(400MHz，CDCl3): δ 7.95(s, 1H), 4.39-4.33 (m, 2H), 4.04-4.00(m, 2H), 3.53(s, 3H), 1.71-1.64 (m, 4H), 1.50-1.46 (m, 5H), 1.28(s, 3H). MS-ESI calculated value [ M + H%]+363, measured value 363.
Example 44
1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000772
Figure BDA0002403430430000781
First step of
1- (1, 4-dioxaspiro [4, 5] decan-8-ylmethyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione
1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl methanesulfonate (200mg, 0.800mmol), 3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione (200g, 0.800mmol), potassium carbonate (334mg, 2.42mmol) and potassium iodide (14.0mg, 0.0800mmol) were dissolved in N, N-dimethylformamide (3mL), and the reaction mixture was heated to 130 ℃ and stirred for 3.5 hours. Directly filtering the reaction solution, and concentrating the filtrate under reduced pressure to obtain a crude product 1- (1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione. MS-ESI calculated value [ M + H%]+403, measured value 403.
Second step of
3-methyl-1- ((4-oxocyclohexyl) methyl) -7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione
1- (1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (2.50g, 6.00mmol) was dissolved in acetone (18mL), and aqueous hydrochloric acid (4N, 2.5mL) was added. The reaction was stirred at 30 ℃ overnight, water (50mL) was added, and extracted with ethyl acetate (20 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (1: 3 petroleum ether/ethyl acetate, Rf ═ 0.3) to give the product 3-methyl-1- ((4-oxocyclohexyl) methyl) -7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione (220mg, white solid), yield: 11 percent.1H NMR：(400MHz，CDCl3) δ 7.68(s, 1H), 5.08-4.99(m, 2H), 4.00(d, J ═ 7.0Hz, 2H), 3.61(s, 3H), 2.46-2.24(m, 5H), 2.04-1.96(m, 2H), 1.63-1.56(m, 2H). MS-ESI calculated value [ M + H%]+359, found 359.
The third step
1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione
3-methyl-1- ((4-oxocyclohexyl) methyl) -7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione (128mg, 0.360mmol) and cesium fluoride (6.0mg, 0.0360mmol) were dissolved in tetrahydrofuran (3mL) and trifluoromethyltrimethylsilane (77.0mg, 0.540mmol) was added slowly under nitrogen. The reaction solution was stirred at 30 ℃ for 3 hours. Cooled to room temperature, 4N aqueous hydrochloric acid (2.5mL) was added, stirred at 25 ℃ for half an hour, adjusted to pH 7, diluted with water and extracted with ethyl acetate (20mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative high performance liquid chromatography to give the product 1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione (14.0mg, white solid), yield: 10 percent.1H NMR：(400MHz，CDCl3) Delta.8.09 (s, 1H), 5.27-5.20(m, 2H), 4.08-3.91(m, 2H), 3.58(s, 3H), 2.07-1.98(m, 2H), 1.89-1.80(m, 2H), 1.62-1.46(m, 5H). MS-ESI calculated value [ M + H%]+429, trueMeasured value 429.
Example 45
Figure BDA0002403430430000791
1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione (500mg, 1.17mmol), isolated by preparation of SFC to give two isomers: 1- (((1R, 4R) -4-hydroxy- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione (isomer 1, first peak) and 1- (((1S, 4S) -4-hydroxy- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione (isomer 2, second peak). Separation conditions are as follows: a chromatographic column: AD 250mm x 30mm, 10um mobile phase: supercritical carbon dioxide, ethanol (0.05% ammonia), flow rate of 550: 45: 80mL/min wavelength: 220 nm.
1- (((1R, 4R) -4-hydroxy- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl-1H-purine-2, 6(3H, 7H) -dione (isomer 1, first peak) (300mg, white solid) yield: 90%.1H NMR:(400MHz，DMSO-d6)δ8.23(s，1H)，5.64(s，1H)，5.31-5.24(m，2H)，3.89(d，J＝3.6Hz，2H)，3.43(s，3H)，2.06-2.05(m，1H)，1.87-1.81(m，2H)，1.73-1.61(m，2H)，1.49-1.45(m，2H)，1.33-1.31(m，2H).MS ESI calc’d.[M+H]+429，found 429。
1- (((1S, 4S) -4-hydroxy- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-7 (2, 2, 2-trifluoroethyl) -1H-purine-2, 6(3H, 7H) -dione (isomer 2, second peak) (150mg, white solid) yield 90%.1H NMR:(400MHz，DMSO-d6)δ8.22(s，1H)，5.63(s，1H)，5.29-5.23(m，2H)，3.74(d，J＝3.6Hz，2H)，3.42(s，3H)，1.68-1.66(m，3H)，1.45-1.31(m，6H).MS ESI calc’d.[M+H]+429，found 429。
Example 46
1- (((1S, 4S) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione
1- (((1R, 4R) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000801
First step of
1- (1, 4-dioxaspiro [4, 5] decan-8-ylmethyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione
1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl methanesulfonate (603mg, 2.41mmol), 3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione (500mg, 2.01mmol) and potassium iodide (33.3mg, 0.201mmol) were dissolved in N, N-dimethylformamide (8mL), potassium carbonate (555mg, 4.02mmol) was added, and the reaction was heated under reflux at 130 ℃ for 4 hours. Cooling the reaction liquid to room temperature, filtering, decompressing and concentrating the filtrate to obtain a crude product 1- (1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione (980mg, yellow oil). MS-ESI calculated value [ M + H%]+403, measured value 403.
Second step of
3-methyl-1- ((4-oxocyclohexyl) methyl) -7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione
1- (1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione (980mg, 1.51mmol) was dissolved in acetone (8mL), and 4N aqueous hydrochloric acid (2mL) was added. The reaction was stirred at rt overnight, water (20mL) was added, extracted with ethyl acetate (30mL x3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the product obtained was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give the product 3-methyl-1- ((4-oxocyclohexyl) methyl) -7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione (78.0mg, yellow solid), yield: 15 percent. MS-ESI calculated value [ M + H%]+359, found 359.
The third step
1- (((1S, 4S) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione
1- (((1R, 4R) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione
3-methyl-1- ((4-oxocyclohexyl) methyl) -7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione (66.0mg, 0.184mmol) was dissolved in tetrahydrofuran (2mL), -methyl Grignard reagent (3M in diethyl ether, 0.184mL, 0.552mmol) was added slowly at 78 ℃ under nitrogen protection, -78 ℃ was stirred for half an hour, followed by reaction at 0 ℃ for 2 hours. Water (10mL) was added, extracted with ethyl acetate (30mL x3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product which was purified by preparative high performance liquid chromatography to give the product 1- (((1S, 4S) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione (8.00mg, white solid) in yield: 12 percent of the total weight of the mixture,1HNMR：(400MHz，Methonal-d4) δ 8.08(s, 1H), 5.27-5.19(m, 2H), 3.92(d, J ═ 7.2Hz, 2H), 3.58(s, 3H), 1.71-1.62(m, 4H), 1.46-1.38(m, 2H), 1.32-1.18(m, 6H). MS-ESI calculated value [ M + H-H2O]+357, found value 357.
Product 1- (((1R, 4R) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-7- (2, 2, 2-trifluoroethyl) -1H-purine-2, 6- (3H, 7H) -dione (12.0mg, white solid) (isomer 2, second peak), yield: 17 percent.1H NMR: (400MHz, method-d 4) δ 8.08(s, 1H), 5.27-5.21(m, 2H), 3.91(d, J ═ 7.2Hz, 2H), 3.57(s, 3H), 1.69-1.66(m, 2H), 1.49-1.44(m, 3H), 1.37-1.28(m, 4H), 1.17(s, 3H). MS-ESI calculated value [ M + H-H2O]+357, found value 357.
Example 47
7-cyclopropyl-3-methyl-1- (6, 6, 6-trifluoro-5-hydroxy-5-methylhexyl) -1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000811
First step of
6-amino-5-bromo-1-methylpyrimidine-2, 4(1H, 3H) -dione
A solution of the mixture of 6-amino-1-methylpyrimidine-2, 4(1H, 3H) -dione (5.46g, 40.0mmol) and bromosuccinimide (7.56g, 42.0mmol) in acetonitrile (100mL) was heated under nitrogen at reflux for 1.5H. The reaction was cooled to room temperature, filtered, the solvent was removed, and the resulting solid was washed with water (20mL) and dried to give 6-amino-5-bromo-1-methylpyrimidine-2, 4(1H, 3H) -dione (8.6g, white solid), yield: 98 percent.1H NMR：(400MHz，DMSO-d6)δ10.90(s，1H)，7.04(s，2H)，3.28(s，3H)。
Second step of
6-amino-5- (cyclopropylamine) -1-methylpyrimidine-2, 4(1H, 3H) -dione
