CN115141125B - Synthesis method and application of modified long-chain fatty acid type PET reagent precursor - Google Patents

Synthesis method and application of modified long-chain fatty acid type PET reagent precursor Download PDF

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CN115141125B
CN115141125B CN202210867041.5A CN202210867041A CN115141125B CN 115141125 B CN115141125 B CN 115141125B CN 202210867041 A CN202210867041 A CN 202210867041A CN 115141125 B CN115141125 B CN 115141125B
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CN115141125A (en
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何立涛
颜寒
郑策
徐新盛
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Beijing Cotimes Biotech Co Ltd
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Abstract

The application discloses a synthesis method and application of a modified long-chain fatty acid type PET reagent precursor, the reaction and post-treatment operation of the route are simple and convenient, the reactants are easy to obtain, the used reagents are safe and environment-friendly, and the overall yield can reach more than 15%.

Description

Synthesis method and application of modified long-chain fatty acid type PET reagent precursor
Technical Field
The application relates to the field of organic chemical synthesis, in particular to a novel process route for modifying fatty acid type PET reagent precursors.
Background
PET (positron emission tomography) is a relatively advanced clinical examination imaging technique in the field of nuclear medicine. The general method is to mix certain substances, generally substances necessary for biological life metabolism, such as: glucose, proteins, nucleic acids, fatty acids, labeled with short-lived radionuclides (e.g 18 F， 11 C, etc.), after being injected into the human body, the situation of life metabolic activity is reflected by the accumulation of the substance in metabolism, thereby achieving the purpose of diagnosis.
In basal aerobic metabolism of the myocardium, 70% of ATP is produced by beta-oxidation of fatty acids, so fatty acids or modified fatty acids are suitable cardiac positron emission computed tomography agents. The modified fatty acids have greater diagnostic value because the metabolism of the unmodified fatty acids is too rapid to enrich the radioactive atoms more in the liver or lung than in the desired location for diagnosis.
[ 18 F]cardioPET is an innovative PET reagent, is a modified long-chain fatty acid PET reagent, and is currently undergoing clinical research. It is characterized in that in CH 2 CO 2 The cyclopropane ring is introduced at the H group to make the absorption and enrichment act similar to fatty acid, but the beta-oxidation is difficult to carry out, so the cyclopropane ring can be retained in the myocardial cells, and the cyclopropane ring can be further used for the following reasons 18 The decay of F produces positrons, forming medically useful images for studying heart metabolism and disease diagnosis, particularly coronary heart disease.
Figure BDA0003759738180000011
Compounds of formulae (I), (Ia) and (Ib) are 18 F]Precursors of cardioPET, which can be combined with K produced by isotopic irradiation 18 F is subjected to substitution reaction, hydrolysis reaction, and purification by semi-preparative chromatography for diagnostic use (reference: US7790142, US 2004253177).
Figure BDA0003759738180000021
Chinese patent CN108727229B also discloses a process for the preparation of compounds of formulae (I), (Ia) and (Ib). But it is prepared by the disclosed preparation method 18 F]The precursor yield of cardioPET was low, only about 5%, and thus improvement was sought after 18 F]The precursor synthesis yield of CardioPET is necessary.
Disclosure of Invention
Therefore, the application develops a new route for synthesizing the modified long-chain fatty acid PET reagent precursor, and specifically, the application adopts the following technical method:
1. A method of synthesizing a compound of formula (I) using compound 7, wherein the compound of formula (I) is as follows:
Figure BDA0003759738180000022
wherein R represents C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl; preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, cyclopropyl, cyclopentyl, and the like; more preferably, R is tert-butyl;
x is sulfonyl; preferably, X is selected from methylsulfonyl, p-toluenesulfonyl, trifluoromethylsulfonyl and the like; preferably, X is methanesulfonyl;
compound 7 is shown below:
Figure BDA0003759738180000023
wherein Pg represents a protecting group; preferably, pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably Pg is benzyl.
2. The method according to item 1, comprising the step of oxidizing compound 7 to compound 8:
Figure BDA0003759738180000031
preferably, the oxidation reaction is carried out using an oxidizing agent selected from the group consisting of: sodium chlorite and potassium permanganate;
preferably, the oxidation reaction temperature is 10-50 ℃.
3. The process according to item 1 or 2, further comprising the step of esterifying compound 8 to give compound 9:
Figure BDA0003759738180000032
4. The method according to any one of items 1 to 3, further comprising the step of deprotecting compound 9 to give compound 10:
Figure BDA0003759738180000033
5. the method according to any one of items 1 to 4, further comprising the step of sulfonylating the compound 10 to obtain a compound of formula (I):
Figure BDA0003759738180000034
6. the method according to any one of items 1 to 5, further comprising the step of converting compound 6 into compound 7 by subjecting compound 6 to a cyclization reaction:
Figure BDA0003759738180000035
preferably, the cyclisation reaction is carried out using a cyclisation reagent selected from the group consisting of: zinc diiodomethyl, (iodomethyl) potassium trifluoroborate, chloroiodomethane and diiodomethane, preferably diiodomethane;
preferably, the cyclisation reaction is carried out in a reagent selected from the group consisting of: n-hexane, dichloromethane, tetrahydrofuran, dichloroethane, toluene, diethyl ether and 1, 4-dioxane, preferably tetrahydrofuran.
7. The method according to any one of items 1-6, further comprising the step of deprotecting compound 5 to convert to compound 6:
Figure BDA0003759738180000041
preferably, the deprotection reaction is performed using a reagent selected from the group consisting of: sulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, boron trifluoride diethyl ether, acetic acid, phosphoric acid or formic acid, and p-toluenesulfonic acid is further preferred.
8. The method according to any one of items 1 to 7, further comprising the step of converting compound 4 into compound 5 by a reduction reaction:
Figure BDA0003759738180000042
Preferably, the molar ratio of the compound 4 to the reducing agent is 1:1.0-1:4.0;
preferably, the reducing agent is lithium aluminum tetrahydroide.
9. The method according to any one of items 1 to 8, further comprising the step of converting compound 3 into compound 4 by a substitution reaction:
Figure BDA0003759738180000043
preferably, said compound 3 is substituted with 2- (4-pentynoxy) tetrahydro-2H-pyran,
further preferably, the molar ratio of compound 3 to 2- (4-pentynoxy) tetrahydro-2H-pyran is 1:1.0 to 1:3.0;
preferably, the deprotonating agent used is selected from the following strongly basic agents: naH, KH, amination or n-butyllithium, preferably n-butyllithium.
10. The method according to any one of items 1 to 9, further comprising the step of converting compound 2 to compound 3 by an Appel reaction:
Figure BDA0003759738180000051
preferably, the Appel reaction is carried out using a halogenating reagent selected from the group consisting of: methyl iodide or elemental iodine, preferably elemental iodine;
preferably, the molar ratio of the compound 2 to the halogenated agent is 1:1.0-1:2.0.
11. The method according to any one of claims 1-10, further comprising the step of converting compound 1 to compound 2 via a Brown borohydride-oxidation reaction:
Figure BDA0003759738180000052
preferably, the reaction is carried out using a reagent selected from the group consisting of:
The solvent is selected from diglyme, tetrahydrofuran, diethyl ether or 1, 4-dioxane, preferably tetrahydrofuran;
preferably, the oxidizing agent is selected from m-chloroperoxybenzoic acid, peroxyacetic acid, hydrogen peroxide, peroxytrifluoroacetic acid or peroxybenzoic acid, preferably hydrogen peroxide;
preferably, the molar ratio of the compound 1 to the oxidant is 1:3.0-1:8.0.
12. A method of synthesizing a compound of formula (I) using compound 1, comprising the steps of:
the compounds of formula (I) are shown below:
Figure BDA0003759738180000053
wherein R represents C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl; preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, cyclopropyl, cyclopentyl, and the like; more preferably, R is tert-butyl;
x is sulfonyl; preferably, X is selected from methylsulfonyl, p-toluenesulfonyl, trifluoromethylsulfonyl and the like; preferably, X is methanesulfonyl;
Figure BDA0003759738180000061
13. the method according to item 12, comprising the steps of:
Figure BDA0003759738180000071
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14. the method according to item 13, comprising the steps of:
Figure BDA0003759738180000081
15. compound 7:
Figure BDA0003759738180000082
wherein Pg represents a protecting group; preferably, pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably Pg is benzyl.
16. A method of synthesizing compound 7 using compound 1 comprising the steps of:
compound 7 is shown below:
Figure BDA0003759738180000083
wherein Pg represents a protecting group; preferably, pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably Pg is benzyl.
Figure BDA0003759738180000091
17. Compound 6:
Figure BDA0003759738180000092
wherein Pg represents a protecting group; preferably, pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably Pg is benzyl.
18. Compound 5:
Figure BDA0003759738180000093
wherein Pg represents a protecting group; preferably, pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably Pg is benzyl.
19. Compound 4:
Figure BDA0003759738180000094
wherein Pg represents a protecting group; preferably, pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably Pg is benzyl.
20. Compound 3:
Figure BDA0003759738180000101
wherein Pg represents a protecting group; preferably, pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably Pg is benzyl.
21. Compound 2:
Figure BDA0003759738180000102
wherein Pg represents a protecting group; preferably, pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably Pg is benzyl.
Effects of the invention
Through a great deal of experimental trials, the application develops a new route for synthesizing the modified long-chain fatty acid PET reagent precursor, and has the following advantages:
1. the synthetic route reaction and post-treatment operation of the method are simple and convenient, reactants are easy to obtain, the used reagent is environment-friendly, and the method for synthesizing and modifying the long-chain fatty acid PET reagent precursor in the prior art is disclosed in Chinese patent CN108727229B, naH is used as the reactant for many times, and the substance can be exploded when meeting water and wet air to release hydrogen, and has high risk. The novel synthesis method provided by the application does not use NaH substances any more, and the safety is better. In the oxidation process of the existing technology, m-chloroperoxybenzoic acid is mostly used, and the m-chloroperoxybenzoic acid is easy to decompose and explode when meeting heat, has corrosiveness and is not friendly to the environment. After the new synthesis method provided by the application changes the reaction route, the water-soluble oxidizing agent hydrogen peroxide is used for reaction, so that the method is more environment-friendly. And the reaction type used in the new reaction route of the application is mostly classical reaction, which has long verification time, stable process and easy completion.
2. Compared with the synthesis method disclosed in the prior art such as Chinese patent CN108727229B, the total yield of the modified long-chain fatty acid PET reagent precursor is obviously improved, and is about 5%, the total yield of the synthesis route provided by the method can reach more than 15%, the yield is improved by more than 2 times, and the method has obvious cost advantages.
3. The synthesis method is generally 10 steps of reactions, the reaction process is simpler and is operated, and compared with the synthesis route of up to 20 steps in the prior art, a large amount of manpower and material resource costs are saved, and the method has a better application prospect.
Detailed Description
Exemplary embodiments of the present application are described below, including various details of embodiments of the present application to facilitate understanding, which should be considered as merely exemplary. Accordingly, one of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the present application. Also, descriptions of well-known functions and constructions are omitted in the following description for clarity and conciseness.
Definition of the definition
All terms used herein have the meanings commonly understood by those skilled in the art. Further, the following meanings are also possible.
The compounds of formula (I) are shown below:
Figure BDA0003759738180000111
the compound (I) refers to a modified long chain fatty acid type PET reagent precursor, namely [ 18 F]CardioPET reagent precursor.
“C 1-6 Alkyl "refers to a straight or branched saturated monovalent alkyl (hydrocarbon) group containing 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl groups are preferred. Typical C 1-6 Alkyl groups include methyl (C) 1 ) Ethyl (C) 2 ) N-propyl (C) 3 ) Isopropyl (C) 3 ) N-butyl (C) 4 ) Tert-butyl (C) 4 ) Sec-butyl (C) 4 ) Isobutyl (C) 4 ) N-pentyl (C) 5 ) 3-pentyl (C) 5 ) Isoamyl (C) 5 ) Neopentyl (C) 5 ) 3-methyl-2-butyl (C) 5 ) Tert-amyl (C) 5 ) And n-hexyl (C) 6 ) Etc. The term "C 1-6 Alkyl "also includes heteroalkyl groups in which 1 to 3 nitrogen atoms selected from O, S, N or substituted may be substituted for a carbon atom.
“C 2-6 Alkenyl "means a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond, including but not limited to vinyl, 3-buten-1-yl, 2-vinylbutyl, 3-hexen-1-yl, and the like. In some embodiments, C 2-4 Alkenyl groups are preferred. The term "C 2-6 Alkenyl groups also include heteroalkenyl groups,wherein 1 to 3 nitrogen atoms selected from O, S, N or substituted nitrogen atoms may replace carbon atoms.