6-amino-5-bromo-1-methylpyrimidine-2, 4(1H, 3H) -dione (2.19g, 10.0mmol) was dissolved in a mixed solvent of cyclopropylamine (20mL) and water (5 mL). The reaction solution was heated under reflux for 5 hours. The reaction solution was filtered to remove the solvent, and a crude product of 6-amino-5- (cyclopropylamine) -1-methylpyrimidine-2, 4(1H, 3H) -dione was obtained and used directly in the next reaction.
The third step
7-cyclopropyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione
6-amino-5- (cyclopropylamine) -1-methylpyrimidine-2, 4(1H, 3H) -dione (1.96g, 10.0mmol), trimethyl orthoformate (2.12g, 20.0mmol) and p-toluenesulphonic acid (86.0mg, 0.500mmol) were dissolved in anhydrous N, N-dimethylformamide (20mL) under nitrogen. The reaction solution was heated to 100 ℃ and reacted overnight. The reaction solution was filtered and the solvent was removed to obtain a crude product of 7-cyclopropyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione which was used directly in the next reaction.
The fourth step
7-cyclopropyl-3-methyl-1- (5-oxohexane) -1H-purine-2, 6(3H, 7H) -dione
7-cyclopropyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (100mg, 0.480mmol), 6-chlorohexan-2-one (97.0mg, 0.730mmol) and potassium carbonate (132mg, 0.960mmol) N, N-dimethyl under nitrogenFormamide (5 mL). The reaction mixture was heated to 120 ℃ and reacted for 3 hours. After the reaction was cooled to room temperature, it was diluted with water (20mL) and ethyl acetate (10mL), extracted with ethyl acetate (30mL x2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude 7-cyclopropyl-3-methyl-1- (5-oxohexane) -1H-purine-2, 6(3H, 7H) -dione, which was used directly in the next reaction. MS-ESI calculated value [ M + H%]+305, measured value 305.
The fifth step
7-cyclopropyl-3-methyl-1- (6, 6, 6-trifluoro-5-hydroxy-5-methylhexyl) -1H-purine-2, 6(3H, 7H) -dione
7-cyclopropyl-3-methyl-1- (5-oxohexane) -1H-purine-2, 6(3H, 7H) -dione (200mg, 0.660mmol) was dissolved in anhydrous tetrahydrofuran (3mL) under nitrogen, followed by the addition of trifluoromethyl trimethylsilane (0.2mL, 0.990mmol) and cesium fluoride (20.0mg, 0.130mmol) in that order. The resulting reaction mixture was reacted at 30 ℃ for 2 hours. The reaction was then diluted with water (30mL), extracted with ethyl acetate (30mL x2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified on preparative TLC plates (1: 2 petroleum ether/ethyl acetate, Rf ═ 0.3) to give 7-cyclopropyl-3-methyl-1- (6, 6, 6-trifluoro-5-hydroxy-5-methylhexyl) -1H-purine-2, 6(3H, 7H) -dione (150mg, white solid) in yield: 61 percent.1H NMR：(400MHz，CDCl3) δ 7.55(s, 1H), 4.13-4.02(m, 2H), 3.63-3.61(m, 1H), 3.55(s, 3H), 2.96(s, 1H), 1.90-1.68(m, 2H), 1.67-1.64(m, 2H), 1.47-1.45(m, 2H), 1.28(s, 3H), 1.18-1.16(m, 2H), 1.06-1.04(m, 2H). MS-ESI calculated value [ M + H%]+375, found 375.
Example 48
7- (cyclopropylmethyl) -1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000831
First step of
1- (1, 4-dioxaspiro [4.5] decan-8-ylmethyl) -7-isopropyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione
1, 4-dioxaspiro [4.5]]Decan-8-ylmethyl methanesulfonate (250mg, 1.00mmol), 7-isopropyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (208mg, 1.00mmol), potassium iodide (15.8mg, 0.100mmol) and potassium carbonate (276mg, 2.00mmol) were dissolved in anhydrous N, N-dimethylformamide (8 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. The reaction was cooled to 20 deg.C, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude 1- (1, 4-dioxaspiro [4.5]]Decan-8-ylmethyl) -7-isopropyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (300mg, white oil), yield: 83 percent. MS-ESI calculated value [ M + H%]+362, measured value 362.
Second step of
7-isopropyl-3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione
1- (1, 4-dioxaspiro [4.5]]Decan-8-ylmethyl) -7-isopropyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (300mg, 0.828mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and hydrochloric acid (0.5mL) was added. The reaction solution was stirred at room temperature for 30 minutes. Water was added to the reaction solution, the pH was adjusted to 7 with saturated aqueous sodium bicarbonate (10mL), extracted with ethyl acetate (10mL x3), the organic phases were combined, washed with saturated sodium chloride (20mL x3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate, Rf ═ 0.3) to give 7-isopropyl-3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (180mg, white oil), yield: 68 percent. MS-ESI calculated value [ M + H%]+319, found 319.
The third step
7-isopropyl-3-methyl-1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione 7-isopropyl-3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (122mg, 0.382mmol) and cesium fluoride (11.5mg, 0.0763mmol) were dissolved in anhydrous tetrahydrofuran (3mL) and trifluoromethyltrimethylsilane (95.0mg, 0.640mmol) was added under nitrogen. The reaction solution was heated to 30 ℃ and stirred for 12 hours. Aqueous hydrochloric acid (1N, 5mL) was then added and stirred for an additional 30 minutes. Adding water into the reaction solution,the pH was adjusted to 7 with saturated aqueous sodium bicarbonate (10mL), extracted with ethyl acetate (10mL x3), the organic phases were combined, washed with saturated sodium chloride (20mL x3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give 7-isopropyl-3-methyl-1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (80.0mg, white solid) in yield: 53 percent.1H NMR：(400MHz，Methonal-d4) Delta 8.10(s, 1H), 5.06-5.00(m, 1H), 4.08-3.91(m, 2H), 3.55(s, 3H), 2.17-2.00(m, 2H), 1.88-1.84(m, 2H), 1.61-1.40(m, 6H), 1.59-1.57(m, 5H). MS-ESI calculated value [ M + H%]+389, found 389.
Example 49
7- (cyclopropylmethyl) -1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000841
First step of
1- (1, 4-dioxaspiro [4.5] decan-8-ylmethyl) -7- (cyclopropylmethyl) -3-methyl-1H-purine 2, 6(3H, 7H) -dione
(cyclopropylmethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (220mg, 1.00mmol), 1, 4-dioxaspiro [4.5]]Decan-8-ylmethylmethylmethylmethylmethanesulfonate (250mg, 1.00mmol), potassium iodide (15.8mg, 0.100mmol) and potassium carbonate (276mg, 2.00mmol) were dissolved in anhydrous N, N-dimethylformamide (8mL), and the reaction solution was heated to 120 ℃ and stirred for 3 hours. The reaction was cooled to 20 deg.C, the mixture was filtered and concentrated under reduced pressure to give crude 1- (1, 4-dioxaspiro [4.5] spiro]Decan-8-ylmethyl) -7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (300mg, white oil), yield: 80 percent. MS-ESI calculated value [ M + H%]+375, found 375.
Second step of
7- (cyclopropylmethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione
1- (1, 4-dioxaspiro [4.5]]Decan-8-ylmethylYl) -3, 7-dimethyl-1H-purine-2, 6(3H, 7H) -dione (300mg, 0.802mmol) was dissolved in anhydrous tetrahydrofuran (10mL), hydrochloric acid (0.5mL) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30mL) was added to the reaction mixture, the PH was adjusted to 7 with saturated aqueous sodium bicarbonate (10mL), extracted with ethyl acetate (10mL x3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate, Rf ═ 0.3) to give 7- (cyclopropylmethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (180mg, white oil), yield: 75 percent. MS-ESI calculated value [ M + H%]+331, found value 331.
The third step
7- (cyclopropylmethyl) -1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
7- (Cyclopropylmethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (126mg, 0.382mmol) and cesium fluoride (11.5mg, 0.0763mmol) were dissolved in anhydrous tetrahydrofuran (3mL) and trifluoromethyltrimethylsilane (95.0mg, 0.640mmol) was added under nitrogen. The mixture was stirred at 30 ℃ for 12 hours. Then 1N aqueous hydrochloric acid (5mL) was added and stirring was continued for 30 minutes. Water (30mL) was added to the reaction solution, adjusted to pH 7 with saturated aqueous sodium bicarbonate (10mL), extracted with ethyl acetate (10mL x3), the organic phases combined, washed with saturated sodium chloride (30mL x2), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give 7- (cyclopropylmethyl) -1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (80.0mg, white solid) yield: 53 percent.1H NMR：(400MHz，Methonal-d4) δ 8.16-8.15(m, 1H), 4.24-4.22(m, 2H), 4.08-3.91(m, 2H), 3.57(s, 3H), 2.18-2.07(m, 2H), 1.85-1.82(m, 2H), 1.61-1.47(m, 6H), 0.64-0.60(m, 2H), 0.50-0.48(m, 2H). MS-ESI calculated value [ M + H%]+401, found value 401.
Example 50
7- (cyclopropylmethyl) -1- (((1R, 4R) -4-hydroxy- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
7- (cyclopropylmethyl) -1- (((1S, 4S) -4-hydroxy- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000851
Figure BDA0002403430430000861
7- (cyclopropylmethyl) -1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (900mg, 2.25mmol), separated by preparation of SFC to give two isomers: 7- (cyclopropylmethyl) -1- (((1R, 4R) -4-hydroxy- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (isomer 1, first peak) and 7- (cyclopropylmethyl) -1- (((1S, 4S) -4-hydroxy- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (isomer 2, second peak). Separation conditions are as follows: a chromatographic column: AD 250mm x 30mm, 5um mobile phase: a: supercritical carbon dioxide, B: methanol (0.05% ammonia), a: b55: flow rate of 45: 40mL/min wavelength: 220 nm. 7- (cyclopropylmethyl) -1- (((1R, 4R) -4-hydroxy- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (isomer 1, first peak) (600mg, white solid), yield: 100 percent.1H NMR：(400MHz，DMSO-d6) δ 8.11(s, 1H), 5.62(s, 1H), 4.08(d, J ═ 7.6Hz, 2H), 3.88(d, J ═ 7.6Hz, 2H), 3.43(s, 3H), 2.05-2.04(m, 1H), 1.85-1.82(m, 2H), 1.48-1.45(m, 2H), 1.33-1.32(m, 2H), 1.30-1.28(m, 3H), 0.48-0.46(m, 2H), 0.41-0.39(m, 2H). MS-ESI calculated value [ M + H%]+401, found value 401.
7- (cyclopropylmethyl) -1- (((1S, 4S) -4-hydroxy- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (isomer 2, second peak) (300mg, white solid) yield 100%.1H NMR：(400MHz，DMSO-d6)δ8.11(s，1H)，5.62(s，1H)，4.09(d，J ═ 7.6Hz, 2H), 3.74(d, J ═ 7.6Hz, 2H), 3.42(s, 3H), 1.69 to 1.45(m, 3H), 1.45 to 1.29(m, 7H), 0.48 to 0.46(m, 2H), 0.41 to 0.39(m, 2H). MS-ESI calculated value [ M + H%]+401, found value 401.
Example 51
7- (cyclopropylmethyl) -1- (((1S, 4S) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione
7- (cyclopropylmethyl) -1- (((1R, 4R) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000862
Figure BDA0002403430430000871
First step of
1- (1, 4-dioxaspiro [4, 5] decan-8-ylmethyl-7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione
1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl methanesulfonate (682mg, 2.72mmol), 7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione (500mg, 2.27mmol) and potassium iodide (37.7mg, 0.227mmol) were dissolved in N, N-dimethylformamide (10mL), potassium carbonate (627mg, 4.54mmol) was added, and the reaction was heated under reflux at 130 ℃ for 4 hours. Cooling the reaction liquid to room temperature, filtering, decompressing and concentrating the filtrate to obtain a crude product 1- (1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl-7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione (1.10g, yellow oil). MS-ESI calculated value [ M + H%]+375, found 375.
Second step of
7- (cyclopropylmethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6- (3H, 7H) -dione
1- (1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl-7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione (1.20g, 2.09mmol) was dissolved in acetone (12mL), and 4N aqueous hydrochloric acid (3mL) was added.The reaction was stirred at rt overnight, water (20mL) was added, extracted with ethyl acetate (30mL x3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the product obtained was purified by silica gel column chromatography (1: 1 petroleum ether/ethyl acetate, Rf ═ 0.3) to give the product 7- (cyclopropylmethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6- (3H, 7H) -dione (52.0mg, yellow solid) in yield: 8 percent. MS-ESI calculated value [ M + H%]+331, found value 331.
The third step
7- (cyclopropylmethyl) -1- (((1S, 4S) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione
7- (cyclopropylmethyl) -1- (((1R, 4R) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione
7- (Cyclopropylmethyl) -3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6- (3H, 7H) -dione (100mg, 0.303mmol) was dissolved in tetrahydrofuran (5mL), methyl Grignard reagent (3M in diethyl ether, 0.600mL, 1.81mmol) was added slowly at 78 ℃ under nitrogen protection, and stirred at 78 ℃ for half an hour followed by reaction at 0 ℃ for 2 hours. Water (10mL) was added, extracted with ethyl acetate (30mL x3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product which was purified by preparative high performance liquid chromatography to give the product 7- (cyclopropylmethyl) -1- (((1S, 4S) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione (26.0mg, white solid) (isomer 1, first peak), yield: 25 percent.1HNMR：(400MHz，Methonal-d4) δ 7.99(s, 1H), 4.19(d, J ═ 7.6Hz, 2H), 3.90(d, J ═ 7.6Hz, 2H), 3.54(s, 3H), 1.90-1.79(m, 1H), 1.70-1.61(m, 4H), 1.45-1.36(m, 3H), 1.27-1.16(m, 5H), 0.65-0.55(m, 2H), 0.49-0.42(m, 2H). MS-ESI calculated value [ M + H-H2O]+329 found, value 329.
The product 7- (cyclopropylmethyl) -1- (((1R, 4R) -4-hydroxy-4-methylcyclohexyl) methyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione (42.0mg, white solid) (isomer 2, second peak), yield: 40 percent.1H NMR：(400MHz，Methonal-d4)δ7.99(s，1H)4.19(d, J ═ 7.6Hz, 2H), 3.89(d, J ═ 7.6Hz, 2H), 3.54(s, 3H), 1.81-1.70(m, 1H), 1.69-1.62(m, 2H), 1.51-1.41(m, 4H), 1.39-1.25(m, 3H), 1.15(s, 3H), 0.63-0.56(m, 2H), 0.48-0.42(m, 2H). MS-ESI calculated value [ M + H-H2O]+329 found, value 329.
Example 52
1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000881
First step of
1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione
(4-hydroxy-1- (methoxymethyl) -4- (trifluoromethyl) cyclohexyl) methyl methanesulfonate (100mg, 0.349mmol, 7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione (76.9mg, 0.349mmol), potassium iodide (5.8mg, 0.0349mmol) and potassium carbonate (149mg, 1.05mmol) were dissolved in anhydrous N, N-dimethylformamide (5mL), the reaction solution was heated to 150 ℃ with a microwave, reacted for 2 hours, the reaction solution was cooled to 20 ℃, filtered, and purified by preparative high performance liquid chromatography to give 1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3, 7-dimethyl-1H-purine-2, 6- (3H, 7H) -dione (10.0mg, white solid), yield: 6 percent.1H NMR：(400MHz，DMSO-d6)δ8.13(s，1H)，4.12(s，2H)，3.94(s，1H)，3.43-3.38(m，4H)，3.31(s，3H)，3.19(s，3H)，1.56-1.45(m，8H)，1.43-1.31(m，1H)，0.51-0.49(m，2H)，0.44-0.42(m，2H)。
MS-ESI calculated value [ M + H%]+445, found 445.
Example 53
7- (cyclopropylmethyl) -1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione
Figure BDA0002403430430000891
First step of
7- (cyclopropylmethyl) -1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione
(4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methylmethanesulfonate (100mg, 0.344mmol), 7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione (75.9mg, 0.344mmol), potassium iodide (5.70mg, 0.0344mmol) and potassium carbonate (47.6mg, 0.344mmol) were dissolved in anhydrous N, N-dimethylformamide (5 mL). The reaction solution is heated to 150 ℃ and reacted for 4 hours by microwave. The reaction was cooled to 20 ℃, filtered, concentrated, and then purified by preparative high performance liquid chromatography to give 7- (cyclopropylmethyl) -1- ((4-hydroxy-1-methyl-4- (trifluoromethyl) cyclohexyl) methyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione (10.0mg, white solid) yield: 7 percent.1H NMR：(400MHz，DMSO-d6) δ 8.13(s, 1H), 4.13-4.09(m, 2H), 3.83(s, 1H), 3.43(s, 3H), 3.34(s, 2H), 1.67-1.53(m, 6H), 1.23-1.20(m, 3H), 0.88(s, 3H), 0.50-0.42(m, 4H). MS-ESI calculated value [ M + H%]+415, found value 415.
Example 54
7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione
Figure BDA0002403430430000892
Figure BDA0002403430430000901
First step of
1- (4- (bromomethyl) -5-methylthiazol-2-yl) ethanone
1- (4, 5-dimethylpyridin-2-yl) ethanone (200mg, 1.29mmol), N-bromosuccinimide (229mg, 1.29mmol), azobisisobutyronitrile (21.2mg, 0.129mmol) were dissolved in carbon tetrachloride (20mL) and reacted at 80 ℃ for 12 hours. Addition of saturated thioThe reaction was quenched with sodium sulfate solution (30 mL). Extraction with dichloromethane (10mL x3), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave 1- (4- (bromomethyl) -5-methylthiazol-2-yl) ethanone (200mg, yellow oil), yield: 46 percent. MS-ESI calculated value [ M + H%]+234, 236, found 234, 236.