“C 2-6 Alkynyl "refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms containing at least one carbon-carbon triple bond and optionally one or more unsaturated carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl groups are preferred. Typical alkynyl groups include ethynyl, propynyl, isopropoxy, butynyl, isobutynyl, pentynyl and hexynyl. The term "C 2-6 Alkynyl "also includes heteroalkynyl groups in which 1 to 3 nitrogen atoms selected from O, S, N or substituted may replace a carbon atom.
The term "halogen" as used in this application refers to F, cl, br and I. Preferably, the halogen in the present application is selected from Cl, br and I; more preferably, the halogen in the present application is selected from Cl or Br.
“C 1-6 Haloalkyl "means" C "as described above 1-6 Alkyl ", substituted with one or more halogens. In some embodiments, C 1-4 Haloalkyl is preferred, more preferably C 1-2 A haloalkyl group. Exemplary such haloalkyl groups include, but are not limited to: -CF 3 、-CH 2 F、-CHF 2 、-CHFCH 2 F、-CH 2 CHF 2 、-CF 2 CF 3 、-CCl 3 、-CH 2 Cl、-CHCl 2 2, 2-trifluoro-1, 1-dimethyl-ethyl, and the like.
“C 3-7 Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl groups. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C) 3 ) Cyclopropenyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl (C) 4 ) Cyclopentyl (C) 5 ) Cyclopentenyl (C) 5 ) Cyclohexane (a. C. And a. C.)Radical (C) 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) Cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) And so on.
"3-7 membered heterocyclyl" refers to a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms; preferably a 3-6 membered heterocyclic group which is a 3 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; preferably a 4-6 membered heterocyclic group which is a 4-to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably a 5-6 membered heterocyclic group which is a 5-to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. Heterocyclyl further includes ring systems in which the above heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or ring systems in which the above heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxetanyl, thietanyl (thio). Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulfuranyl) and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6 membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl (thianyl). Exemplary 6 membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, and dithiocyclohexyl A dioxane group. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepinyl, and thiepanyl. Exemplary AND C 6 Aryl ring fused 5-membered heterocyclyl groups (also referred to herein as 5, 6-bicyclic heterocyclyl groups) include, but are not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary AND C 6 Aryl ring fused 6 membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) groups include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
“C 6-10 Aryl "refers to a group of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C 6 Aryl "; for example, phenyl). In some embodiments, aryl groups have ten ring carbon atoms ("C 10 Aryl "; for example, naphthyl groups, such as 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system.
"5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: a pyridyl group. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetrazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azetidinyl, oxepinyl, and thiepinyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazole, benzothienyl, isobenzothienyl, benzofuranyl, benzisotofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.
"Sulfonyl" means a radical R-SO 2 -, wherein R represents C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl.
"methylsulfonyl" means a group Me-SO 2 -。
"p-toluenesulfonyl" means the radical p-CH 3 -C 6 H 4 -SO 2 -。
"trifluoromethanesulfonyl" means a group CF 3 -SO 2 -。
The term "aldehyde" as used herein refers to the group-C (O) H.
Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like as defined herein are optionally substituted groups.
Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OR aa 、-ON(R bb ) 2 、-N(R bb ) 2 、-N(R bb ) 3+ X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(＝O)R aa 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(＝O)R aa 、-OCO 2 R aa 、-C(＝O)N(R bb ) 2 、-OC(＝O)N(R bb ) 2 、-NR bb C(＝O)R aa 、-NR bb CO 2 R aa 、-NR bb C(＝O)N(R bb ) 2 、-C(＝NR bb )R aa 、-C(＝NR bb )OR aa 、-OC(＝NR bb )R aa 、-OC(＝NR bb )OR aa 、-C(＝NR bb )N(R bb ) 2 、-OC(＝NR bb )N(R bb ) 2 、-NR bb C(＝NR bb )N(R bb ) 2 、-C(＝O)NR bb SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(＝O)R aa 、-OS(＝O)R aa 、-Si(R aa ) 3 、-OSi(R aa ) 3 、-C(＝S)N(R bb ) 2 、-C(＝O)SR aa 、-C(＝S)SR aa 、-SC(＝S)SR aa 、-SC(＝O)SR aa 、-OC(＝O)SR aa 、-SC(＝O)OR aa 、-SC(＝O)R aa 、-P(＝O) 2 R aa 、-OP(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-OP(＝O)(R aa ) 2 、-OP(＝O)(OR cc ) 2 、-P(＝O) 2 N(R bb ) 2 、-OP(＝O) 2 N(R bb ) 2 、-P(＝O)(NR bb ) 2 、-OP(＝O)(NR bb ) 2 、-NR bb P(＝O)(OR cc ) 2 、-NR bb P(＝O)(NR bb ) 2 、-P(R cc ) 2 、-P(R cc ) 3 、-OP(R cc ) 2 、-OP(R cc ) 3 、-B(R aa ) 2 、-B(OR cc ) 2 、-BR aa (OR cc ) Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