Second step of
1- ((2-acetyl-5-methylthiazol-4-yl) methyl) -7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione
1- (4- (bromomethyl) -5-methylthiazol-2-yl) ethanone (200mg, 0.598mmol), 7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6-dione (132mg, 0.598mmol), potassium iodide (19.8mg, 0.119mmol) and potassium carbonate (248mg, 1.79mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure and purified by preparative TLC plates (1: 1 petroleum ether/ethyl acetate, Rf 0.4) to give 1- ((2-acetyl-5-methylthiazol-4-yl) methyl) -7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione (100mg, yellow solid) in yield: 45 percent.1H NMR：(400MHz，Methonal-d4) δ 8.02(s, 1H), 5.35(s, 2H), 4.21(d, J ═ 7.6Hz, 2H), 3.56(s, 3H), 2.66(s, 3H), 2.60(s, 3H), 1.46-1.41(m, 1H), 0.65-0.61(m, 2H), 0.60-0.48(m, 2H). MS-ESI calculated value [ M + H%]+374, found value 374.
The third step
7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione
1- ((2-acetyl-5-methylthiazol-4-yl) methyl) -7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6- (3H, 7H) -dione (100mg, 0.267mmol), cesium fluoride (40.6mg, 0.267mmol) was dissolved in tetrahydrofuran (10mL), and trimethyl-trifluoromethyl-silane (114mg, 0.803mmol) was added at room temperature and stirred for 12 hours. The reaction was quenched by the addition of water (20 mL). Extract with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purifying by preparative high performance liquid chromatographyConversion to 7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione (50.0mg, yellow solid), yield: 42 percent.1H NMR：(400MHz，Methonal-d4) δ 8.11(s, 1H), 5.33(s, 2H), 4.23(d, J ═ 7.6Hz, 2H), 3.57(s, 3H), 2.64(s, 3H), 1.81(s, 3H), 1.45-1.41(m, 1H), 0.65-0.61(m, 2H), 0.60-0.49(m, 2H). MS-ESI calculated value [ M + H%]+444, found value 444.
Example 55
7- (cyclopropylmethyl) -3-methyl-1- ((6- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) pyridin-3-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione
Figure BDA0002403430430000911
First step of
1- [5- (bromomethyl) -2-pyridyl ] ethanone
1- (5-methyl-2-pyridyl) ethanone (500mg, 3.70mmol), N-bromosuccinimide (658mg, 3.70mmol), azobisisobutyronitrile (182mg, 1.11mmol) were dissolved in carbon tetrachloride (20mL) and reacted at 90 ℃ for 12 hours. The reaction was quenched by the addition of saturated sodium thiosulfate solution (30 mL). Extraction with dichloromethane (10mL x3), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave 1- [5- (bromomethyl) -2-pyridinyl]Ethanone (125mg, yellow oil), yield: 16 percent. MS-ESI calculated value [ M + H%]+214 and 216, measured values 214 and 216.
Second step of
1- [ (6-acetyl-3-pyridyl) methyl ] -7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6-dione
1- [5- (bromomethyl) -2-pyridyl]Ethanone (100mg, 0.467mmol), 7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6-dione (103mg, 0.467mmol), potassium iodide (15.5mg, 0.0934mmol) and potassium carbonate (193mg, 1.40mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooling to room temperature, filtering, concentrating the filtrate under reduced pressure, and separating and purifying with preparative TLC plate (ethyl acetate, Rf 0.4) to obtainTo 1- [ (6-acetyl-3-pyridyl) methyl group]-7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6-dione (50.0mg, yellow solid), yield: 30 percent. MS-ESI calculated value [ M + H%]+354, found 354.
The third step
7- (cyclopropylmethyl) -3-methyl-1- ((6- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) pyridin-3-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione
1- [ (6-acetyl-3-pyridyl) methyl group]-7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6-dione (100mg, 0.283mmol), cesium fluoride (43.0mg, 0.283mmol) was dissolved in tetrahydrofuran (10mL), and trimethyl-trifluoromethyl-silane (60.4mg, 0.424mmol) was added thereto at room temperature, followed by stirring for 12 hours. The reaction was quenched by the addition of water (20 mL). Extract with ethyl acetate (10 mL. times. 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification by preparative high performance liquid chromatography gave 7- (cyclopropylmethyl) -3-methyl-1- ((6- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) pyridin-3-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione (40.0mg, yellow solid), yield: 32 percent.1HNMR：(400MHz，Methonal-d4) δ 9.00(s, 1H), 8.80-8.72(m, 1H), 8.46(s, 1H), 8.35-8.29(m, 1H), 5.43(s, 2H), 4.28(d, J ═ 7.6Hz, 2H), 3.58(s, 3H), 1.95(s, 3H), 1.50-1.46(m, 1H), 0.68-0.64(m, 2H), 0.53-0.51(m, 2H). MS-ESI calculated value [ M + H%]+424, found value 424.
Example 56
7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione
Figure BDA0002403430430000921
First step of
1- [ (5-acetyl-2-pyridyl) methyl ] -7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6-dione
1- [6- (bromomethyl) -3-pyridyl]Ethanone (100mg, 0.467mmol), 7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6-dione (103mg, 0.467mmol), potassium iodide (15.5mg, 0.0934mmol) and potassium carbonate (193mg, 1.40mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction solution was heated to 120 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative TLC plate separation (ethyl acetate, Rf 0.5) to give 1- [ (5-acetyl-2-pyridyl) methyl group]-7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6-dione (50.0mg, yellow solid), yield: 30 percent. MS-ESI calculated value [ M + H%]+354, found 354.
Second step of
7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione
1- [ (5-acetyl-2-pyridyl) methyl group]-7- (cyclopropylmethyl) -3-methyl-1H-purine-2, 6-dione (100mg, 0.283mmol), cesium fluoride (43.0mg, 0.283mmol) was dissolved in tetrahydrofuran (10mL), and trimethyl-trifluoromethyl-silane (60.4mg, 0.424mmol) was added thereto at room temperature, followed by stirring for 12 hours. The reaction was quenched by the addition of water (20 mL). Extract with ethyl acetate (10 mL. times. 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification by preparative high performance liquid chromatography gave 7- (cyclopropylmethyl) -3-methyl-1- ((5-methyl-2- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) thiazol-4-yl) methyl) -1H-purine 2, 6- (3H, 7H) -dione (10.0mg, yellow solid), yield: 8 percent.1H NMR：(400MHz，Methonal-d4) δ 8.92(s, 1H), 8.75(d, J ═ 7.6Hz, 1H), 8.09(d, J ═ 7.6Hz, 1H), 7.97(s, 1H), 5.54(s, 2H), 4.21(d, J ═ 7.6Hz, 2H), 3.58(s, 3H), 1.85(s, 3H), 1.45-1.42(m, 1H), 0.64-0.59(m, 2H), 0.50-0.46(m, 2H). MS-ESI calculated value [ M + H%]+424, found value 424.
Example 57
1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000931
First step of
1- (1, 4-dioxaspiro [4, 5] decan-8-ylmethyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione
1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl methanesulfonate (1.07g, 4.81mmol), 7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (1.00g, 4.01mmol) and potassium carbonate (647mg, 4.81mmol) were dissolved in N, N-dimethylformamide (14mL), potassium iodide (66.5mg, 0.401mmol) was added, and the reaction was heated under reflux at 130 ℃ for 3 hours. Directly filtering the reaction solution, and concentrating the filtrate under reduced pressure to obtain a crude product 1- (1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (crude 2.56g, brown oil). MS-ESI calculated value [ M + H%]+377, found 377.
Second step of
7-isobutyl-3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione
1- (1, 4-dioxaspiro [4, 5]]Decan-8-ylmethyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (2.50g, 6.00mmol) was dissolved in acetone (12mL), and 4N aqueous hydrochloric acid (2mL) was added. The reaction was stirred overnight at 30 ℃ and a saturated aqueous solution of sodium bicarbonate (8mL) was added to adjust the pH to 7. Water (100mL) was added to the reaction solution, extracted with ethyl acetate (150mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained product was purified by silica gel column chromatography (1: 2 petroleum ether/ethyl acetate, Rf ═ 0.3) to give product 7-isobutyl-3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (150mg, white solid) in yield: 13 percent.1H NMR：(400MHz，Methonal-d4) δ 7.94(s, 1H), 4.14(d, J ═ 7.6Hz, 2H), 3.99(d, J ═ 7.6Hz, 2H), 3.55(s, 3H), 2.29-2.38(m, 5H),2.20-2.13(m, 1H), 2.03-1.98(m, 2H),1.53-1.47(m, 2H), 0.92(d, J ═ 6.4Hz, 6H). MS-ESI calculated value [ M + H%]+333, found value 333.
The third step
1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione
7-isobutyl-3-methyl-1- ((4-oxocyclohexyl) methyl) -1H-purine-2, 6(3H, 7H) -dione (150mg, 0.450mmol) and cesium fluoride (8.0mg, 0.0450mmol) were dissolved in tetrahydrofuran (3mL) and trifluoromethyltrimethylsilane (950mg, 0.640mmol) was added slowly under nitrogen. After reaction at 30 ℃ for 16H with stirring, 4N aqueous hydrochloric acid (3mL) was added and stirring was carried out at 25 ℃ for half an hour, saturated aqueous sodium bicarbonate (15mL) was added to adjust pH to 7, water (50mL) was added and ethyl acetate (50mL x3) was used, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by preparative high performance liquid chromatography to give the product 1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (86.0mg, white solid), yield: 48 percent.1H NMR：(400MHz，Methanol-d4) δ 7.93(s, 1H), 4.15-4.04(m, 2H), 3.89(d, J ═ 7.6Hz, 1H), 3.54(s, 3H), 2.20-1.98(m, 3H), 1.86-1.79(m, 2H), 1.61-1.42(m, 5H), 0.92(d, J ═ 6.4Hz, 6H). MS-ESI calculated value [ M + H%]+403, measured value 403.
Example 58
1- ((((1R, 4R) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione
1- ((((1S, 4S) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000941
Figure BDA0002403430430000951
1- ((4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (900mg, 2.24mmol), two isomers were isolated by preparation of SFC: 1- (((1R, 4R) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (isomer 1, first peak) and 1- (((1S, 4S) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (isomer 2, second peak). Conditions for isomer 1 separation: a chromatographic column: AD 250mm x 30mm, 5um mobile phase: a: supercritical carbon dioxide, B: ethanol (0.05% ammonia), a: b-80: 20 flow rate: 50mL/min wavelength: 220 nm. Isomer 2 separation conditions: a chromatographic column: WEEK-1300 mm x 25mm, 5um mobile phase: a: supercritical carbon dioxide, B: ethanol (0.05% ammonia), a: b is 60: 40, flow rate: 60mL/min, wavelength: 220 nm.
1- (((1R, 4R) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (isomer 1, first peak) (216mg, white solid), yield: 36 percent.1H NMR：(400MHz，DMSO-d6) δ 8.09(s, 1H), 5.65(s, 1H), 4.07(d, J ═ 7.2Hz, 2H), 3.90(d, J ═ 7.2Hz, 2H), 3.43(s, 3H), 2.14-2.00(m, 2H), 1.92-1.80(m, 2H), 1.77-1.66(m, 2H), 1.52-1.44(m, 2H), 1.37-1.30(m, 2H), 0.84(d, J ═ 6.4Hz, 6H). MS-ESI calculated value [ M + H%]+403, measured value 403.
1- (((1S, 4S) -4-hydroxy-4- (trifluoromethyl) cyclohexyl) methyl) -7-isobutyl-3-methyl-1H-purine-2, 6(3H, 7H) -dione (isomer 2, second peak) (101mg, white solid) yield 37%.1H NMR：(400MHz，DMSO-d6) δ 8.07(s, 1H), 5.64(s, 1H), 4.05(d, J ═ 7.6Hz, 2H), 3.75(d, J ═ 7.6Hz, 2H), 3.42(s, 3H), 2.16-2.03(m, 1H), 1.71-1.66(m, 3H), 1.48-1.30(m, 6H), 0.83(d, J ═ 6.4Hz, 6H). MS-ESI calculated value [ M + H%]+403, measured value 403.
Example 59
7- (2, 3-dihydroxypropyl) -1- (5-ethyl-5-hydroxyheptyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000952
Figure BDA0002403430430000961
First step of
7- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
3-methyl-1H-purine-2, 6(3H, 7H) -dione (200mg, 1.20mmol), sodium carbonate (128mg, 1.20mmol), 4- (chloromethyl) -2, 2-dimethyl-1, 3-dioxolane (217mg, 1.44mmol) and potassium iodide (20.0mg, 0.120mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction solution was heated to 110 ℃ and reacted for 36 hours. The reaction was quenched with water (30mL), extracted with ethyl acetate (10mL × 3), the organic phase washed with saturated brine (5mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative TLC plate separation (ethyl acetate, Rf ═ 0.5) to give 7- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (169mg, yellow solid) in yield: 50 percent. MS-ESI calculated value [ M + H%]+281, found 281.
Second step of
Ethyl 5- (7- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate
7- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (169mg, 0.604mmol), ethyl bromovalerate (178mg, 0.906mmol), potassium carbonate (167mg, 1.21mmol) and potassium iodide (20.0mg, 0.0600mmol) were dissolved in N, N-dimethylformamide (10 mL). The reaction was heated to 130 ℃ for 3H, filtered, concentrated and purified by preparative TLC plate (ethyl acetate, Rf ═ 0.4) to give ethyl 5- (7- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate ethyl ester (124mg, yellow solid) yield: 50 percent. MS-ESI calculated value [ M + H%]+409, measured value 409.
The third step
7- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1- (5-ethyl-5-hydroxyheptyl) -3-methyl-1H-purine-2, 6(3H, 7H) dione
Ethyl 5- (7- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purineEthyl (pyrrolidin-1-yl) pentanoate (30.0mg, 0.0750mmol) was dissolved in anhydrous tetrahydrofuran (1mL) and ethyl magnesium bromide (3M tetrahydrofuran solution, 0.15mL, 0.450mmol) was slowly added dropwise at-65 ℃. The reaction was carried out at-65 ℃ for 0.5 hour and then at 0 ℃ for 0.5 hour. The reaction was quenched by pouring into water (5mL), extracted with ethyl acetate (5mLx 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative TLC plate separation (ethyl acetate, Rf ═ 0.5) to give 7- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1- (5-ethyl-5-hydroxyheptyl) -3-methyl-1H-purine-2, 6(3H, 7H) dione (20.0mg, yellow oil), yield: and 63 percent. MS-ESI calculated value [ M + H%]+423, measured value 423.
The fourth step
7- (2, 3-dihydroxypropyl) -1- (5-ethyl-5-hydroxyheptyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
7- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1- (5-ethyl-5-hydroxyheptyl) -3-methyl-1H-purine-2, 6(3H, 7H) dione (20.0mg, 0.0470mmol) was dissolved in anhydrous tetrahydrofuran (1mL) and diluted hydrochloric acid (0.3mL) and reacted at 25 ℃ for 36 hours. After completion of the reaction, concentrated under reduced pressure and purified by preparative TLC plate separation (8: 1 ethyl acetate/methanol, Rf ═ 0.3) to give 7- (2, 3-dihydroxypropyl) -1- (5-ethyl-5-hydroxyheptyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (5.0mg, white solid) in yield: 28 percent.1H NMR：(400MHz，Methonal-d4) δ 7.90(s, 1H), 4.57-4.53(m, 1H), 4.26-4.22(m, 1H), 4.03-3.96(m, 3H), 3.58-3.55(m, 2H), 3.54(s, 3H), 1.66-1.61(m, 2H), 1.48-1.44(m, 6H), 1.34-1.29(m, 2H), 0.85(t, J ═ 8.0Hz, 6H). MS-ESI calculated value [ M + H%]+383, found 383.
Example 60
1- (5-Ethyl-5-hydroxyheptyl) -7- (2-hydroxyethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000971
First step of
7- (2-hydroxyethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
3-methyl-1H-purine-2, 6(3H, 7H) -dione (1.00g, 6.00mmol), potassium carbonate (830mg, 6.00mmol) was dissolved in N, N-dimethylformamide (10 mL). The reaction mixture was heated to 80 ℃ and reacted for 0.5 hour, and 2-bromoethanol (900mg, 7.20mmol) was added thereto. The reaction solution was heated to 130 ℃ and reacted overnight. The reaction solution was concentrated to give crude 7- (2-hydroxyethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione which was used directly in the next step.
Second step of
Ethyl 5- (7- (2-hydroxyethyl) -3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate
7- (2-hydroxyethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (1.05g, 5.00mmol), ethyl 5-bromovalerate (1.25g, 6.00mmol) and potassium carbonate (1.66g, 12.0mmol) were dissolved in N, N-dimethylformamide (3 mL). The reaction mixture was heated to 130 ℃ and reacted for 3 hours. The reaction mixture was poured into water (20mL) to quench the reaction, and extracted with ethyl acetate (20mLx 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative TLC plates to give ethyl 5- (7- (2-hydroxyethyl) -3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate (700mg, yellow oil) in yield: 35 percent. MS-ESI calculated value [ M + H%]+339, found 339.
The third step