or two geminal hydrogen-cover groups on carbon atom=o, =s, =nn (R bb ) 2 、＝NNR bb C(＝O)R aa 、＝NNR bb C(＝O)OR aa 、＝NNR bb S(＝O) 2 R aa 、＝NR bb Or=nor cc Substitution;
R aa independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
R bb independently selected from: hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(＝O)R aa 、-C(＝O)N(R cc ) 2 、-CO 2 R aa 、-SO 2 R aa 、-C(＝NR cc )OR aa 、-C(＝NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(＝S)N(R cc ) 2 、-C(＝O)SR cc 、-C(＝S)SR cc 、-P(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-P(＝O) 2 N(R cc ) 2 、-P(＝O)(NR cc ) 2 Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
R cc independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
R dd independently selected from: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OR ee 、-ON(R ff ) 2 、-N(R ff ) 2 、-N(R ff ) 3+ X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(＝O)R ee 、-CO 2 H、-CO 2 R ee 、-OC(＝O)R ee 、-OCO 2 R ee 、-C(＝O)N(R ff ) 2 、-OC(＝O)N(R ff ) 2 、-NR ff C(＝O)R ee 、-NR ff CO 2 R ee 、-NR ff C(＝O)N(R ff ) 2 、-C(＝NR ff )OR ee 、-OC(＝NR ff )R ee 、-OC(＝NR ff )OR ee 、-C(＝NR ff )N(R ff ) 2 、-OC(＝NR ff )N(R ff ) 2 、-NR ff C(＝NR ff )N(R ff ) 2 、-NR ff SO 2 R ee 、-SO 2 N(R ff ) 2 、-SO 2 R ee 、-SO 2 OR ee 、-OSO 2 R ee 、-S(＝O)R ee 、-Si(R ee ) 3 、-OSi(R ee ) 3 、-C(＝S)N(R ff ) 2 、-C(＝O)SR ee 、-C(＝S)SR ee 、-SC(＝S)SR ee 、-P(＝O) 2 R ee 、-P(＝O)(R ee ) 2 、-OP(＝O)(R ee ) 2 、-OP(＝O)(OR ee ) 2 Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R gg Substituted by a group, or by two gem R dd Substituents may combine to form =o or =s;
R ee independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R gg Group substitution;
R ff independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R gg Group substitution;
R gg independently is: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OC 1-6 Alkyl, -ON (C) 1-6 Alkyl group 2 、-N(C 1-6 Alkyl group 2 、-N(C 1-6 Alkyl group 3+ X - 、-NH(C 1-6 Alkyl group 2+ X - 、-NH 2 (C 1-6 Alkyl group + X - 、-NH 3+ X - 、-N(OC 1-6 Alkyl) (C) 1-6 Alkyl), -N (OH) (C 1-6 Alkyl), -NH (OH), -SH, -SC 1-6 Alkyl, -SS (C) 1-6 Alkyl), -C (=o) (C 1-6 Alkyl) -CO 2 H、-CO 2 (C 1-6 Alkyl), -OC (=o) (C 1-6 Alkyl), -OCO 2 (C 1-6 Alkyl), -C (=O) NH 2 、-C(＝O)N(C 1-6 Alkyl group 2 、-OC(＝O)NH(C 1-6 Alkyl), -NHC (=o) (C 1-6 Alkyl), -N (C) 1-6 Alkyl) C (=O) (C 1-6 Alkyl), -NHCO 2 (C 1-6 Alkyl), -NHC (=o) N (C) 1-6 Alkyl group 2 、-NHC(＝O)NH(C 1-6 Alkyl), -NHC (=o) NH 2 、-C(＝NH)O(C 1-6 Alkyl), -OC (=nh) (C 1-6 Alkyl), -OC (=nh) OC 1-6 Alkyl, -C (=nh) N (C 1-6 Alkyl group 2 、-C(＝NH)NH(C 1-6 Alkyl), -C (=nh) NH 2 、-OC(＝NH)N(C 1-6 Alkyl group 2 、-OC(NH)NH(C 1-6 Alkyl), -OC (NH) NH 2 、-NHC(NH)N(C 1-6 Alkyl group 2 、-NHC(＝NH)NH 2 、-NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 Alkyl group 2 、-SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 、-SO 2 C 1-6 Alkyl, -SO 2 OC 1-6 Alkyl, -OSO 2 C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si (C) 1-6 Alkyl group 3 、-OSi(C 1-6 Alkyl group 3 、-C(＝S)N(C 1-6 Alkyl group 2 、C(＝S)NH(C 1-6 Alkyl), C (=S) NH 2 、-C(＝O)S(C 1-6 Alkyl), -C (=S) SC 1-6 Alkyl, -SC (=s) SC 1-6 Alkyl, -P (=o) 2 (C 1-6 Alkyl), -P (=o) (C 1-6 Alkyl group 2 、-OP(＝O)(C 1-6 Alkyl group 2 、-OP(＝O)(OC 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, C 6 -C 10 Aryl, C 3 -C 7 Heterocyclyl, C 5 -C 10 Heteroaryl; or two gem R gg Substituents may combine to form =o or =s; wherein X is - Is a counter ion.
Exemplary substituents on nitrogen atoms include, but are not limited to: hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(＝O)R aa 、-C(＝O)N(R cc ) 2 、-CO 2 R aa 、-SO 2 R aa 、-C(＝NR bb )R aa 、-C(＝NR cc )OR aa 、-C(＝NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(＝S)N(R cc ) 2 、-C(＝O)SR cc 、-C(＝S)SR cc 、-P(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-P(＝O) 2 N(R cc ) 2 、-P(＝O)(NR cc ) 2 Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R's attached to a nitrogen atom cc The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Substituted with radicals, and wherein R aa 、R bb 、R cc And R is dd As described above.
The term "oxidation reaction" as used herein refers to a reaction in which oxygen is introduced or dehydrogenized in the compounds of the present application. More specifically, it refers to a reaction that converts an aldehyde group into a carboxylic acid group. The oxidation reaction may be accomplished using a variety of oxidizing agents well known in the art including, but not limited to, sodium chlorite, potassium permanganate, PCC (pyridinium chlorochromate), and manganese dioxide.
The temperature of the oxidation reaction in the present application is preferably 10 to 50℃and may be, for example, 10℃15℃20℃25℃30℃35℃40℃45℃50 ℃.
The term "protecting group" as used herein refers to a group that is capable of covalently binding to a functional group, protecting it from chemical reaction, and can be removed after the reaction is complete to restore the functional group. More specifically, a protecting group in the present application refers to an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, t.w. greene and p.g. m.wuts, third edition, john wiley & Sons,1999, which is incorporated herein by reference.