1- (5-Ethyl-5-hydroxyheptyl) -7- (2-hydroxyethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Ethyl 5- (7- (2-hydroxyethyl) -3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate (700mg, 2.07mmol) was dissolved in anhydrous tetrahydrofuran (7mL), and ethylmagnesium bromide (3M in tetrahydrofuran, 7mL, 2.10mmol) was slowly added dropwise at-78 ℃. The reaction mixture was reacted at-78 ℃ for 1 hour. The reaction was quenched by pouring into water (20mL) and extracted with ethyl acetate (30 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography to give 1- (5-ethyl-5-hydroxyheptyl) -7- (2-hydroxyethyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (110mg, white)Solid), yield: 15 percent.1H NMR：(400MHz，Methonal-d4): δ 7.90(s, 1H), 4.41(t, J ═ 5.0Hz, 2H), 4.00(t, J ═ 7.6Hz, 2H), 3.87(t, J ═ 5.0Hz, 2H), 3.54(s, 3H), 1.68-1.59(m, 2H), 1.50-1.42(m, 5H), 1.39-1.29(m, 3H), 0.95-0.77(m, 6H). MS-ESI calculated value [ M + H-H2O]+335, measured value 335.
Example 61
1- (5-Ethyl-5-hydroxyheptanol) -7- (2-hydroxy-3- ((2-hydroxyethyl) (methyl) amino) propyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Figure BDA0002403430430000981
Figure BDA0002403430430000991
First step of
1-bromo-3- ((2-hydroxyethyl) (methyl) amino) propan-2-ol
2- (methylamino) ethanol (135mg, 1.80mmol) was dissolved in N, N-dimethylformamide (5mL), and 2- (bromomethyl) oxirane (206mg, 1.51mmol) was added and reacted at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was used directly for the next reaction.
Second step of
7- (2-hydroxy-3- ((2-hydroxyethyl) (methyl) amino) propyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
To a solution of 1-bromo-3- ((2-hydroxyethyl) (methyl) amino) propan-2-ol was added 3-methyl-1H-purine-2, 6(3H, 7H) -dione (100mg, 0.602mmol), sodium carbonate (64.0mg, 0.602mmol) and potassium iodide (10.0mg, 0.0600 mmol). The reaction solution was heated to 80 ℃ and reacted for 10 hours. After the reaction was complete, it was filtered and concentrated under reduced pressure to give crude 7- (2-hydroxy-3- ((2-hydroxyethyl) (methyl) amino) propyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione, which was used directly in the next step. MS-ESI calculated value [ M + H%]+298, found 298.
The third step
Ethyl 5- (7- (2-hydroxy-3- ((2-hydroxyethyl) (methyl) amino) propyl) -3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate
7- (2-hydroxy-3- ((2-hydroxyethyl) (methyl) amino) propyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (170mg, 0.572mmol), ethyl bromovalerate (169mg, 0.858mmol), potassium carbonate (158mg, 1.14mmol) and potassium iodide (10.0mg, 0.0570mmol) were dissolved in N, N-dimethylformamide (5 mL). The reaction solution was heated to 130 ℃ and reacted for 3 hours. The reaction was quenched by pouring into water (5mL) and extracted with ethyl acetate (10 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative TLC plates (8: 1 dichloromethane/methanol, Rf ═ 0.4) to give ethyl 5- (7- (2-hydroxy-3- ((2-hydroxyethyl) (methyl) amino) propyl) -3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate (118mg, yellow oil), yield: 49 percent. MS-ESI calculated value [ M + H%]+426, found value 426.
The fourth step
1- (5-Ethyl-5-hydroxyheptanol) -7- (2-hydroxy-3- ((2-hydroxyethyl) (methyl) amino) propyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione
Ethyl 5- (7- (2-hydroxy-3- ((2-hydroxyethyl) (methyl) amino) propyl) -3-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) pentanoate (100mg, 0.235mmol) was dissolved in anhydrous tetrahydrofuran (4mL), and ethylmagnesium bromide (3M tetrahydrofuran solution, 0.47mL, 1.41mmol) was slowly dropped under-65 ℃. The reaction was carried out at-65 ℃ for 0.5 hour and then at 0 ℃ for 0.5 hour. After completion of the reaction, the reaction solution was quenched by pouring into water (5mL), extracted with ethyl acetate (5mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative TLC plate separation (6: 1 ethyl acetate/methanol, Rf ═ 0.3) to give 1- (5-ethyl-5-hydroxyheptanol) -7- (2-hydroxy-3- ((2-hydroxyethyl) (methyl) amino) propyl) -3-methyl-1H-purine-2, 6(3H, 7H) -dione (3.0mg, white solid), yield: 3 percent.1H NMR：(400MHz，Methonal-d4)δ7.92(s，1H)，4.91-4.59(m，2H)，4.52-4.39(m，3H)，4.30-4.25(m，2H)，4.03-3.99(m，2H)，3.88-3.84(m，2H)，3.55(s，3H)，2.90(s, 3H), 1.68-1.59(m, 4H), 1.48-1.45(m, 6H), 0.88-0.84(m, 6H). MS-ESI calculated value [ M + H%]+440, found value 440.
Experimental example 1: in vitro evaluation of PDE2 phosphodiesterase inhibitory Activity
Purpose of the experiment: detecting the concentration of AMP/GMP generated in the reaction system by detecting AlexaFluor633 fluorescent dye substituted on the AMP/GMP antibody through a fluorescence polarization analysis method, and calculating the PDE2 phosphodiesterase inhibition IC of the compound to be detected50The value is obtained.
Experimental materials:
a slipstream of 10mM Tris-HCl, pH 7.5,5mM MgCl was assayed at 2,0.01％Brij 35,1mM DTT,and1％DMSO.
Enzyme expression of recombinant full-length human PDE2A protein in insect Sf9 cells with baculovirus using N-terminal GST tag
Substrate 1. mu.M cGMP
The detection method comprises the following steps:
Figure BDA0002403430430001001
AMP2/GMP2antibody, AMP2/GMP2AlexaFluor 633 fluorescent dye
And (3) experimental operation:
an enzyme solution is prepared from a freshly prepared buffer solution, then the enzyme solution is added into a reaction hole, a DMSO solution of a compound to be detected is added through an Echo550 non-contact nano-liter level acoustic wave pipetting system, then the reaction is initiated by pre-incubation for 10 minutes at room temperature and adding a substrate (1 mu M cGMP) for reaction for one hour at room temperature. Then add to the detection system (
Figure BDA0002403430430001003
AMP2/GMP2Antibody, AMP2/GMP2AlexaFluor 633 fluorescent dye), reacted at room temperature for 90 minutes, and then the fluorescence polarization was detected using Ex/Em 620/688.
Fluorescence polarization intensity was converted to nM concentration by AMP/GMP standard curve, then the relative enzyme activity inhibition to DMSO blank was calculated, and IC was calculated using Prism Software package (GraphPad Software, San Diego California, USA)50Value and curve
The experimental results are as follows:
TABLE 1 PDE2 phosphodiesterase inhibition test results
Figure BDA0002403430430001002
Figure BDA0002403430430001011
Figure BDA0002403430430001021
Note: less than 50 μ M; + + < 10. mu.M; 1 μ M +++; - - -N/A
And (4) conclusion: the compounds of the present invention have significant and even unexpected PDE2A protease inhibitory activity.
Experimental example 2: in vitro evaluation of the Effect of Compounds on LPS-induced TNF-in rat blood
Purpose of the experiment: the effect of the compound on the induction of TNF-by LPS in rat blood was examined in vitro to evaluate the inhibitory effect of the compound on the induction of TNF-by LPS in rat blood.
Experimental materials:
sprague Dawley rats (Male, 210-260 g, 8-10 weeks old, Shanghai Si Laike)
Rat TNF-alpha Quantikine ELISA Kit(R&D,#SRTA00)
And (3) experimental operation:
test compound solutions were prepared at 1mM concentration and 40ul (100 uM final compound concentration) was added to each of the 48-well cell culture plates. Rats were anesthetized with isoflurane and then blood was collected from the heart (heparin anticoagulation). Blood was added to a 48-well plate to which test compound had been added, 320ul per well. The 48-well plate was placed in a cell incubator, incubated for 30 minutes, then removed, and 40ul LPS solution (100ug/ml) was added, mixed well, and placed in the incubator for further incubation. Taking out 48-well plate after 5 hr, transferring blood sample to 1.5ml centrifuge tube, centrifuging in centrifuge (4,500rpm,4 deg.C, 5minutes), separating upper layer to obtain plasma, packaging, quick freezing, and storing in-80 deg.C refrigerator. TNF-levels in plasma samples were measured the next day using the R & D ELISA kit following the kit protocol.
The experimental results are as follows:
table 2 TNF α inhibitory activity test results
Figure BDA0002403430430001031
Note: + >60 percent; 80 percent of + + + > C; - - -N/A
The compounds of the invention were concluded to have significant and even unexpected TNF α inhibitory activity.