Exemplary oxygen protecting groups include, but are not limited to, methyl, t-butoxycarbonyl (BOC or Boc), methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-Pentenyloxymethyl (POM), silyloxymethyl, 2-methoxyethoxymethyl (MEM), 2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-Methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl S, S-dioxide, 1- [ (2-chloro-4-methyl) phenyl ] -4-methoxypiperidin-4-yl (CTMP), 1, 4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothienyl, 2, 3a,4,5,6,7 a-octahydro-7, 8-trimethyl-4, 7-methanolbenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl-2-fluoroethyl, 2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2, 4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-halobenzyl, 2, 6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p, p ' -dinitrobenzhydryl, 5-dibenzocycloheptatrienyl, triphenylmethyl, alpha-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4 ' -bromobenzoyloxyphenyl) diphenylmethyl, 4', 4' -tris (4, 5-dichlorobenzimidophenyl) methyl, 4' -tris (levulinyloxyphenyl) methyl, 4', 4' -tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-yl) bis (4 ', 4' -dimethoxyphenyl) methyl, 1, 1-bis (4-methoxyphenyl) -1' -pyrenylmethyl, 9-anthryl, 9- (9-phenyl) xanthyl, 9- (9-phenyl-10-oxo) anthryl, 1, 3-benzodithiophene (disulfuran) -2-yl, benzisothiazolyl S, S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-valerate, 4- (4-methoxyvalerate), 4-acetylthio-4, 4-propanoate, 4-acetylthio-pentanoate, 4-propanoate, 2-methoxybenzoate, 2-propanoate, p-methoxybenzoate, p-propanoate, p-methoxybenzoate, alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2, 2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl) ethyl carbonate (TMSEC), 2- (phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphine) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3, 4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthio carbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylphenyl sulfonate, 2- (methylthiomethoxy) ethyl, 4- (methylthiomethoxy) methyl) butyrate, 2- (methylthio) butyl acetate, 2-methoxy-2, 6-chloro-2, 1-chloro-2-methyl-2-phenylbutyrate, 1-chloro-1, 4-dimethyl-phenylbutyrate, 1-chloro-dimethyl-1-chloro-phenylacetate, 4-dimethyl-chloro-1-phenylbutyrate (E) -2-methyl-2-butenoate, o (methoxyacyl) benzoate, alpha-naphthoate, nitrate, alkyl N, N' -tetramethyl phosphoryl diamine ester (phosphodiamide), alkyl N-phenyl carbamate, borate, dimethylphosphino sulfinyl, alkyl 2, 4-dinitrophenyl sulfenate, sulfate, methane sulfonate (methane sulfonate), benzyl sulfonate and toluene sulfonate (Ts).
"hydroxy protecting" and "deprotecting" refer to the reaction of introducing a protecting group to a hydroxy function, and removing the protecting group to restore the hydroxy function, respectively. The reaction conditions for introducing and removing protecting groups are well known to those skilled in the art. Preferred reagents in this application are sulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, boron trifluoride etherate, acetic acid, phosphoric acid or formic acid, with p-toluenesulfonic acid being the more preferred reagent.
The term "esterification reaction" as used herein refers to a reaction that converts a carboxyl group to an ester group. The esterification reaction may be accomplished using a variety of reagents well known in the art including, but not limited to, halogenated hydrocarbons, alcohols, and the like.
The term "sulfonylation" as used herein refers to the reaction of converting a hydroxyl group to a sulfonyloxy group. For example, methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like may be used to effect the reaction.
The term "cyclization reaction" as used herein refers to a reaction in an organic compound molecule that forms a new carbocyclic or heterocyclic ring, also known as ring closure or ring-forming condensation. In forming a carbocyclic ring, the cyclization reaction is completed by carbon-carbon bond formation; when a ring structure containing a heteroatom is formed, the ring reaction may be performed by forming a carbon-carbon bond, or by forming a carbon-heteroatom bond (C-N, C-O, C-S bond, etc.), or by forming a bond (N-N, N-S bond, etc.) between two heteroatoms. The cyclization reaction may be accomplished using a variety of reagents well known in the art including, but not limited to, zinc iodomethyl, (iodomethyl) potassium trifluoroborate, chloroiodomethane and diiodomethane, with diiodomethane being a further preferred reagent herein; the present application further preferably performs the cyclization reaction in a reagent selected from the group consisting of: n-hexane, dichloromethane, tetrahydrofuran, dichloroethane, toluene, diethyl ether and 1, 4-dioxane, preferably tetrahydrofuran.
The term "reduction reaction" as used herein refers to a reaction of introducing hydrogen or removing oxygen in a compound of the present application. More specifically, it refers to a reaction of converting an ester group into an aldehyde group. The reduction reaction may be accomplished using a variety of reducing agents well known in the art, including but not limited to one-step conversion of DIBAL-H, and prior to NaBH 4 In a further preferred embodiment, the molar ratio of the compound 4 to the reducing agent in the process of converting the compound 4 into the compound 5 by the reduction reaction is 1:1.0 to 1:4.0, for example, 1:1.0, 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5, and 1:4.0.
The term "substitution reaction" as used herein refers to a reaction in which any one atom or group of atoms in a compound or organic molecule is replaced by another atom or group of atoms of the same type in the reagent. The substitution reaction may be accomplished using a variety of reagents well known in the art, and in preferred embodiments of the present application, the compound 3 is substituted with 2- (4-pentynoxy) tetrahydro-2H-pyran, and more preferably, the molar ratio of compound 3 to 2- (4-pentynoxy) tetrahydro-2H-pyran is from 1:1.0 to 1:3.0; for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0 may be used. In a preferred embodiment of the present application, the deprotonating agent used during the substitution reaction is selected from the following agents: the base NaH, KH, lithium amide or n-butyllithium, preferably n-butyllithium.
The term "Appel reaction" as used herein refers to the conversion of primary and secondary alcohols to alkyl halides using carbon tetrahalides and triphenylphosphine. Alkyl bromides and alkyl iodides may also be prepared by substituting carbon tetrabromide or bromine, carbon tetraiodide, methyl iodide or iodine, respectively, for carbon tetrachloride. The reaction is a milder method for introducing halogen atoms. The Appel reaction may be accomplished using a variety of reagents well known in the art including, but not limited to, carbon tetrabromide, bromine, methyl iodide, or elemental iodine, with the preferred halogenated reagents herein being elemental iodine. In a preferred embodiment, the molar ratio of compound 2 to halogenated agent in the process of converting compound 2 to compound 3 by an Appel reaction is 1:1.0 to 1:2.0, for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0.
The term "Brown borohydride-oxidation" as used herein refers to a reaction in which borane is co-cis-added to an olefin to give an organoboron addition product, which is then oxidized under basic conditions to give an alcohol. The Brown borohydride-oxidation reaction can be accomplished using a variety of reagents well known in the art, in one preferred embodiment the solvent is selected from diglyme, tetrahydrofuran, diethyl ether or 1, 4-dioxane, further preferably tetrahydrofuran, and in another preferred embodiment the oxidant is selected from m-chloroperoxybenzoic acid, peroxyacetic acid, hydrogen peroxide, peroxytrifluoroacetic acid or peroxybenzoic acid, further preferably hydrogen peroxide. In the process of converting the compound 1 into the compound 2 through the borohydride-oxidation reaction, the molar ratio of the compound 1 to the oxidant is 1:3.0-1:8.0, for example, may be 1:3.0, 1:3.5, 1:4.0, 1:4.5, 1:5.0, 1:5.5, 1:6.0, 1:6.5, 1:7.0, 1:7.5, 1:8.0.
Examples
1. Synthesis of Compound 2a from Compound 1a
The synthetic route is as follows:
Figure BDA0003759738180000211
the specific synthesis steps are as follows: compound 1a (25.0 g,86.73 mmol) was added to a 500 ml three-necked flask, 100 ml of anhydrous Tetrahydrofuran (THF) was added under nitrogen atmosphere, borane dimethyl sulfide complex (13.4 g,173.46mmol,1M THF solution) was added dropwise at 0-5 ℃, after the addition was completed, the reaction system was allowed to warm to room temperature, and then heated to reflux for 4 hours, the reaction system was cooled to 0 ℃, ethanol 30 ml, 4M NaOH solution (30 ml), 30% hydrogen peroxide (H 2 O 2 ) (35 ml) the solution of Compound 1a was stirred at room temperature for 2 hours to effect an oxidation reaction. 100 ml of water and 100 ml of methyl tertiary butyl ether are added into the system, and extraction and liquid separation are carried out; the organic phase is washed with 200 ml of saturated ammonium chloride solution and separated; the organic phase is washed with 200 ml of saturated sodium chloride solution and separated; the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure, and the crude product was purified by flash chromatography on silica gel (eluent: cyclohexane/EtOAc 100/0 to 10/90) to give 20.0g of product. Yield: 75.3%.
1H-NMR(400MHz，CDCl3)δ：0.86(t，3H)，1.24～1.58(m，20H)，2.98(m，2H)，3.38(m,1H)，4.62(s，2H)，4.76(m，1H)，7.28-7.32(m，5H)
2. Synthesis of Compound 3a from Compound 2a
The synthetic route is as follows:
Figure BDA0003759738180000212
the specific synthesis steps are as follows: compound 2a (18.0 g,58.75 mmol) and imidazole (8.0 g,0.1175 mol) and triphenylphosphine (PPh) 3 ) (32.6 g,0.1243 mol) and anhydrous Tetrahydrofuran (THF) (250 mL) were added to 500 milliAdding iodine (I) into three bottles at 0deg.C under nitrogen atmosphere 2 ) (31.5 g,0.1242 mol) Compound 2a, after the addition was completed, was allowed to warm to room temperature and stirred overnight. After quenching with saturated sodium sulfite solution, the combined organic solutions were washed with ethyl acetate (2X 100 ml) and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a viscous oil which was purified by silica gel column chromatography (eluent: cyclohexane/EtOAc 100/10 to 5/95) to give 14.8g of compound 3a. Yield: 81.1%.
1H-NMR(400MHz，CDCl3)δ：0.88(t，3H)，1.24～1.85(m，18H)，2.92(m，2H)3.40(m,1H)，3.64(m，2H)，4.52(s，2H)，7.30-7.35(m，5H)
3. Synthesis of Compound 4a from Compound 3a
The synthetic route is as follows:
Figure BDA0003759738180000221
the specific synthesis steps are as follows:
2- (4-pentynoxy) tetrahydro-2H-pyran (2- (Pent-4-yn-1-yloxy) tetrahyd-2H-pyran, 4-pentynoxide OTHP) (15.4 g,91.38 mmol) and anhydrous Tetrahydrofuran (THF) (200 mL) were added to a 500 mL three-necked flask, and n-butyllithium (n-BuLi) (1.6M in hexane, 57.1mL,91.38 mmol) and compound 3a (19.0 g,45.66 mmol) were added at a low temperature of-30℃under nitrogen atmosphere, and the solution was allowed to react at room temperature for 6 hours. Saturated NH is added after the reaction is finished 4 Cl. The resulting mixture was extracted with hexane/EtOAc (1:1) (3X 100 mL). The combined extracts were washed with water, dried over magnesium sulfate and concentrated to leave a residue which was purified by column chromatography (n-heptane: ethyl acetate=100:1 to 50:1) to give 17.8g of a colourless oil. Yield: 88.1%.
1H NMR(400MHz,CDCl 3 ))δ0.88(m,3H),1.26-1.79(m,26H),2.15(m，2H)，2.40(m，2H)3.11(p,1H),3.52(m，2H)，3.72(m，2H)4.56(m，H)4.63(d,2H),7.30-7.32(m,5H)
4. Synthesis of Compound 5a from Compound 4a
The synthetic route is as follows:
Figure BDA0003759738180000222
the specific synthesis steps are as follows: lithium aluminum hydride (LAH/LiAlH) 4 ) (1.88 g,49.54 mmol) was suspended in 200mL of anhydrous Tetrahydrofuran (THF), ethanol (4.2 g,91.16 mmol) was added dropwise to the suspension, then compound 4a (20.0 g,45.21 mmol) was added dropwise to 50mL of anhydrous Tetrahydrofuran (THF), after the addition was completed, the two solutions were mixed, the reaction mixture was warmed to room temperature, and then heated under reflux for 1 hour. The mixture was carefully quenched with water and 2M NaOH and the resulting white aluminum salt was vacuum filtered through a sintered glass funnel. The salt was repeatedly washed with 100ml of hot tetrahydrofuran, and the combined filtrates were dried over anhydrous sodium sulfate and concentrated under reduced pressure at 30-40 ℃. Column chromatography was purified by silica gel chromatography (n-heptane: ethyl acetate=100:1 to 50:1) to give 16.5g of compound 5a, yield: 82.1%.
1H NMR(400MHz,CDCl 3 ))δ0.88(m,3H),1.24-1.78(m,26H),2.15(m，2H)，2.20(m，2H)3.21(p,1H),3.43(m，2H)，3.72(m，2H)4.58(m，H)4.62(d,2H),5.42-5.46(m，2H)，7.26-7.32(m,5H)
5. Synthesis of Compound 6a from Compound 5a
The synthetic route is as follows:
Figure BDA0003759738180000231
the specific synthesis steps are as follows: methanol (MeOH) (150 ml.) and water 5ml were added to a 500 ml three-port flask under nitrogen, p-toluene sulfonic acid (PTSA) (0.6 g,4.0% wt.) and compound 5a (15.0 g,33.76 mmol) were added and the reaction mixture was heated to 60 ℃ and stirred for 2 hours. Then cooled to room temperature, diluted with water and adjusted to ph=8-10 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (3×100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 30-40 ℃ to give the crude product. Column chromatography (n-heptane: ethyl acetate=100:1 to 50:1) was purified by silica gel chromatography to give 9.8g. Yield: 80.6%.
1H NMR(400MHz,CDCl 3 ))δ0.86(m,3H),1.16-1.45(m,20H),2.15(m，2H)，2.20(m，2H)3.21(p,1H),3.58(m,2H)，4.24(m，H)4.62(d,2H),5.43-5.46(m，2H)，7.28-7.32(m,5H)
6. Synthesis of Compound 7a from Compound 6a
The synthetic route is as follows:
Figure BDA0003759738180000232
the specific synthesis steps are as follows: anhydrous Tetrahydrofuran (THF) (250 ml) was used as solvent, added to a 500 ml three-necked flask, cooled to-30 ℃, and diethyl zinc (DEZ) solution (15.4 g,124.9 mmol), dimethyl ether (DME) (5.8 g,124.9 mmol), diiodomethane (CH) were sequentially added at controlled temperature 2 I 2 ) (33.5 g,124.9 mmol) was added dropwise to anhydrous tetrahydrofuran while keeping the reaction temperature between-25℃and-10℃and, after the addition, compound 6a (9.0 g,24.98 mmol) was added, warmed to room temperature, quenched with saturated ammonium chloride, extracted 2X 100mL with ethyl acetate, washed with 100mL of water, separated, dried, filtered, concentrated under reduced pressure at 30-40℃and purified by silica gel chromatography to give 8.2g of the product. Yield: 88.0%.
1 H-NMR(400MHz，CDCl 3 )δ：0.23-0.31(m，2H)，0.43-0.46(m，1H)，0.59-0.62(m，1H)，0.88(m，3H)，1.18-1.52(m，22H)，2.19(m，2H)，3.27(m，1H)，3.80(m，2H)，4.62(m，2H)7.31-7.33(m，5H)，9.71(d，1H)
7. Synthesis of Compound 8a from Compound 7a
The synthetic route is as follows:
Figure BDA0003759738180000241
the specific synthesis steps are as follows: compound 7a (8.0 g,21.37 mmol) was added to a 500 ml three-port flask, 100ml acetonitrile (MeCN) was added, 0.22g Tetramethylpiperidine (TEMPO) was added to the reaction flask, then 150 ml (0.67 m, ph=6.7) sodium dihydrogen phosphate/sodium hydrogen phosphate buffer was added, the temperature was raised to 30 ℃,30 ℃, sodium chlorite (4.38 g,48.43mmol, dissolved in 20ml water) was added, and 1ml 2.52% sodium hypochlorite was added. Stirring for 2 hours, cooling to 0 ℃, quenching with saturated sodium sulfite solution, adding 200ml of methyl tertiary butyl ether into the system for extraction, separating liquid, adjusting the pH value of the organic phase to be 2-4 by using 2.0N hydrochloric acid, washing the organic phase with water, separating liquid, filtering, drying, concentrating the organic phase at 30-40 ℃ under reduced pressure to obtain 7.3g of compound 8a, and obtaining the yield of 84.9%.
1 H-NMR(400MHz，CDCl 3 )δ：0.26(m，2H)，0.48(m，1H)，0.70(d，1H)，0.82(t，3H)，1.19-1.46(m，22H)，2.21(d，2H)，3.29(m，1H)，4.63(s，2H)，7.26-7.33(m，5H),11.02(s，1H)
8. Synthesis of Compound 9b from Compound 8a
The synthetic route is as follows:
Figure BDA0003759738180000242
the specific synthesis steps are as follows: compound 8a (7 g,18.02 mmol) was added to a 250 ml three-necked flask, methylene chloride (35 ml) was added to the reaction flask, 4-Dimethylaminopyridine (DMAP) (4.4 g) and t-butanol (tBuOH) (6.7 g,90.40 mmol) were added, the reaction system was cooled to about 10℃and Dicyclohexylcarbodiimide (DCC) (4.5 g in 40ml of methylene chloride) was added dropwise. After the completion of the dropwise addition, the mixture was warmed to room temperature and stirred at room temperature for 4 hours, 35ml of methylene chloride and 2ml of water were added to the system, stirred for 3 hours, filtered, and the filtrate was concentrated at 30 to 40 ℃, and 6.5g of compound 9b was purified by silica gel chromatography (n-heptane: ethyl acetate=100:1 to 40:1), yield: 84.0%.
1 H-NMR(400MHz，CDCl 3 )δ：0.21(m，2H)，0.45(m，1H)，0.64(m，1H)，0.88(t，3H)，1.19-1.44(m，31H)，2.03(m，2H)，3.28(m，1H)，4.62(s，2H)，7.28-7.32(m，5H)。
9. Synthesis of Compound 10b from Compound 9b
The synthetic route is as follows:
Figure BDA0003759738180000251
the specific synthesis steps are as follows: compound 9b (4.0 g,9.0 mmol) was added to a 200 ml autoclave, methanol (100 ml) was added, 1.0g of 10% palladium on carbon (Pd/C) catalyst was replaced with hydrogen for 3 times, the temperature was controlled at 40-50℃and hydrogen was introduced for 4 hours, the mixture was cooled to room temperature and then filtered, and the filtrate was concentrated under reduced pressure at 30-40℃to give 2.9g of compound 10b in a yield of 90.9%.
1 H-NMR(400MHz，CDCl 3 )δ：0.22(m，2H)，0.48(m，1H)，0.69(m，1H)，0.86(t，3H)，1.21-1.47(m，31H)，1.92-2.14(m，2H)，3.42(m，1H)，4.82(m，H)
10. Synthesis of Compounds of formula (Ib)
The synthetic route is as follows:
Figure BDA0003759738180000252
The specific synthesis steps are as follows: compound 10b (2.0 g, 6.640 mmol) was added to a 100 mL three-necked flask, dichloromethane (30 mL) was added, pyridine (4.46 g) was added, methanesulfonyl chloride (MsCl) (0.97 g, 8.4638 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (n-heptane: ethyl acetate=100:1 to 20:1) to obtain 1.8g of a product with a yield of 77.8%.
1 H-NMR(400MHz，CDCl 3 )δ：0.26(m，2H)，0.55(m，1H)，0.74(m，1H)，0.88(t，3H)，1.22-1.46(m，27H)，1.62-1.72(m，4H)，2.17(m，2H)，3.12(s，3H)，4.65(m，1H)。
MS：[M+H] + ＝433.66，[M+Na] + ＝455.3
In summary, the overall yield of this route is the multiplication of the yields per step:
75.3％*81.1％*88.1*82.1％*80.6％*88.0％*84.9％*84.0％*90.9％*77.8％＝15.8％。
although described above in connection with the embodiments of the present application, the present application is not limited to the specific embodiments and fields of application described above, which are intended to be illustrative, instructive, and not limiting. Those skilled in the art, having the benefit of this disclosure, may make numerous forms, and equivalents thereof, without departing from the scope of the invention as defined by the claims.

Claims (40)

1. A method of synthesizing a compound of formula (I) using compound 7, wherein the compound of formula (I) is as follows:
Figure QLYQS_1
wherein R represents C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl; x is sulfonyl;
compound 7 is shown below:
Figure QLYQS_2
wherein Pg represents a protecting group;
the method comprises the step of converting compound 6 into compound 7 by a cyclization reaction:
Figure QLYQS_3
step of deprotection conversion of compound 5 to compound 6:
Figure QLYQS_4
step of converting compound 4 into compound 5 by reduction reaction:
Figure QLYQS_5
step of converting compound 3 into compound 4 by substitution reaction:
Figure QLYQS_6
step of converting compound 2 into compound 3 by an Appel reaction:
Figure QLYQS_7
/>
step of converting compound 1 into compound 2 via Brown borohydride-oxidation:
Figure QLYQS_8
comprising the step of oxidizing compound 7 to compound 8:
Figure QLYQS_9
comprising the step of esterifying compound 8 to give compound 9:
Figure QLYQS_10
step of removing the protecting group from compound 9 to obtain compound 10:
Figure QLYQS_11
2. the process according to claim 1, wherein R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, cyclopropyl, and cyclopentyl.
3. The process according to claim 2, wherein R is tert-butyl.
4. The method according to claim 1, wherein X is selected from the group consisting of methanesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl.
5. The method according to claim 4, wherein X is methanesulfonyl.
6. The process according to claim 1, wherein Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl.
7. The method of claim 6, wherein Pg is benzyl.
8. The process according to claim 1, wherein the cyclisation reaction is carried out with a cyclisation reagent selected from the group consisting of: zinc diiodomethyl, (iodomethyl) potassium trifluoroborate, chloroiodomethane and diiodomethane.
9. The method of claim 8, wherein the cyclizing reagent is diiodomethane.
10. The process according to claim 1, wherein the cyclisation reaction is carried out in a reagent selected from the group consisting of: n-hexane, dichloromethane, tetrahydrofuran, dichloroethane, toluene, diethyl ether and 1, 4-dioxane.
11. The method of claim 10, wherein the reagent is tetrahydrofuran.
12. The method according to claim 1, wherein the deprotection reaction is performed using a reagent selected from the group consisting of: sulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, boron trifluoride etherate, acetic acid, phosphoric acid or formic acid.
13. The method of claim 12, wherein the reagent is p-toluene sulfonic acid.
14. The method of claim 1, wherein during the step of oxidizing compound 7 to compound 8, the oxidation reaction is performed using an oxidizing agent selected from the group consisting of: sodium chlorite and potassium permanganate.
15. The method of claim 14, wherein the oxidation reaction temperature is 10-50 ℃.
16. The process of claim 1, further comprising the step of sulfonylating compound 10 to provide a compound of formula (I):
Figure QLYQS_12
17. the method of claim 1, wherein the molar ratio of compound 4 to reducing agent is 1:1.0 to 1:4.0.
18. The method of claim 17, wherein the reducing agent is lithium aluminum tetrahydroide.
19. The method according to claim 1, wherein in the step of converting compound 3 into compound 4 by a substitution reaction, compound 3 is substituted with 2- (4-pentynoxy) tetrahydro-2H-pyran.
20. The method of claim 19, wherein the molar ratio of compound 3 to 2- (4-pentynoxy) tetrahydro-2H-pyran is from 1:1.0 to 1:3.0.
21. The method of claim 19, further comprising adding a deprotonating agent to the reaction process, the deprotonating agent used being selected from the following strongly basic agents: naH, KH, lithium amide or n-butyllithium.
22. The method of claim 21, wherein the deprotonating agent is n-butyllithium.
23. The method of claim 1, wherein in the step of converting compound 2 into compound 3 by an Appel reaction, the Appel reaction is performed using a halogenating reagent selected from the group consisting of: methyl iodide or elemental iodine.
24. The method of claim 23, wherein the halogenating agent is elemental iodine.
25. The method of claim 23, wherein the molar ratio of compound 2 to halogenating agent is from 1:1.0 to 1:2.0.
26. The method of claim 1, wherein the Brown borohydride-oxidation reaction is performed using a reagent selected from the group consisting of:
the reagent is selected from diglyme, tetrahydrofuran, diethyl ether or 1, 4-dioxane.
27. The method of claim 26, wherein the reagent is tetrahydrofuran.
28. The method of claim 26, wherein the oxidizing agent in the oxidation reaction is selected from m-chloroperoxybenzoic acid, peroxyacetic acid, hydrogen peroxide, peroxytrifluoroacetic acid, or peroxybenzoic acid.
29. The method of claim 28, wherein the oxidizing agent is hydrogen peroxide.
30. The method of claim 28, wherein the molar ratio of compound 1 to oxidant is 1:3.0 to 1:8.0.
31. A method of synthesizing a compound of formula (I) using compound 1, comprising the steps of:
the compounds of formula (I) are shown below:
Figure QLYQS_13
wherein R represents C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl;
x is sulfonyl;
pg represents a protecting group;
Figure QLYQS_14
32. the method of claim 31, wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, cyclopropyl, or cyclopentyl.
33. The method of claim 32, wherein R is tert-butyl.
34. The method of claim 31, wherein X is selected from the group consisting of methanesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl.
35. The method of claim 34, wherein X is methanesulfonyl.
36. The method of claim 31, comprising the steps of:
Figure QLYQS_15
37. the method of claim 31, comprising the steps of:
Figure QLYQS_16
38. a method of synthesizing compound 7 using compound 1 comprising the steps of: compound 7 is shown below:
Figure QLYQS_17
wherein Pg represents a protecting group,
Figure QLYQS_18
39. the method of claim 38, wherein Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl.
40. A process as set forth in claim 39 wherein Pg is benzyl.
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