Claims (9)

1. A compound of formula (I), a tautomer thereof, or a pharmaceutically acceptable salt thereof,
Figure FDA0002403430420000011
wherein the content of the first and second substances,
can form a structural unit
Figure FDA0002403430420000012
Is replaced by
Figure FDA0002403430420000013
Is concretely replaced by
Figure FDA0002403430420000014
L11Selected from the group consisting of null, C (R) (R');
r, R' are each independently selected from H, halogen, OH, NH2CN, optionally substituted 1-to 6-membered alkyl or heteroalkyl;
optionally, R, R' may be cyclized to form a 3-6 membered cycloalkyl, heterocycloalkyl; a is empty, or is selected from optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
L12selected from optionally substituted 1-to 6-membered alkyl or heteroalkyl;
R1selected from optionally substituted 1-6-membered alkyl or heteroalkyl;
"hetero" stands for N, O, S, C (═ O), S (═ O)2The number of heteroatoms per group is selected from 1, 2, 3 or 4.
2. The compound of claim 1, wherein R, R', A, L12、R1Wherein the substituents are respectively and independently selected from halogen, OH and NH2CN, optionally substituted 1-6 membered alkyl or heteroalkyl, each independently selected from 1, 2 or 3; in particular R, R', A, L12、R1Wherein the substituents are independently selected from halogen and CF3CN, OH, Me, Et, n-propyl, isopropyl, cyclopropyl,
Figure FDA0002403430420000015
3. The compound of claim 1 or 2, wherein R, R' are each independently selected from H, Me, CF3Et; in particular, L11Is selected from
Figure FDA0002403430420000016
4. The compound of claim 1 or 2, wherein a is selected from optionally substituted: 3-12 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl;
in particular, a is selected from optionally substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypentyl, phenyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, or selected from the group consisting of bicyclic, spirocyclic or fused rings of any two of the foregoing groups;
in particular, a is selected from optionally substituted:
Figure FDA0002403430420000021
Figure FDA0002403430420000022
specifically, A is selected from
Figure FDA0002403430420000023
Figure FDA0002403430420000024
5. The compound of claim 1 or 2, wherein L12Selected from methylene, methyl, ethyl, propyl, butyl,
Figure FDA0002403430420000025
Figure FDA0002403430420000026
6. the compound of claim 1 or 2, wherein R1Selected from Me and CHF2、CF3、Et、CH2CF3An isopropyl group,
Figure FDA0002403430420000027
A cyclopropyl group,
Figure FDA0002403430420000031
7. A compound of the formula:
Figure FDA0002403430420000032
Figure FDA0002403430420000041
8. a compound of the formula:
Figure FDA0002403430420000042
Figure FDA0002403430420000051
9. use of a compound according to any one of claims 1 to 8, a tautomer thereof or a chemically acceptable salt thereof for the preparation of a PDE2 inhibitor and a TNFa inhibitor.
CN202010154010.6A 2014-10-09 2014-10-09 Hydroxyl purine compound and application thereof Active CN111233863B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010154010.6A CN111233863B (en) 2014-10-09 2014-10-09 Hydroxyl purine compound and application thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410529928.9A CN105566324B (en) 2014-10-09 2014-10-09 Hydroxyl purine compound and application thereof
CN202010154010.6A CN111233863B (en) 2014-10-09 2014-10-09 Hydroxyl purine compound and application thereof

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201410529928.9A Division CN105566324B (en) 2014-10-09 2014-10-09 Hydroxyl purine compound and application thereof

Publications (2)

Publication Number Publication Date
CN111233863A true CN111233863A (en) 2020-06-05
CN111233863B CN111233863B (en) 2022-10-25

Family

ID=55877014

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201410529928.9A Active CN105566324B (en) 2014-10-09 2014-10-09 Hydroxyl purine compound and application thereof
CN202010154010.6A Active CN111233863B (en) 2014-10-09 2014-10-09 Hydroxyl purine compound and application thereof

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201410529928.9A Active CN105566324B (en) 2014-10-09 2014-10-09 Hydroxyl purine compound and application thereof

Country Status (1)

Country Link
CN (2) CN105566324B (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2015330490B2 (en) 2014-10-09 2018-08-09 Guangdong Raynovent Biotech Co., Ltd. Hydroxyl purine compounds and applications thereof
WO2016184313A1 (en) * 2015-05-20 2016-11-24 南京明德新药研发股份有限公司 Hydroxyl purine compounds and use thereof
ES2784826T3 (en) * 2015-10-29 2020-10-01 Guangdong Raynovent Biotech Co Ltd Crystalline form of a 4H-pyrazole [1,5-] benzimidazole compound, method of preparation thereof and intermediate thereof
CN107936022A (en) * 2017-11-30 2018-04-20 郑州大学 Xanthine LSD1 inhibitor and its preparation method and application
CN116264834A (en) * 2020-08-25 2023-06-16 广东众生睿创生物科技有限公司 Use of hydroxy purines for the treatment of skin disorders
CN114380829A (en) * 2021-12-28 2022-04-22 赤峰万泽药业股份有限公司 Pentoxifylline and synthetic method and application thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1085557A (en) * 1992-03-04 1994-04-20 细胞治疗有限公司 The enantiomorph hydroxylated xanthine compounds
WO1995022546A1 (en) * 1994-02-18 1995-08-24 Cell Therapeutics, Inc. Intracellular signalling mediators
US5780476A (en) * 1992-11-16 1998-07-14 Cell Therapeutics, Inc. Hydroxyl-containing xanthine compounds
EP0956855A1 (en) * 1998-04-24 1999-11-17 K.U. Leuven Research & Development Immunosuppressive effects of 8-substituted xanthine derivatives
WO2000007541A2 (en) * 1998-07-31 2000-02-17 Aventis Pharma Deutschland Gmbh Use of xanthine derivatives for treating erectile disorder
WO2013013052A1 (en) * 2011-07-19 2013-01-24 Concert Pharmaceuticals, Inc. Substituted xanthine derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110053961A1 (en) * 2009-02-27 2011-03-03 Concert Pharmaceuticals, Inc. Substituted xanthine derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1085557A (en) * 1992-03-04 1994-04-20 细胞治疗有限公司 The enantiomorph hydroxylated xanthine compounds
US5780476A (en) * 1992-11-16 1998-07-14 Cell Therapeutics, Inc. Hydroxyl-containing xanthine compounds
WO1995022546A1 (en) * 1994-02-18 1995-08-24 Cell Therapeutics, Inc. Intracellular signalling mediators
EP0956855A1 (en) * 1998-04-24 1999-11-17 K.U. Leuven Research & Development Immunosuppressive effects of 8-substituted xanthine derivatives
WO2000007541A2 (en) * 1998-07-31 2000-02-17 Aventis Pharma Deutschland Gmbh Use of xanthine derivatives for treating erectile disorder
WO2013013052A1 (en) * 2011-07-19 2013-01-24 Concert Pharmaceuticals, Inc. Substituted xanthine derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BHAUN SINHA 等: "Enhanced tumor necrosis factor suppression and cyclic adenosine monophosphate accumulation by combination of phosphodiesterase inhibitors and prostanoids", 《EUROPEAN JOURNAL OF IMMUNOLOGY》 *
ZE HAN 等: "Photochemistry synthesis. Part 1： Syntheses of xanthine derivatives by photolysis of 1-(5′-oxohexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (pentoxifylline)：an ambident chromophore", 《TETRAHEDRON》 *

Also Published As

Publication number Publication date
CN111233863B (en) 2022-10-25
CN105566324B (en) 2020-04-03
CN105566324A (en) 2016-05-11

Similar Documents

Publication Publication Date Title
CN105566324B (en) Hydroxyl purine compound and application thereof
TWI689511B (en) Hydroxtyl purine compound and application thereof
US11046697B2 (en) Compounds and compositions useful for treating disorders related to NTRK
JP6419990B2 (en) Benzimidazole derivatives as bromodomain inhibitors
CN105228997A (en) CARM1 inhibitor and uses thereof
JP7459094B2 (en) Benzamides of pyrazolyl-amino-pyrimidinyl derivatives, and compositions and methods thereof
CN107531714A (en) Imidazopyrazines ketone as PDE1 inhibitor
TW201734021A (en) Inhibitors of BRUTON&#39;s tyrosine kinase and methods of their use
CN112898309A (en) Tricyclic compounds as immunomodulators
CN107709323B (en) Hydroxyl purine compound and application thereof
CN107614498B (en) Diaza-benzofluoranthenes
CN109661391B (en) S1P1 agonist and application thereof
JP2023506741A (en) Antagonists of the muscarinic acetylcholine receptor M4
CN108348525B (en) Medical application of hydroxyl purine compound
CN115557913A (en) Benzoazaheterocyclic compounds and application thereof in medicines
CN107614501B (en) Hydroxyl purine compound and application thereof
TWI690526B (en) Hydroxyl purine compound and application thereof
TWI690529B (en) Hydroxyl purine compound and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant