WO2023143402A1 - 甾类化合物、其制备方法和应用 - Google Patents

甾类化合物、其制备方法和应用 Download PDF

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WO2023143402A1
WO2023143402A1 PCT/CN2023/073240 CN2023073240W WO2023143402A1 WO 2023143402 A1 WO2023143402 A1 WO 2023143402A1 CN 2023073240 W CN2023073240 W CN 2023073240W WO 2023143402 A1 WO2023143402 A1 WO 2023143402A1
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independently
alkyl
cycloalkyl
cyclopenta
membered heterocycloalkyl
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French (fr)
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刘金镖
唐静洁
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珂阑(上海)医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a steroid compound, its preparation method and application.
  • lipid synthesis pathway in mammalian cells is an important factor in regulating the balance of lipid metabolism.
  • the key factor regulating the synthesis of cholesterol and fatty acid is a kind of transcription factor protein sterol response element binding protein SREBP (Sterol-Regulatory Element Binding Protein).
  • the precursor of this type of protein is first synthesized on the endoplasmic reticulum (ER), and the precursor is transported to the Golgi apparatus through SREBP cleavage-activating protein (SCAP, SREBP cleavage-activating protein), and then passed through two proteases (Site-1protease (S1P ) and Site-2protease (S2P)) to release its N-terminal active domain, enter the nucleus to play the role of a transcription factor, bind to the SREBP response element (SRE) in the promoter region of the target gene, and initiate the expression of downstream genes.
  • SCAP SREBP cleavage-activating protein
  • S1P Site-1protease
  • S2P Site-2protease
  • SRE SREBP response element
  • the splicing and maturation of SREBP protein is strictly regulated by the level of intracellular sterols (such as cholesterol, 25-hydroxycholesterol).
  • statins and fibrates are the main lipid-lowering drugs in clinical practice.
  • the mechanism of action of statins is to inhibit the synthesis of cholesterol in cells while promoting the reverse transport of blood cholesterol. It shows that targeting the key factors in the lipid synthesis pathway of cells is an important means to effectively reduce the lipid level.
  • steatosis that may be caused by the accumulation of triglycerides in the form of lipid droplets, abnormally increased cholesterol and fatty acids in cells, which can cause endoplasmic reticulum stress and mitochondrial dysfunction, thereby Leads to cell death, inflammation and fibrosis.
  • free cholesterol accumulation has been reported as a key driver of the transition from pure steatosis to aggressive steatohepatitis.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • R 21 is -L 1 -C(O) RA , -L 1 -S(O) 2 R A , -L 1 -R B , -L 2 -R C or -L 3 -R D ;
  • Each of L 1 and L 2 is independently a single bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, or -(CH 2 ) 6 -, wherein -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 - and -( One of the -CH 2 - moieties in CH 2 ) 6 - is optionally replaced by -X-;
  • L 3 is -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 - or -(CH 2 ) 6 -, wherein -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 - and -(CH 2 ) 6 -, one of the -CH 2 - moiety is replaced by -Y-;
  • Each X is independently -CHR 5a -, -CR 5a R 5b -, C 3-6 cycloalkyl, C 3-6 oxacycloalkyl, C 3-6 azacycloalkyl or -Y-;
  • each R 5a and R 5b is independently F or fluoroC 1-4 alkyl
  • R g is -C 1-4 alkylene-OH
  • each RA is independently -NR 21a R 21b ;
  • R B is -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O) 2 R 21b ;
  • RD is -OH, -CH 2 OH, R C , -CH(CH 3 )-OH or -C(CH 3 ) 2 -OH;
  • Each R C is independently -C(R 21c )(R 21d )-OH, -C(R 21c )(R 21d )-CN, CN, -C(O) RE , NH 2 , C 1-4 alkoxy, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl; the 5-10 membered heteroaryl is unsubstituted or substituted by p R c ;
  • R E is C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; wherein said C 1-4 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl is independently unsubstituted or substituted by m R a ;
  • Each R 21a is independently H, C 1-6 alkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl and 3-6 membered heterocycloalkyl are independently unsubstituted or replaced by m R a ;
  • Each R 21b is independently H, C 1-6 alkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted by q R b ;
  • each m, p and q is independently 1, 2, 3, 4 or 5;
  • R a , R b and R c is independently F, Cl, OH, COOH, CN, NO 2 , C 1-4 alkyl, fluoro C 1-4 alkyl, C 1-4 alkoxy ,
  • R 21c is H, F, C 1-4 alkyl, fluoro C 1-4 alkyl, C 2-4 alkenyl or C 3-6 cycloalkyl;
  • R 21d is F, C 2-4 alkyl, fluoro C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 members Heteroaryl or -L 4 -R 21e , wherein the phenyl and 5-6 membered heteroaryl are independently unsubstituted or substituted by j R d ;
  • L 4 is methylene or ethylene
  • R 21e is OH, CN, C 1-4 alkoxy, phenyl or 5-6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl are independently unsubstituted or replaced by j R d replaces;
  • each j is independently 1, 2, 3 or 4;
  • each r is independently 0, 1, 2, 3 or 4;
  • Each R d and R f is independently F, Cl, OH, CN, NO 2 , C 1-4 alkyl, fluoro C 1-4 alkyl, fluoro C 1-4 alkoxy or C 1- 4 alkoxy;
  • heteroatoms in the heterocycloalkyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S;
  • the carbon atom marked with * in formula I is in S configuration, R configuration or a mixture of both.
  • certain groups in the compound shown in formula I or a pharmaceutically acceptable salt thereof are defined as follows, and the unmentioned groups are the same as described in any scheme of the present invention (abbreviated as "in some embodiments” or “in some preferred embodiments”).
  • R 21 is -L 1 -C(O) RA , -L 1 -S(O) 2 R A , -L 1 -R B , -L 2 -R C or -L 3 -R D ;
  • Each of L 1 and L 2 is independently a single bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, or -(CH 2 ) 6 -, wherein -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 - and -( One of the -CH 2 - moieties in CH 2 ) 6 - is optionally replaced by -X-;
  • L 3 is -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 - or -(CH 2 ) 6 -, wherein -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 - and -(CH 2 ) 6 -, one of the -CH 2 - moiety is replaced by -Y-;
  • each X is independently -CHR 5a -, -CR 5a R 5b -, or -Y-;
  • Each R 5a and R 5b is independently F, C 1-4 alkyl or fluoro C 1-4 alkyl;
  • R g is -C 1-4 alkylene-OH
  • each RA is independently -NR 21a R 21b ;
  • RB is -N(R 21a )-C(O)R 21b ;
  • RD is -OH, -CH 2 OH, R C , -CH(CH 3 )-OH or -C(CH 3 ) 2 -OH;
  • Each R C is independently -C(R 21c )(R 21d )-OH, CN, -C(O) RE , NH 2 , C 1-4 alkoxy, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl; the 5-10 membered heteroaryl is unsubstituted or substituted by p R c ;
  • R E is C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; wherein said C 1-4 alkyl, C 1-4 alk Oxygen, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are independently unsubstituted or substituted by m R a ;
  • Each R 21a is independently H, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are independently unsubstituted or substituted by m R a ;
  • Each R 21b is independently H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein The C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are independently unsubstituted or replaced by q R b replaces;
  • each m, p and q is independently 1, 2, 3, 4 or 5;
  • R a , R b and R c is independently F, Cl, OH, COOH, CN, NO 2 , C 1-4 alkyl, fluoro C 1-4 alkyl, C 1-4 alkoxy ,
  • R 21c is H, F, C 1-4 alkyl, fluoro C 1-4 alkyl, C 2-4 alkenyl or C 3-6 cycloalkyl;
  • R 21d is F, C 2-4 alkyl, fluoro C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl or -L 4 -R 21e , wherein the phenyl and 5-6 membered heteroaryl are independently unsubstituted or substituted by j R d ;
  • L 4 is C 1-4 alkylene
  • R 21e is OH, CN, C 1-4 alkoxy, phenyl or 5-6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl are independently unsubstituted or replaced by j R d replaces;
  • each j is independently 1, 2, 3 or 4;
  • each r is independently 0, 1, 2, 3 or 4;
  • Each R d and R f is independently F, Cl, OH, CN, NO 2 , C 1-4 alkyl, fluoro C 1-4 alkyl or C 1-4 alkoxy;
  • heteroatoms in the heterocycloalkyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S;
  • the carbon atom marked with * in formula I is in S configuration, R configuration or a mixture of both.
  • R 21 is -L 1 -C(O) RA , -L 1 -S(O) 2 R A , -L 1 -R B , -L 2 -R C or -L 3 -R D ;
  • Each of L 1 and L 2 is independently a single bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, or -(CH 2 ) 6 -, wherein -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 - and -( One of the -CH 2 - moieties in CH 2 ) 6 - is optionally replaced by -X-;
  • L 3 is -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 - or -(CH 2 ) 6 -, wherein -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 - and -(CH 2 ) 6 -, one of the -CH 2 - moiety is replaced by -Y-;
  • each X is independently -CHR 5a -, -CR 5a R 5b -, or -Y-;
  • Each R 5a and R 5b is independently F, C 1-4 alkyl or fluoro C 1-4 alkyl;
  • R g is -C 1-4 alkylene-OH
  • each RA is independently -NR 21a R 21b ;
  • R B is -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O) 2 R 21b ;
  • RD is -OH, -CH 2 OH, R C , -CH(CH 3 )-OH or -C(CH 3 ) 2 -OH;
  • Each R C is independently -C(R 21c )(R 21d )-OH, CN, -C(O) RE , NH 2 , C 1-4 alkoxy, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl; the 5-10 membered heteroaryl is unsubstituted or substituted by p R c ;
  • R E is C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; wherein said C 1-4 alkyl, C 1-4 alk Oxygen, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are independently unsubstituted or substituted by m R a ;
  • Each R 21a is independently H, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are independently unsubstituted or substituted by m R a ;
  • Each R 21b is independently H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein The C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are independently unsubstituted or replaced by q R b replaces;
  • each m, p and q is independently 1, 2, 3, 4 or 5;
  • R a , R b and R c is independently F, Cl, OH, COOH, CN, NO 2 , C 1-4 alkyl, fluoro C 1-4 alkyl, C 1-4 alkoxy ,
  • R 21c is H, F, C 1-4 alkyl, fluoro C 1-4 alkyl, C 2-4 alkenyl or C 3-6 cycloalkyl;
  • R 21d is F, C 2-4 alkyl, fluoro C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl or -L 4 -R 21e , wherein the phenyl and 5-6 membered heteroaryl are independently unsubstituted or substituted by j R d ;
  • L 4 is C 1-4 alkylene
  • R 21e is OH, CN, C 1-4 alkoxy, phenyl or 5-6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl are independently unsubstituted or replaced by j R d replaces;
  • each j is independently 1, 2, 3 or 4;
  • each r is independently 0, 1, 2, 3 or 4;
  • Each R d and R f is independently F, Cl, OH, CN, NO 2 , C 1-4 alkyl, fluoro C 1-4 alkyl or C 1-4 alkoxy;
  • heteroatoms in the heterocycloalkyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S;
  • the carbon atom marked with * in formula I is in S configuration, R configuration or a mixture of both.
  • R 21 is -L 1 -C(O) RA , -L 1 -R B , -L 2 -R C or -L 3 -R D .
  • L 1 is a single bond, -CH 2 -, -(CH 2 ) 2 - or -(CH 2 ) 3 -.
  • each R 21a is independently H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or Substituted by m R a ; each R 21b is independently H, C 1-6 alkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted by q R b ; or, in -NR 21a In R 21b , R 21a and R 21b and the nitrogen atoms connecting them together form a 3-10 membered heterocycloalkyl group, wherein the 3-10 membered heterocycloalkyl group is unsubstituted or substituted by p R c .
  • each m, p and q are independently 1 or 2.
  • L 2 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 - or -(CH 2 ) 4 -; wherein one of the -CH 2 - moieties of -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 - and -(CH 2 ) 4 - is optionally replaced by -X- ; each Each X is independently -CHR 5a -, each R 5a and R 5b is independently F; preferably, L 2 is -(CH 2 ) 3 -.
  • each R C is independently -C(R 21c )(R 21d )-OH, CN, -C(O) RE , NH 2 , C 1-4 alkoxy, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl; said 5-10 membered heteroaryl is unsubstituted or substituted by p R c .
  • R 21c is H or C 1-4 alkyl
  • R 21d is F, C 2-4 alkyl, fluoro C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl or -L 4 -R 21e , wherein the phenyl and 5 -6-membered heteroaryl is independently unsubstituted or substituted by j Rd ; alternatively, R 21c and R 21d and the carbon atoms connecting them together form C 3-6 cycloalkyl or 3-6 membered heterocycloalkane base.
  • R is independently F, Cl, OH, CN, C 1-4 alkyl, fluoroC 1-4 alkyl, fluoroC 1-4 alkoxy, or C 1-4 alkane Oxygen.
  • R E is C 1-4 alkyl or C 3-6 cycloalkyl.
  • R D is -OH, -CH 2 OH or -C(CH 3 ) 2 -OH.
  • each j is 1 or 2 independently in the compound represented by formula I as described in any one of the preceding schemes.
  • each r is independently 0.
  • each X is independently -CHR 5a - or -CR 5a R 5b -, for example -CHR 5a -.
  • L 1 is a single bond.
  • L 1 is -(CH 2 ) 2 - or -CH 2 -CHR 5a -.
  • each R 5a and R 5b is independently F, methyl, ethyl or trifluoromethyl.
  • L 1 is -(CH 2 ) 3 -.
  • L 1 is -(CH 2 ) 4 -.
  • L 1 is -(CH 2 ) 5 -.
  • L 1 is -(CH 2 ) 6 -.
  • R 21 is -L 1 -C(O) RA .
  • R 21 is -L 1 -S(O) 2 R A .
  • R 21 is -L 1 -R B .
  • each R 21a is independently H, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1- 6 alkyl and C 3-6 cycloalkyl are independently unsubstituted or substituted with m R a .
  • m is 1, 2 or 3 in the compound represented by formula I as described in any of the preceding schemes.
  • each R a is independently F, OH, CN or methoxy.
  • each R 21a is independently H, C 1-4 alkyl, -C 1-4 alkylene-OH, -C 1 -4 alkylene-OC 1-4 alkyl, fluoro C 1-4 alkyl or cyclopropyl.
  • each R 21a is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, Cyclopropyl or trifluoromethyl.
  • each R 21b is independently H, C 1-6 alkyl, C 6-10 aryl or 5-10 membered heteroaryl , wherein the C 1-6 alkyl, C 6-10 aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted by q R b .
  • each R 21b is independently H, -C 1-4 alkylene-OH, -C 1-4 alkylene-OC 1-4 alkyl, fluoro C 1-4 alkyl, tetrahydromorpholinyl, phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole Base, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl or benzopyrazolyl, wherein said phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazole
  • each R 21b is independently H, -C 1-4 alkylene-OH, -C 1-4 alkylene-OC 1-4 alkyl, fluoro C 1-4 alkyl, tetrahydromorpholinyl, phenyl, Wherein the phenyl, are independently unsubstituted or substituted with q R b .
  • q is 1, 2 or 3 in the compound represented by formula I as described in any of the preceding schemes.
  • each R b is independently F, Cl, OH, COOH, CN, NO 2 , methyl, trifluoromethyl, methoxy base,
  • each R 21b is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, phenyl,
  • each R 21b is independently
  • p is 1, 2 or 3 in the compound represented by formula I as described in any of the preceding schemes.
  • each R c is independently F, OH, CN, C 1-4 alkyl or fluoro C 1-4 alkyl.
  • each R c is independently F, OH, CN, methyl or trifluoromethyl.
  • each R A is independently -NH 2 ,
  • each RA is independently
  • each R A is independently
  • R B is
  • R B is
  • R 21 is -L 2 -R C .
  • L 2 is a single bond.
  • L 2 is -CH 2 -.
  • L 2 is -(CH 2 ) 2 -.
  • L 2 is -(CH 2 ) 3 -.
  • L 2 is -(CH 2 ) 4 -.
  • L 2 is -(CH 2 ) 5 -.
  • L 2 is -(CH 2 ) 6 -.
  • each R C is independently -C(R 21c )(R 21d )-OH.
  • R C is -C(R 21c )(R 21d )-OH
  • R 21c is H
  • R 21d is C 2-4 Alkyl, fluoro C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, fluorophenyl, 5-6 membered heteroaryl or -L 4 -R 21e .
  • R C is -C(R 21c )(R 21d )-OH
  • R 21c is H
  • R 21d is C 2-4 Alkyl, fluoro C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl or -L 4 -R 21e , wherein, phenyl is optionally replaced by 1 or 2 Rd is substituted, each Rd is independently F, OH, CN or C1-4 alkoxy.
  • L 4 is methylene or ethylene.
  • R 21e is OH, CN, C 1-4 alkoxy, phenyl or
  • R C is -C(R 21c )(R 21d )-OH
  • R 21c is F
  • R 21d is C 2-4 Alkyl (eg ethyl).
  • R C is -C(R 21c )(R 21d )-OH
  • R 21c is CH 3 or trifluoromethyl
  • R 21d is C 2-4 alkyl (eg ethyl) or trifluoromethyl.
  • R C is -C(R 21c )(R 21d )-OH
  • R 21c is C 2-4 alkyl, C 2 -4 alkenyl (for example ) or C 3-6 cycloalkyl (such as cyclopropyl)
  • R 21d is C 2-4 alkyl, C 2-4 alkenyl (such as ) or C 3-6 cycloalkyl (eg cyclopropyl).
  • R C is -C(R 21c )(R 21d )-OH
  • R 21c is ethyl, n-propyl, isopropyl base, Or cyclopropyl
  • R 21d is ethyl, n-propyl, isopropyl, or cyclopropyl.
  • R C is -C(R 21c )(R 21d )-OH
  • R 21c and R 21d and the carbon atoms connecting them are together Form C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl (such as ).
  • R C is -C(R 21c )(R 21d )-OH
  • R 21c and R 21d and the carbon atoms connecting them are together form cyclopropyl, cyclobutyl or
  • R C is CN
  • R C is -C(O) RE .
  • R E is C 1-4 alkyl or C 3-6 cycloalkyl.
  • RE is methyl, ethyl or cyclohexyl.
  • R C is NH 2 .
  • R C is C 1-4 alkoxy, such as methoxy.
  • R C is For example
  • R C is For example
  • R C is For example
  • R C is a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is unsubstituted or replaced by p R C replace.
  • R C is
  • R C is a 3-6 membered heterocycloalkyl group.
  • the 3-6 membered heterocycloalkyl group in the definition of R C is
  • R 21 is -L 3 -RD .
  • L 3 is The b-terminus of the above structure is connected with RD .
  • R D is -OH, -CH 2 OH, -CH( CH3 )-OH or -C( CH3 ) 2 -OH.
  • R 21 is
  • R 21 is
  • R 21 is
  • R 21 is
  • R 21 is
  • R 21 is
  • the carbon atom marked with * in formula I is in S configuration.
  • the carbon atom marked with * in formula I is in R configuration.
  • the compound shown in formula I is the compound shown in the following formula I-1 or I-2:
  • R21 is as described in any one of the present invention.
  • the compound shown in formula I is any of the following compounds:
  • the compounds of the present invention can be obtained by known raw materials (such as lanosterol) through various conventional reaction methods in the art (such as hydroxyl protection, double bond ozonation, wittig reaction, hydrolysis reaction, amide condensation reaction, Grignard reagent addition reaction, reduction reaction) , nucleophilic substitution reaction, epoxidation reaction) to obtain. Exemplary preparation methods are described in the preparation examples of this application.
  • the preparation method of compound 37 and its analogs can be lanosterol as a starting material, after hydroxyl protection, double bond ozonation, wittig reaction, hydrolysis, condensation to obtain compound 37 and its analogs;
  • the reaction scheme is as follows:
  • the preparation method of compound 101 and its analogs can be lanosterol as a starting material, through hydroxyl protection, double bond ozonation, wittig reaction, hydrolysis, Grignard reagent addition reaction to obtain compound 101 and its analogs; the reaction scheme is as follows Show:
  • the preparation method of compound 80 and its analogs can use lanosterol as a raw material, through hydroxyl protection, double bond ozonation, reduction, two-step substitution, and addition reaction to obtain compound 80 and its analogs;
  • the reaction scheme is as follows:
  • the preparation method of compound 125 and its analogs can use lanosterol as a raw material, through hydroxyl protection, double bond ozonation, wittig reaction, hydrolysis, epoxidation, and hydrolysis to finally obtain compound 125 and its analogs;
  • the reaction scheme is as follows :
  • the preparation method of compound 193 and its analogues can use lanosterol as a starting material, undergo hydroxyl protection, double bond ozonation, double bond displacement, double bond ozonation, reductive amination, condensation, hydrolysis, to obtain compound 193 .
  • the reaction scheme of the preparation method is shown in the figure below:
  • the preparation method of compound 199 and its analogues uses (22E,24S)-stigmaster-6(5),22(23)-diene-3 ⁇ -alcohol as starting material, after hydroxyl protection, double bond ozone Oxidation, Wittig reaction, hydrolysis, Wittig reaction, double bond reduction, addition of organolithium reagents, and epoxidation gave product 199.
  • the reaction scheme of the preparation method is shown in the figure below:
  • the present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.
  • the present invention also provides an application of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disease, wherein the disease is obesity , hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer or skin damage.
  • the present invention also provides an application of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a medicament for inhibiting SREBP pathway.
  • the present invention also provides a method for inhibiting SREBP pathway, which comprises administering to a subject an effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for preventing and/or treating a disease, which comprises administering to a subject an effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the disease is obesity, hyperlipidemia , fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer or skin damage.
  • substituted or “substituent” is a group in which a hydrogen atom is replaced by the indicated group. when no replacement position is specified When , substitutions can be at any position, but are only permitted if they result in a stable or chemically feasible chemical compound. Examples are as follows: The structure indicates that the hydrogen atom on the benzene ring is replaced by q R 8 , and when there are multiple R 8 , each R 8 is the same or different.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • the linking direction can be arbitrary, including both left-to-right connection and right-to-left connection.
  • the linking group L in -A-L-B is -C-D-.
  • -A-L-B includes -A-C-D-B and -A-D-C-B.
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon group.
  • C 1 -C 6 alkyl represents an alkyl group having 1 to 6 carbon atoms.
  • the C 1 -C 6 alkyl group can be a C 1 -C 4 alkyl group.
  • C 1 -C 4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
  • alkenyl refers to a linear or branched monovalent hydrocarbon group containing at least one carbon-carbon double bond. When the alkenyl group contains saturated carbon atoms and unsaturated carbon atoms, it can be connected to other structures through saturated carbon atoms, and can also be connected to other structures through unsaturated carbon atoms.
  • C 2 -C 4 alkenyl denotes alkenyl having 2, 3 or 4 carbon atoms. Specific examples of alkenyl include, but are not limited to vinyl, allyl.
  • alkylene refers to a saturated linear or branched divalent hydrocarbon group.
  • C 1 -C 4 alkylene refers to an alkylene group having 1-4 carbon atoms, specifically methylene, ethylene (eg -CH 2 CH 2 -, -CH(CH 3 )-), Propylene (eg -CH 2 CH 2 CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH(CH 3 )-), butylene (eg -CH 2 CH 2 CH 2 CH 2 -, - CH( CH3 )CH( CH3 )-, -CH2CH ( CH3 ) CH2- ).
  • fluoroalkyl refers to a group formed by replacing one or more hydrogen atoms in the alkyl group with fluorine, wherein the definition of the alkyl group is as described above.
  • fluoroalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl.
  • alkoxy refers to -O-alkyl, wherein alkyl is as previously defined.
  • C 1 -C 4 alkoxy refers to -O-(C 1 -C 4 alkyl), wherein the definition of C 1 -C 4 alkyl is as described above, that is, C 1 -C 4 alkoxy can specifically be is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (eg fused, spiro or bridged) cyclic hydrocarbon group.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the C 3-10 cycloalkyl group can specifically be C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , or C 10 cycloalkyl group.
  • the C 3-6 cycloalkyl group can be C 3 , C 4 , C 5 , or C 6 cycloalkyl group.
  • cycloalkyl groups are monocyclic.
  • a cycloalkyl group is polycyclic (e.g., fused ring, spiro ring or bridge ring).
  • heterocycloalkyl refers to a saturated monocyclic or polycyclic (eg, fused, spiro, or bridged) cyclic group formed by carbon atoms and at least one heteroatom, wherein the heteroatoms are independently is selected from N, O and S. Heterocycloalkyl groups can be attached to other structures through ring carbon atoms and heteroatoms. Examples of heterocycloalkyl include, but are not limited to Tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl.
  • the 3-10 membered heterocycloalkyl group can specifically be 3, 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group.
  • the 3-6 membered heterocycloalkyl group can specifically be 3, 4, 5 or 6 membered heterocycloalkyl groups.
  • heterocycloalkyl is monocyclic.
  • a heterocycloalkyl is polycyclic (eg, fused, spiro, or bridged).
  • C 6-10 aryl refers to phenyl or naphthyl.
  • heteroaryl refers to an aromatic monocyclic or condensed ring group formed by carbon atoms and at least one heteroatom, wherein the heteroatoms are independently selected from N, O and S.
  • the 5-10 membered heteroaryl group can be 5, 6, 7, 8, 9 or 10 membered heteroaryl group, for example, 5-6 membered heteroaryl group or 8-10 membered heteroaryl group.
  • 5-6 membered heteroaryl is monocyclic, specific examples include but are not limited to pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine.
  • Examples of 8-10 membered fused heteroaryl groups include, but are not limited to, benzopyrrole, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzopyrazole , benzimidazole, benzopyridine, benzopyrimidine, benzopyrazine, thiazolothiazole, pyridopyridine, pyridopyrazine, pyridopyrimidine.
  • the chemical structure in the Indicates the connection location. when Included in a cyclic group and not specified When the attached ring atom, Attachment to any ring atom is possible, but is only permitted to form a stable or chemically viable chemical species. For example, include and other structures.
  • the term "pharmaceutically acceptable salt” means a salt formed with a compound from a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base, which retains the biological activity of the compound.
  • Described organic acid can be various organic acids that can form salt conventionally in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid , propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid, and salicylic acid.
  • the inorganic acid may be various inorganic acids conventional in the art capable of forming salts, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
  • the organic base can be various organic bases that are conventional in the art and can form salts, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines kind.
  • the tertiary amine organic base is preferably triethylamine and/or N,N-diisopropylethylamine.
  • the aniline organic base is preferably N,N-dimethylaniline.
  • the pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine.
  • Described inorganic base can be various inorganic bases that can form salt conventionally in the art, preferably alkali metal hydride, hydroxide of alkali metal, alkoxide of alkali metal, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate One or more of , potassium bicarbonate and sodium bicarbonate.
  • the alkali metal hydride is preferably sodium hydride and/or potassium hydride.
  • the hydroxide of the alkali metal is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • the alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide.
  • bonded with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter.
  • key configuration is not specified, i.e. if there is configurational isomerism in the chemical structure, the bond can be or both Two configurations (e.g. The ratio is 1:1).
  • the carbon-carbon double bond does not specify its specific configuration, it may be in E or Z configuration.
  • Stereoisomers can be prepared synthetically using chiral starting materials, by chiral resolution or can be resolved using conventional techniques such as, but not limited to, high performance liquid chromatography (HPLC) using chiral columns.
  • HPLC high performance liquid chromatography
  • the term "subject” includes any animal, preferably a mammal, more preferably a human.
  • the term "effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance.
  • the appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is: the present invention provides a class of novel compounds that have inhibitory activity on the SREBP pathway and can be used for the prevention and/or treatment of obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, Cardiovascular and cerebrovascular diseases, liver cancer, skin damage and other diseases.
  • Triester and cholesterol levels are an effective strategy for the prevention and/or treatment of metabolic disorders including fatty liver.
  • Figure 1 shows the results of 25-hydroxylanosterol inhibiting the weight gain of mice induced by AMLN diet.
  • Figure 2 is the effect of 25-hydroxylanosterol on the food intake of mice.
  • Figure 3 shows that 25-hydroxylanosterol reduces the content of total cholesterol in the blood of mice.
  • Fig. 4 shows that 25-hydroxylanosterol reduces the content of total triglyceride in blood of mice.
  • Figure 5 shows that 25-hydroxylanosterol reduces the content of total cholesterol in the liver of mice.
  • Figure 6 shows that 25-hydroxylanosterol reduces the content of total triglyceride in the liver of mice.
  • FIG. 7 shows that 25-hydroxylanosterol reduces blood aspartate aminotransferase (AST) levels in mice.
  • AST blood aspartate aminotransferase
  • Figure 8 shows that 25-hydroxylanosterol reduces blood alanine aminotransferase (ALT) levels in mice.
  • Figure 9 shows the HE staining results of mouse liver sections: C57BL/6J CD group.
  • Figure 10 is the HE staining results of mouse liver sections: Ldlr -/- CD group.
  • Figure 11 shows the HE staining results of mouse liver sections: Ldlr -/- AMLN group.
  • Fig. 12 is HE staining results of mouse liver sections: Ldlr -/- AMLN+25-HL group.
  • Figure 13 shows the results of HE staining and the integral quantitative statistics of NAFLD activity in the liver sections of the four groups of mice.
  • Figure 14 shows the oil red O staining results of mouse liver sections: C57BL/6J CD group.
  • Figure 15 is the oil red O staining results of mouse liver sections: Ldlr -/- CD group.
  • Figure 16 is the oil red O staining results of mouse liver sections: Ldlr -/- AMLN group.
  • Figure 17 is the oil red O staining results of mouse liver sections: Ldlr -/- AMLN+25-HL group.
  • Figure 18 shows the quantification results of oil red O staining of liver slices of mice in four groups.
  • Figure 19 shows the Sirius red staining results of mouse liver sections: C57BL/6J CD group.
  • Figure 20 is the results of Sirius red staining of mouse liver sections: Ldlr -/- CD group.
  • Figure 21 is the results of Sirius red staining of mouse liver sections: Ldlr -/- AMLN group.
  • Figure 22 is the results of Sirius red staining of mouse liver sections: Ldlr -/- AMLN+25-HL group.
  • Figure 23 is the quantification results of Sirius red staining in liver slices of mice in four groups.
  • Figure 24 shows the results of F4/80 immunostaining of mouse liver sections, and the imaging results of polarized light imaging indicating cholesterol crystals: C57BL/6J CD group.
  • Figure 25 shows the results of F4/80 immunostaining of mouse liver sections, and the imaging results of polarized light imaging indicating cholesterol crystals: Ldlr -/- CD group.
  • Figure 26 shows the F4/80 immunostaining results of mouse liver sections, and the imaging results of polarized light imaging indicating cholesterol crystals: Ldlr -/- AMLN group.
  • Figure 27 shows the results of F4/80 immunostaining of mouse liver sections, and the imaging results of polarized light imaging indicating cholesterol crystals: Ldlr -/- AMLN+25-HL group.
  • Figure 28 is the quantification results of F4/80 immunostaining of mouse liver sections in four groups.
  • Fig. 29 is the imaging quantification results of cholesterol crystals indicated by polarized light imaging of liver slices in four groups of mice.
  • Figure 30 is the staining results of the mouse aortic tree Sudan Red IV: C57BL/6J CD group.
  • Figure 31 shows the results of Sudan Red IV staining of mouse aortic tree: Ldlr -/- CD group.
  • Figure 32 shows the results of Sudan Red IV staining of mouse aortic tree: Ldlr -/- AMLN group.
  • Figure 33 shows the results of Sudan Red IV staining of mouse aortic tree: Ldlr -/- AMLN+25-HL group.
  • Figure 34 is the quantitative results of Sudan IV staining of the aortic tree of mice in 4 groups.
  • Figure 35 shows that 25-hydroxylanosterol reduces the expression of lipid production-related genes (Hmgcs, Hmgcr and SCD1, FASN) in liver organoids.
  • Figure 36 shows that 25-hydroxylanosterol reduces the expression of fibrosis-related genes (Col1a1, ⁇ SMA) in liver organoids.
  • Figure 37 is the bright field imaging results of mouse liver organoids: vehicle control group.
  • Figure 38 is the bright-field imaging results of mouse liver organoids: obeticholic acid 1 ⁇ M group.
  • Figure 39 is the bright-field imaging results of mouse liver organoids: obeticholic acid 3 ⁇ M group.
  • Figure 40 shows the bright-field imaging results of mouse liver organoids: 25-HL 1 ⁇ M group.
  • Figure 41 shows the bright-field imaging results of mouse liver organoids: 25-HL 3 ⁇ M group.
  • Figure 42 shows the results of Nile red staining of mouse liver organoids: vehicle control group.
  • Figure 43 shows the results of Nile red staining of mouse liver organoids: obeticholic acid 1 ⁇ M group.
  • Figure 44 shows the results of Nile red staining of mouse liver organoids: obeticholic acid 3 ⁇ M group.
  • Figure 45 shows the results of Nile Red staining of mouse liver organoids: 25-HL 1 ⁇ M group.
  • Figure 46 shows the results of Nile red staining of mouse liver organoids: 25-HL 3 ⁇ M group.
  • Figure 47 shows the quantification results of Nile red staining of mouse liver organoids in 5 groups.
  • Figure 48 is the results of immunofluorescent staining of fibrosis marker protein ⁇ SMA in mouse liver organoids: vehicle control group.
  • Figure 49 shows the results of immunofluorescent staining of fibrosis marker protein ⁇ SMA in mouse liver organoids: obeticholic acid 1 ⁇ M group.
  • Figure 50 shows the results of immunofluorescent staining of the fibrosis marker protein ⁇ SMA in mouse liver organoids: obeticholic acid 3 ⁇ M group.
  • Figure 51 shows the results of immunofluorescent staining of the fibrosis marker protein ⁇ SMA in mouse liver organoids: 25-HL 1 ⁇ M group.
  • Figure 52 shows the results of immunofluorescent staining of the fibrosis marker protein ⁇ SMA in mouse liver organoids: 25-HL 3 ⁇ M group.
  • Figure 53 is the quantitative results of immunofluorescent staining of the fibrosis marker protein ⁇ SMA in mouse liver organoids from five groups.
  • 25-hydroxylanosterol refers to the compound of Example 68.
  • mice Adult male C57BL/6J mice were purchased from Shanghai Slack Company, and low-density lipoprotein receptor knockout mice (Ldlr -/- mice, T001464) were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. The mice were all kept under the condition of no pathogenic source, kept under light/dark conditions for 12 hours, and had free access to water and feed.
  • the vehicle for intragastric administration is: 0.5% Tween-80, 0.5% methylcellulose, 0.9% sodium chloride.
  • AMLN feed (AMLN, Dyets) contains 40% (kcal percentage) fat (80% of which is trans fat), 22% (mass ratio) fructose and 2% (mass ratio) cholesterol.
  • Mevalonic acid (41288), paraformaldehyde (P6148), Tween-80 (P8074), methylcellulose (V900506), Oil Red O (O0625), and nuclear staining reagent DAPI were purchased from Sigma-Aldrich Company.
  • Lovastatin (purity ⁇ 98.5%, HPLC) was purchased from Shanghai Pharmaceutical Valley Company.
  • the dulbecco's modified eagle medium (DMEM) medium for cell culture was purchased from Thermo Scientific, and fetal bovine serum (S1580) was purchased from Biowest.
  • Lipoprotein-free serum (LPDS) was prepared by ultracentrifugation in our laboratory.
  • Obeticholic acid Obeticholic acid, OCA, CAS registration number 459789-99-2, purity 98% (HPLC).
  • Total cholesterol and total triglyceride kits were purchased from Shanghai Kehua Bioengineering Co., Ltd.
  • Alanine aminotransferase ( ALT) and aspartate aminotransferase (AST) kits were purchased from Lai Er Bio-tech company.
  • Hematoxylin-eosin staining kit (6765001, 6766010) was purchased from Thermo Scientific company. Sirius red staining kit (ab150681) was purchased from Abcam Company.
  • Sudan Red IV (A610914) was purchased from Sangon Bioengineering (Shanghai) Co., Ltd.
  • Nile Red (HY-D0718) was purchased from MCE Company.
  • Antibodies used for immunofluorescence staining analysis were as follows: anti-alpha smooth muscle Actin ( ⁇ SMA, ab7817, 1:500) antibody was purchased from Abcam; secondary antibody fluorescein (FITC)-coupled goat anti-mouse IgG (H+L ) (115-095-003) was purchased from Jackson Immunoresearch Company. Anti-F4/80 primary antibody (14-4801-85, Invitrogen, 1:100), fluorescent secondary antibody Alexa Fluor Plus 488-coupled goat anti-rat IgG (A-11006, 1:500) were purchased from Invitrogen.
  • ⁇ SMA anti-alpha smooth muscle Actin
  • FITC secondary antibody fluorescein-coupled goat anti-mouse IgG
  • H+L 115-095-003
  • Anti-F4/80 primary antibody 14-4801-85, Invitrogen, 1:100
  • fluorescent secondary antibody Alexa Fluor Plus 488-coupled goat anti-rat IgG A-11006, 1:500
  • the human hepatocellular carcinoma cell line Huh-7/SRE-Luc was grown in DMEM containing 10% fetal bovine serum, 100units/ml penicillin, 100 ⁇ g/ml streptomycin and 200 ⁇ g/ml G418 in the medium.
  • the Huh-7/SRE-Luc cell line is a human hepatocellular carcinoma cell line Huh-7 that stably expresses LDLR promoter-luciferase and green fluorescent protein (GFP).
  • the LDLR promoter region contains a sterol-regulatory-element (SRE), which can effectively and sensitively respond to the regulation of the transcription factor SREBP, and the GFP signal is used as an internal reference to indicate changes in cell number. Therefore, this cell line can be used to screen active small molecules that regulate the SREBP signaling pathway. In our work, this cell line is used to screen inhibitors that can effectively inhibit the SREBP signaling pathway.
  • SRE sterol-regulatory-element
  • the cells were incubated in a sterol-deficient medium (5% lipoprotein-free serum, 2 ⁇ M lovastatin, 10 ⁇ M mevalonic acid) and treated with corresponding concentrations of compounds for 16 hours. After compound treatment, cells were lysed with lysate (E397A, Promega), and after adding luciferase substrate (E1500, Promega), the activity of SRE-driven luciferase was detected by BioTek Synergy HTX microplate reader (including but not limited to A class of instruments) measurement. The fluorescence intensity of green fluorescent protein (EGFP) is also measured by the above-mentioned BioTek microplate reader (including but not limited to this type of instrument) and used as an internal reference. The ratio of SRE-driven luciferin activity divided by the fluorescence intensity of green fluorescent protein was used as an indicator of SREBP pathway activity. The test data of each test compound was analyzed by prism software to obtain the IC 50 parameter of the compound.
  • RNA template was used to synthesize cDNA with oligo dT primers and MLV reverse transcriptase (Promega).
  • the quantitative data of the gene was collected by Bio-Rad CFX96real-time PCR System, and the relative amount of gene mRNA was quantified by the relative CT method.
  • the primer sequences used are shown in the table below:
  • mice After the mice were treated with drugs, the mice were sacrificed after removing the feed and starved for 4 hours, and the blood and liver were collected. After coagulation, the blood was centrifuged at 1500g at 4°C for 10 minutes, and the supernatant was the serum. The lipids in the liver were extracted by the method of chloroform/methanol. First, the homogenate was crushed with a Precelly 24 homogenizer, and centrifuged at 16000g at 4°C for 10 minutes. The organic phase was transferred to a new tube, dried with nitrogen, and then dissolved in ethanol.
  • ALT and AST in the serum were respectively according to the manual of the corresponding manufacturer, using Sysmex Medical Electronics (Shanghai) Co., Ltd. The analysis system performs the measurement.
  • Hematoxylin-eosin staining the excised liver was fixed with 4% paraformaldehyde at 4°C, embedded in paraffin, sliced with a paraffin microtome (Leica RM2235) with a thickness of 7 ⁇ m, and used after dewaxing and rehydration. Hematoxylin-eosin staining kit (6765001, 6766010, Thermo Scientific) was used for staining, and images were taken with Olympus VS 120 slide microscope, and quantified with ImageJ software.
  • Oil red O staining the liver was embedded with OCT embedding medium (Leica), cut into 7 ⁇ m thick slices with a cryostat (Leica CM1950), and stained with Oil Red O (O0625, Sigma), and the images were taken with an Olympus VS120 slide microscope. And quantified by ImageJ software. Sirius Red (Sirius Red) collagen staining: After the paraffin sections of the liver were dewaxed and rehydrated, they were stained with the Sirius Red staining kit (ab150681, Abcam) according to the manufacturer's instructions.
  • Immunofluorescent staining the liver was embedded with OCT embedding medium (Leica), cut into 7 ⁇ m thick slices with a cryostat (Leica CM1950), and frozen sections were treated with anti-F4/80 rat monoclonal antibody (14-4801-85, Invitrogen, 1:100), Alexa Fluor 488-coupled goat anti-rat IgG secondary antibody (A-11006, Invitrogen, 1:500) stained, DAPI (Sigma) 30 specifically stained the nucleus. After staining and mounting, photographs were taken with a spinning disk confocal microscope (Nikon CSU-W1SoRa), and quantitative analysis was performed with ImageJ software. Polarized light imaging of cholesterol crystals: F4/F80 and DAPI stained frozen sections were photographed with a spinning disk confocal microscope (Nikon CSU-W1SoRa) equipped with a polarizing filter, and quantified with ImageJ software.
  • the aorta was isolated and fixed in 4% PFA, the perivascular adipose tissue was removed with ophthalmic forceps under a stereo microscope, stained with Sudan IV, and the atherosclerosis was cleaned with 70% ethanol plaque. After staining, the aortic tree was imaged with a ZEISS Axio Zoom.V16 stereomicroscope. Atherosclerotic lesions were quantified using ImageJ software.
  • C57BL/6N mice were fed fatty liver induction diet (TrophicDiet, TP2630052A, containing 10.2% kcal protein, 37.3% kcal carbohydrate, 52.6% kcal fat) and fructose-containing drinking water (23.1g fructose and 18.9 g glucose was dissolved in 1L water, and then filter sterilized) for a total of 16 weeks to generate a fatty liver model.
  • fatty liver induction diet TrophicDiet, TP2630052A, containing 10.2% kcal protein, 37.3% kcal carbohydrate, 52.6% kcal fat
  • fructose-containing drinking water 23.1g fructose and 18.9 g glucose was dissolved in 1L water, and then filter sterilized
  • liver tissue from fatty liver mice was minced and digested in digestion buffer at 37°C for 30-60 minutes.
  • Digestion buffer included DMEM/F-12 (Cytiva, SH30023.01) and 2.5 mg/mL collagenase D (Roche, COLLD-RO), 0.1 mg/mL DNaseI (Sigma-Aldrich, DN25). Separated single hepatocytes were filtered through a 70 ⁇ m filter membrane and washed once. The cells were collected by centrifugation, and the culture medium and basement membrane extract (BME) (R&D Systems, 3533-010-02) were mixed and resuspended at a ratio of 1:3.
  • BME culture medium and basement membrane extract
  • Medium includes AdDMEM/F12, 10mM Hepes, 1x Glutamax, 1% pen/strep, 1x B27, 1x N2, NAC (1mM), NIC (10mM), Gastrin (10nM), EGF (50ng/mL), In the culture conditions of FGF10 (100ng/mL), A83-01 (5 ⁇ M), Rki (10 ⁇ M), 10% RSPO1 conditioned medium, 30% Wnt3a conditioned medium, 5% Noggin conditioned medium. Before administration, organoids were digested with trypsin (Gibco, Cat#25200072) and resuspended. After 24 hours, using DMSO as a blank control, the organoids were replaced with media containing different concentrations of OCA or 25-HL. The fatty liver organoids were divided into 5 groups (1 ⁇ DMSO, 1 ⁇ M OCA, 3 ⁇ M OCA, 1 ⁇ M 25-HL and 3 ⁇ M 25-HL), and they were given drug treatment for 72 hours.
  • Organoids were fixed in immunostaining fixative (Beyotime Biotechnology, P0098) overnight at 4°C. They were then washed in PBS and treated with 0.5% Triton X-100 in PBS for 20 minutes at room temperature. Organoids were then treated with PBS blocking solution containing 10% goat serum for 1 hour at room temperature, and incubated with primary antibody (Anti-alpha smooth muscle Actin, ab7817, Abcam, 1:500 dilution) at 4°C overnight. The next day, the organoids were washed and incubated with the secondary antibody fluorescein (FITC)-conjugated goat anti-mouse IgG (H+L) (Jackson Immunoresearch, 115-095-003). Nuclei were counterstained with FluorShield TM and DAPI (Sigma-Aldrich, F6057).
  • FITC secondary antibody fluorescein
  • organoids were fixed with 4% paraformaldehyde (PFA) for 1 hour and stained with 250 nmol/L Nile Red (MCE, HY-D0718) for 3 minutes at room temperature. Rinse organoids twice with PBS before imaging. The stained organoids were observed under the Dragonfly high-speed confocal microscope system (Andor, Dragonfly 200).
  • PFA paraformaldehyde
  • the inhibitory effect of the compound of the present invention on the SREBP pathway was tested by the method of biological test example 2.
  • the concentration gradient of each compound was designed to be 0.01, 0.03, 0.1, 0.3, 1.0, 3.0, 10 ⁇ M, and the control was solvent DMSO.
  • the IC 50 values of some compounds are shown in Table 1.
  • the present invention further analyzes whether 25-hydroxylanosterol can slow down the typical symptoms of diet-induced fatty liver in mice: lipid accumulation, liver damage , inflammation and fibrosis.
  • mice 8-week-old male C57BL/6J mice and male Ldlr -/- mice (T001464, Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were purchased, grouped and fed with different feeds and given different drug treatments. The mice were randomly divided into 4 groups, 8-9 mice in each group: Group 1 was C57BL/6J wild-type mice fed basal diet (chow diet, CD) vehicle control group.
  • the other 3 groups are all Ldlr -/- gene knockout mice, which are basal diet (CD) vehicle control group, AMLN diet (AMLN diet, containing 20% fat, 22% fructose, 2% cholesterol) vehicle control group, AMLN diet Feed 25-hydroxylanosterol administration group (administration concentration of 25-hydroxylanosterol is 30 mg/kg/day).
  • CD basal diet
  • AMLN diet AMLN diet, containing 20% fat, 22% fructose, 2% cholesterol
  • AMLN diet Feed 25-hydroxylanosterol administration group administration concentration of 25-hydroxylanosterol is 30 mg/kg/day.
  • the mice in the four groups were gavaged once a day, and the changes in food intake and body weight of the mice in different treatment groups were counted during this period. After 8 weeks, the blood and liver of the mice were collected and analyzed for blood lipids, hepatic lipids, and the phenotype of liver injury.
  • Figures 1-8 The results are shown in Figures 1-8, wherein, Figure 1 is the statistical results of weekly weighing of mice in each group, Figure 2 is the cumulative statistics of food intake of mice in each group, and Figure 3 is the reduction in blood pressure of mice by 25-hydroxylanosterol.
  • the content of total cholesterol Fig. 4 is that 25-hydroxy lanosterol reduces the content of total triglycerides in mouse blood
  • Fig. 5 is that 25-hydroxy lanosterol reduces the content of mouse liver total cholesterol
  • Fig. 1 is the statistical results of weekly weighing of mice in each group
  • Figure 2 is the cumulative statistics of food intake of mice in each group
  • Figure 3 is the reduction in blood pressure of mice by 25-hydroxylanosterol.
  • the content of total cholesterol Fig. 4 is that 25-hydroxy lanosterol reduces the content of total triglycerides in mouse blood
  • Fig. 5 is that 25-hydroxy lanosterol reduces the content of mouse liver total cholesterol
  • the pathological features of fatty liver disease mainly include hepatic steatosis, liver injury, inflammatory infiltration and fibrosis.
  • Figures 9-29 show the results of F4/80 immunostaining and quantification of mouse liver sections, as well as the imaging and quantification results of polarized light imaging indicating cholesterol crystals: 25-hydroxylanosterol reduces the aggregation and accumulation of Kupffer cells in the liver Cholesterol crystal formation.
  • 25-hydroxylanosterol significantly reduced the crown structure formed by Kupffer cells, indicating that 25-hydroxylanosterol can significantly reduce the inflammatory infiltration of the liver.
  • the results of polarized light imaging of cholesterol crystals in liver slices showed that in vehicle control mice, the crown structure formed by Kupffer cells contained a large number of cholesterol crystals. These cholesterol crystals and the corona structure formed by Kupffer cells are hallmark features of fatty liver compared with pure steatosis. Macrophages are attracted to cholesterol crystals and attempt to clear these residual lipid droplets, similar to that described in atherosclerosis The phenomenon is similar. More importantly, 25-hydroxylanosterol significantly reduced the crown structure and the number of cholesterol crystals (Figs. 24-29).
  • AMLN-fed Ldlr -/- mice are also a commonly used model of atherosclerosis, so we can study fatty liver and atherosclerosis simultaneously.
  • Eight-week-old male Ldlr -/- mice were fed with AMLN diet and administered orally once a day for a total of 8 weeks. After the mice were sacrificed, the aortas were isolated and fixed with 4% paraformaldehyde. Perivascular adipose tissue was removed under a stereomicroscope, stained with Sudan Red IV, and rinsed with 70% ethanol. The aortic tree was imaged with a stereomicroscope (Zeiss, Germany, Axio Zoom Vl6). Quantitative analysis of atherosclerotic plaques was performed with ImageJ software.
  • Figures 30-34 are the staining and quantification results of the mouse aorta Sudan IV: 25-hydroxylanosterol reduces the formation of atherosclerotic plaques.
  • Figure 1-8 to Figure 9-34 show that 25-hydroxylanosterol reduces elevated blood lipid levels, reduces liver fat accumulation, cholesterol crystallization, hepatocyte injury, inflammatory infiltration and fibrosis, and reduces atherosclerotic plaque Block formation and number. It shows that 25-hydroxylanosterol has a good curative effect on hyperlipidemia, fatty liver and atherosclerosis.
  • liver organoids as an in vitro fatty liver research model to analyze the effects of 25-hydroxylanosterol on lipid production and expression of fibrosis marker molecules in liver organoids.
  • C57BL/6N mice with fatty liver induction diet (TrophicDiet, TP2630052A, containing 10.2% kcal protein, 37.3% kcal carbohydrate, 52.6% kcal fat) and fructose-containing drinking water (23.1g fructose and 18.9g of glucose dissolved in 1L of water, and then filter sterilized) for a total of 16 weeks to generate a fatty liver model.
  • Liver organoids were isolated from the model mice and prepared for in vitro culture. At the same time, the organoids were administered in vitro.
  • Obeticholic acid OCA
  • FXR farnesoid X receptor
  • Embodiment adopts this medicine as contrast medicine.
  • the organoids were grouped and treated with obeticholic acid and 25-hydroxylanosterol at the same concentration gradient for 3 days, and the RNA of the organoids was collected and analyzed by real-time quantitative PCR for lipid synthesis-related genes (Hmgcs, Hmgcr, SCD1, FASN) and fiber The differences in the expression of the marker molecules ( ⁇ SMA, Col1 ⁇ 1).
  • Figures 35-53 show that 25-hydroxylanosterol reduces lipid production-related genes (Hmgcs, Hmgcr and SCD1, FASN) expression, and the effect is better than the same concentration of the control drug obeticholic acid;
  • Figure 36 shows that 25-hydroxylanosterol reduces the expression of fibrosis-related genes (Col1a1, ⁇ SMA) in liver organoids, and The effect is better than that of the control drug obeticholic acid at the same concentration;
  • Figures 37-53 are the bright-field imaging results of liver organoids, the results of Nile red staining and quantification, and the results of immunofluorescence staining and quantification of the fibrosis marker protein ⁇ SMA: 25-hydroxy Lanosterol reduces lipid accumulation in liver organoids and at the same time reduces expression of the fibrosis marker protein ⁇ SMA in liver organoids.
  • Fig. 35 and Fig. 36 are represented by mean ⁇ standard deviation.
  • P values were analyzed by one-way ANOVA. ns means no statistical difference, * means P ⁇ 0.05, ** means P ⁇ 0.01, *** means P ⁇ 0.001.
  • Quantitative analysis of Figure 47 and Figure 53 was performed using Image J software. Data are presented as mean ⁇ standard deviation. The P value was analyzed by one-way ANOVA * means P ⁇ 0.05, ** means P ⁇ 0.01, *** means P ⁇ 0.001.
  • test compound and reference compound testosterone were carried out by LC-MS/MS method.
  • Use Analyst software to integrate, calculate and process chromatographic peaks.
  • Both the test compound and the reference compound testosterone were analyzed by semi-quantitative method, and the peak area ratio was used for calculation.
  • the metabolic stability of the compound of the present invention in rat liver microsomes is significantly improved, which is significantly better than that of the compound 68.
  • the first step (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-6-methylhept-5-ene-2- Base]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7 -Alcohol (10.00g, 23.4mmol, 1.0eq) was dissolved in DCM (250mL), and after complete dissolution, acetic anhydride (6.7mL, 71.0mmol, 3.0eq), DMAP (0.57g, 4.7mmol, 0.2eq) and TEA (16.3mL, 117.2mmol, 5.0eq), after the addition was complete, it was stirred at room temperature for 2 hours.
  • Example 2 the amine in the first step was replaced with tetrahydropyran-4-amine to finally obtain (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a ,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta [1,2-a]phenanthren-1-yl]-N-(3,4,5,6-tetrahydro-2H-pyran-4-yl)pentanamide (3).
  • Example 2 the amine in the first step was replaced with 2-methylaniline to finally obtain (4R)–4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6, 6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1, 2-a]phenanthren-1-yl]-N-(2-methylphenyl)pentanamide (4).
  • Example 2 the amine in the first step was replaced with 2-fluoroaniline to finally obtain (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR) -7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro -1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (5).
  • Example 2 the amine in the first step was replaced with 2-chloroaniline to finally obtain (4R)-N-(2-chlorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR) -7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro -1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (6).
  • Example 2 the amine in the first step was replaced with 2,6-dimethylaniline to finally obtain (4R)-N-(2,6-dimethylphenyl)-4-[(1R,3aR, 5aR,7S,9aS,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10 ,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (9).
  • Example 2 the amine in the first step was replaced with 2-isopropylaniline to finally obtain (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6 ,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1 ,2-a]phenanthrene-1-yl]-N-[2-(propan-2-yl)phenyl]pentanamide (10).
  • Example 2 the amine in the first step was replaced with 2-methoxyethylamine, and the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a was finally obtained ,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta [1,2-a]phenanthrene-1-yl]-N-(2-methyl Oxyethyl)pentanamide (11).
  • Example 2 the amine in the first step was replaced with 3-cyanoaniline, and the compound (4R)-N-(3-cyanophenyl)-4-[(1R,3aR,5aR,7S,9aS was finally obtained ,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a- Tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (12).
  • Example 12 the amine in the first step was replaced with 3-fluoroaniline to finally obtain the compound (4R)-N-(3-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR )-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecyl Hydrogen-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (13).
  • Example 2 the amine in the first step was replaced with 2-aminopyridine to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6, 6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1, 2-a]phenanthrene-1-yl]-N-(pyridin-2-yl)pentanamide (14).
  • Example 2 the amine in the first step was replaced with pyridin-3-amine to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6 ,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1 ,2-a]phenanthrene-1-yl]-N-(pyridin-3-yl)pentanamide (15).
  • Example 2 the amine in the first step was replaced with pyridin-4-amine to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6 ,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1 ,2-a]phenanthrene-1-yl]-N-(pyridin-4-yl)pentanamide (16).
  • Example 12 the amine in the first step was replaced with 4-cyanoaniline to finally obtain the compound (4R)-N-(4-cyanophenyl)-4-[(1R,3aR,5aR,7S,9aS ,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a- Tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (17).
  • Example 12 the amine in the second step was replaced by 2,6-difluoroaniline to finally obtain the compound (4R)-N-(2,6-difluorophenyl)-4-[(1R,3aR,5aR ,7S,9aS,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10, 11,11a-tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (18).
  • Example 12 the amine in the second step was replaced with 3-trifluoromethylaniline to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a ,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta [1,2-a]phenanthrene-1-yl]-N-[3-(trifluoromethyl)phenyl]pentanamide (19).
  • Example 12 the amine in the second step was replaced by 2-cyanoaniline to finally obtain the compound (4R)-N-(2-cyanophenyl)-4-[(1R,3aR,5aR,7S,9aS ,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a- Tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (20).
  • Example 2 the amine in the first step was replaced with aniline to finally obtain the compound 4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6,6,9a, 11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1,2-a] Phenanthrene-1-yl]-N-phenylpentanamide (21).
  • Example 2 the amine in the first step was replaced by p-fluoroaniline to finally obtain the compound (4R)-N-(4-fluorophenyl)-4-[(1R, 3aR, 5aR, 7S, 9aS, 11aR) -7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro -1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (22).
  • Example 12 the amine in the second step was replaced with methyl 2-aminobenzoate to finally obtain the compound 2- ⁇ [(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7 -Hydroxy-3a,6,6,9a,11a-Pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetradetrahydro-1H -Cyclopenta[1,2-a]phenanthrene-1-yl]-1-oxyylidenepentyl]amino ⁇ benzoic acid (23).
  • the second step weighs (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6,6,9a,11a-pentamethyl-2,3,3a, 4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanoic acid (VIII)( 50mg, 0.19mmol, 1.0eq.) was dissolved in N,N'-dimethylformamide (2.0mL), and 2-(7-azobenzotriazole)-N,N,N' was added at room temperature , N'-tetramethyluronium hexafluorophosphate (54.76mg, 0.144mmol, 1.2eq.), was added dropwise to diisopropylethylamine (24-1) (0.03mL, 0.18mmol, 1.5eq.), Stir at room temperature
  • the fourth step refers to Example 24, and the amine is replaced with prop-2-enoic acid-2-aminophenyl ester trifluoroacetate, and finally the compound prop-2-enoic acid-2- ⁇ [(4R)-4 -[(1R,3aR,5aR,7S,9aS,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7, 8,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-oxylidenepentyl]amino ⁇ phenyl ester (25 ).
  • Example 2 the amine in the first step was replaced with 3-fluoro-4-aminopyridine to finally obtain the compound (4R)-N-(3-fluoropyridin-4-yl)-4-[(1R,3aR, 5aR,7S,9aS,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10 ,11,11a-tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (26).
  • Example 2 the amine in the first step was replaced with 1-methyl-5-aminopyrazole to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7- Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H- Cyclopentano[1,2-a]phenanthrene-1-yl]-N-(2-methylpyrazol-3-yl)pentanamide (27).
  • Example 2 the amine in the first step was replaced with isoxazol-3-amine to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a ,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta [1,2-a]phenanthrene-1-yl]-N-(isoxazol-3-yl)pentanamide (28).
  • Example 2 the amine in the second step was replaced by piperidine to finally obtain the compound (4R)-1-(hexahydropyridin-1-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR) -7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro -1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-one(30).
  • Example 2 the amine in the second step was replaced by morpholine, and the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6,6,9a was finally obtained ,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1,2-a ]phenanthrene-1-yl]-1-(1,4-oxazacyclohex-4-yl)pentan-1-one (31).
  • Example 2 the amine in the second step was replaced by tetrahydropyrrole, and the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6,6, 9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1,2- a]phenanthrene-1-yl]-1-(tetrahydro-1H-pyrrol-1-yl)pentan-1-one (32).
  • Example 2 the amine in the second step was replaced by azetidine, and finally the compound (4R)-1-(azetidin-1-yl)-4-[(1R,3aR,5aR,7S, 9aS,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a -Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-one (33).
  • Example 2 the amine in the second step was replaced by piperazine, and the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy- 3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta And[1,2-a]phenanthrene-1-yl]-1-(piperazin-1-yl)pentan-1-one (34).
  • Example 2 the amine in the second step was replaced with dipropylamine, and the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6,6,9a was finally obtained ,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1,2-a ]phenanthrene-1-yl]-N,N-dipropylpentanamide (35).
  • Example 38 the amine in the first step was replaced by hexahydropyridine to finally obtain the compound (3R)-1-(hexahydropyridin-1-yl)-3-[(1R,3aR,5aR,7S,9aS, 11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-deca Tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]butan-1-one (39).
  • Example 12 the amine was replaced with dimethylamine to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6,6,9a,11a -Pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene -1-yl]-N,N-dimethylpenta Amide (40).
  • Example 12 the amine was replaced by diethylamine to finally obtain the compound (4R)-N,N-diethyl-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a ,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta [1,2-a]phenanthrene-1-yl]pentanamide (41).
  • Example 12 the amine was replaced by 4-fluoropiperidine to finally obtain the compound (4R)-1-(4-fluorohexahydropyridin-1-yl)-4-[(1R,3aR,5aR,7S,9aS ,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a- Tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-one(42).
  • Example 12 the amine was replaced with 4,4-difluoropiperidine to finally obtain the compound (4R)-1-(4-fluorohexahydropyridin-1-yl)-4-[(1R,3aR,5aR, 7S,9aS,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11 ,11a-tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-one (43).
  • Example 12 the amine was replaced by 4-cyanopiperidine to finally obtain the compound 1-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6 ,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1 ,2-a]phenanthrene-1-yl]-1-oxyylidenepentyl]hexahydropyridine-4-carbonitrile (48).
  • Example 2 the amine was replaced by diisopropylamine to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6,6,9a,11a -Pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene -1-yl]-N,N-di(propan-2-yl)pentanamide (50).
  • Example 2 the amine was replaced with 2-(propylamino)ethan-1-ol, and the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy- 3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta And[1,2-a]phenanthrene-1-yl]-N-(2-hydroxyethyl)-N-propylpentanamide (51).
  • Example 2 the amine was replaced by N-methylaniline to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6,6,9a ,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1,2-a ]phenanthrene-1-yl]-N-methyl-N-phenylpentanamide (53).
  • the second step weighs acetic acid-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-4-(methylamino)butyl -2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1,2-i] Phenanthrene-7-yl ester (54-1) (90mg, 0.142mmol, 1.0eq.), add dichloromethane (5.0mL), triethylamine (0.02mL, 0.142mmol), then add o-fluorobenzene under ice-cooling Formyl chloride (22.51mg, 0.142 mmol), then stirred overnight at room temperature, monitored by LC-MS, after the reaction was completed, concentrated to remove dichloromethane, then added saturated aqueous sodium bicarbonate solution (1
  • the third step is to weigh acetic acid-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4- ⁇ [(2-fluorophenyl)carbonyl](methyl)amino ⁇ butan-2 -yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro- 1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (54-2) (80mg, 0.141mmol) was dissolved in a mixed solvent of tetrahydrofuran (3.0mL) and methanol (3.0mL), stirred at room temperature Add 1M lithium hydroxide aqueous solution (1.5mL), then stir at room temperature, and monitor by LCMS.
  • Example 2 the amine was replaced by N-methyl-2-thiazolamine to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6 ,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1 ,2-a]phenanthrene-1-yl]-N-methyl-N-(1,3-thiazacyclopentyl-2-yl)pentanamide (55).
  • the first step is to weigh (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3, 3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanoic acid (VII ) (100mg, 0.218mmol) was dissolved in dichloromethane (10.0mL), N,N'-dimethylformamide (1d) was added to replace N2, and placed in an ice bath.
  • the third step weighs the acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-3a, 6, 6, 9a, 11a-pentamethyl-1-[(2R)-5-[methyl(2-methyl ylpyrazol-3-yl)amino]-5-oxylidenepent-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a -Tetrahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (56-2) (114mg, 0.21mmol) was dissolved in tetrahydrofuran (5.0mL), methanol (3.00mL) was added, and finally A solution of lithium hydroxide (8.91mg, 0.372mmol) in water (1M, 2.0mL) was added, and stirred at room temperature for 18h after the addition was complete.
  • the second step weighs acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-4-(ethylamino)butan-2-yl]-3a,6,6,9a,11a -Pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-i]phenanthrene -7-yl ester (57-1) (50mg, 0.11mmol) was dissolved in dichloromethane (5.0mL), replaced with nitrogen, cooled in an ice bath, diisopropylethylamine (19.4mg, 0.15mmol) was added, and then Add o-fluorobenzoyl chloride (19.0mg, 0.12mmol) dropwise.
  • the third step is to weigh acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-4- ⁇ ethyl[(2-fluorophenyl)carbonyl]amino ⁇ butan-2-yl] -3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-ring Penta[1,2-i]phenanthrene-7-yl ester (57-2) (39.6mg, 0.07mmol, 1.0eq.), added tetrahydrofuran (4.0mL), methanol (4.0mL), 1M lithium hydroxide aqueous solution (2.5mL), stirred overnight at room temperature, LCMS monitoring, after the reaction was completed, concentrated to remove tetrahydrofuran and methanol, then added water (10.0mL) to the concentrated solution, and then Extracted with
  • Example 2 the amine was replaced by 4-hydroxyl-piperidine to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl-3a,6,6, 9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[1,2- a]phenanthrene-1-yl]-1-(4-hydroxyhexahydropyridin-1-yl)pentan-1-one (58).
  • the third step is to weigh acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-[ethyl(2-fluorophenyl)amino]-5-oxoylidenepenta-2 -yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro- 1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (59-2) (50mg, 0.086mmol) was dissolved in tetrahydrofuran (3mL), methanol (3mL) was added, and 1M hydroxide was added under stirring at room temperature Lithium aqueous solution (3.62mg, 0.086mmol), and then continue to stir at room temperature for 16 hours.
  • the second and third steps refer to Example 2, and the amine in the first step is replaced by 60-1, and finally the compound (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR ,7S,9aS,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10, 11,11a-tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(2-hydroxy-2-methylpropyl)pentanamide (60).
  • the first step Referring to Example 2, the amine was replaced by 3-fluoro-4-amino-pyridine to obtain the compound acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-[( 3-fluoropyridin-4-yl)amino]-5-oxylidenepent-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a, 6,7,8,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (61-1) (300 mg).
  • the second step weighs acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-[(3-fluoropyridin-4-yl)amino]-5-oxoylidene- 2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro -1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (61-1) (300mg, 0.54mmol, 1.0eq.) was dissolved in N,N'-dimethylformamide (7.0mL) , nitrogen replacement, ice bath cooling, adding sodium hydride (65.13mL, 1.63mmol), then iodomethane (80.89mg, 0.57mmol) was dissolved in N,N'-dimethylformamide (3.0mL), Added to the
  • the system was diluted with water (20 mL), extracted with EA (ethyl acetate) (20 mL ⁇ 3), the combined organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product .
  • EA ethyl acetate
  • Example 64 the amine in the first step was replaced with bromomethoxymethyl ether to finally obtain the compound (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS ,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a- Tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(methoxymethyl)pentanamide (65).
  • Example 63 the amine in the first step was replaced with 1,3-thiazol-5-amine to finally obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxyl -3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-ring Penta[1,2-a]phenanthrene-1-yl]-N-methyl-N-(1,3-thiazacyclopent-5-yl)pentanamide (66).
  • the first step is to dissolve the raw material lanosterol (3.00g, 7.03mmol, 1.0eq) in THF (tetrahydrofuran) (273mL), add water (68mL), add NBS (0.73g, 4.08mmol, 0.58eq) at room temperature, 25°C Stir for 2hrs.
  • the reaction solution was poured into water, extracted with dichloromethane (50mL x 3), and the combined organic phases were washed with saturated brine (50mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • the base ester (72-1) (100mg, 0.21mmol, 1eq) was dissolved in anhydrous tetrahydrofuran (10mL), and 1.0 mol/L methylmagnesium bromide (2.1mL, 2.1mmol, 10eq) was added dropwise under ice-cooling.
  • the reaction solution was poured into saturated ammonium chloride water, extracted with dichloromethane (50mL x 3), and the combined organic phases were washed with saturated brine (50mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • reaction liquid oil bath was heated to 80° C. and stirred at this temperature for 6 hrs, and the reaction was detected by LCMS.
  • the reaction solution was introduced into ice water, extracted with dichloromethane (50mL x 3), and the combined organic phases were washed with saturated brine (50mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • reaction solution was introduced into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (50 mL x 2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • (2E,6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2, 3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetrahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hept- 2-enoic acid methyl ester (75-1) (380mg, 0.762mmol) was dissolved in ethyl acetate (380mL), Pd/C (palladium carbon) (38mg, 0.762mmol) was added, hydrogen gas was exchanged three times, and stirred at room temperature 30min.TLC (PE:EtOAc 10:1) had no raw material remaining, TLC detected that the reaction was complete, filtered with diatomaceous earth, rinsed with ethyl acetate, spin-dried, and the concentrate was separated
  • the third step acetic acid (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-iodopent-2-yl]-3a,6,6,9a,11a-pentamethyl-2 ,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl ester ( 76-2) (3.50g, 6.31mmol, 1.0eq) was dissolved in DMF (50mL), potassium cyanide (4.78g, 73.4mmol, 11.6eq) was added, and the system was heated to 100°C.
  • the fourth step is acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-cyanopent-2-yl]-3a,6,6,9a,11a-pentamethyl- 2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl ester (76-3) (1.00g, 2.2mmol, 1.0eq) was dissolved in methanolic hydrogen chloride solution (30mL, 4mol/L), and the reaction was heated to reflux.
  • ethylmagnesium chloride (1MOL/L)
  • the base ester (III) 200mg, 0.47mmol, 1.0eq
  • dichloromethane (10mL) was dissolved in dichloromethane (10mL), and 3-aminocyclobutan-1-ol (81mg, 0.93mmol, 2.0eq) was added, and the reaction solution was stirred at room temperature for 30 minutes, Stirring was continued overnight after addition of sodium triacetoxyborohydride (177 mg, 4.7 mmol, 10 eq).
  • reaction liquid oil bath was heated to 80° C. and stirred at this temperature for 16 hrs, and the reaction was detected by LCMS.
  • the reaction solution was introduced into ice water, extracted with dichloromethane (50mL x 3), and the combined organic phases were washed with saturated brine (50mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • Example 84 the amine in the first step was replaced with azetidin-3-ylmethanol to finally obtain the compound (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-4-[ 3-(Hydroxymethyl)azetidin-1-yl]but-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6 ,7,8,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (85).
  • Example 86 the amine in the third step was replaced with azetidin-3-ol to finally obtain the compound 1-[(2S)-2- [(1R,3aR,5aR,7S,9aS,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8 ,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]azetidin-3-ol (87).
  • Example 86 the amine in the third step was replaced with 3-aminocyclobutanol to finally obtain the compound (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2S)-1-[(3- Hydroxycyclobutyl)amino]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a, 10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (88).
  • Example 86 the amine in the third step was replaced by azetidin-3-ylmethanol to finally obtain the compound (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2S)-1- [3-(Hydroxymethyl)azetidin-1-yl]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a, 6,7,8,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (89).
  • the Grignard reagent in the fifth step was replaced with isopropylmagnesium chloride, and finally the compound (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-6-hydroxyl- 7-methyl-6-(propan-2-yl)oct-2-yl]-3a,6,6,9a,11a-pentamethyl- 2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol ( 91).
  • Example 86 the amine in the third step was replaced with 1-amino-2-methylpropanol to finally obtain the compound (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2S)-1- [(2-Hydroxy-2-methylpropyl)amino]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6, 7,8,9,9a,10,11,11a-Tetradetrahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (93).
  • ethyl isobutyrate (63mg, 0.361mmol) was dissolved in tetrahydrofuran (1ml), cooled to -70°C, lithium diisopropylamide (0.902mL, 1.803mmol) was added dropwise, and the temperature was kept at - Stirring at 70°C for 10 min, the compound acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-iodopent-2-yl]-3a,6,6,9a,11a-five Methyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro-1H-cyclopenta[2,1-i]phenanthrene-7
  • the -yl ester (76-2) (100mg, 0.180mmol) was dissolved in tetrahydrofuran (1ml), added dropwise to the above system at -70
  • the second step is to add lithium tetrahydrogen aluminum (26mg, 0.183mmol) into tetrahydrofuran, nitrogen protection, cool to zero, compound (6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7- Acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradetrahydro -1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-dimethylheptanoic acid methyl ester (94-1) (20mg, 0.038mmol) was dissolved in tetrahydrofuran, and the above The system was raised to room temperature and stirred for two hours.
  • the first step The compound methyl triphenyl iodide (189mg, 0.47mmol, 1.0eq) was dissolved in anhydrous toluene (3mL), and n-butyllithium (0.37mL, 0.93mmol, 2.0eq) was added at 0°C, stirred After 30 minutes, a light yellow solution was obtained, and epichlorohydrin (43.17mg, 0.47mmol, 1.0eq) was added, and n-butyl lithium (0.37mL, 0.93mmol, 2.0eq) was added after stirring for 30 minutes, and stirred for another 30 minutes, Then the system was cooled to -40°C.
  • Acetic acid (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-formylpropan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3 ,3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetrahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (III) 200mg, 0.47mmol, 1.0eq
  • anhydrous toluene 3mL
  • the compound acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-4-hydroxybutan-2-yl]-3a,6,6,9a,11a-pentamethyl -2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetrahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl Ester (96-1) (50.0mg, 0.023mmol) was dissolved in dichloromethane (2mL), and tetrabutylammonium bromide (43.52mg, 0.135mmol) was added at room temperature, bromoacetic acid-2-methylpropan-2- Base ester (262.42mg, 1.345mmol), 40% sodium hydroxide aqueous solution (2mL, 0.022mmol) was added at room temperature, reacted overnight at room temperature, TLC (PE:EA 10:1),
  • lithium aluminum tetrahydrogen (32.0mg, 0.184mmol) was dissolved in tetrahydrofuran (1.0mL), under nitrogen protection, the temperature was lowered to zero, and [(3R)-3-[(1R,3aR,5aR,7S,9aS ,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11 ,11a-Tetradecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]butyl]oxy ⁇ acetic acid-2-methylpropan-2-yl ester 4-yl]butoxy]acetate (40mg, 0.073mmol) was dissolved in tetrahydrofuran (1.0mL), and added dropwise to the above system.
  • the compound acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-iodopent-2-yl]-3a,6,6,9a,11a-pentamethyl -2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetrahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl Ester (97-2) (50.0mg, 0.046mmol) was dissolved in tetrahydrofuran (2mL), and sodium hydrogen (36.1mg, 0.90mmol) was added. Warm up to reflux and stir for 3h, TLC (PE:EtOAc 10:1).
  • acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(1S)-1-formylethyl]-3a,6,6,9a,11a-pentamethyl-2, 3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl ester (86 -2) (800mg, 1.81mmol, 1.0eq.) was dissolved in dichloromethane (20mL) and isopropanol (20mL), added sodium borohydride (30.0mg 0.80mmol) at room temperature, stirred at room temperature for 1h, Spot plate detection (PE:EtOAc 10:1), raw material reaction is complete, add saturated aqueous ammonium chloride solution at low temperature, extract three times with dichloromethane, dry over anhydrous sodium sulfate, spin dry, pass column
  • the second step weighs acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2S)-1-hydroxypropan-2-yl]-3a,6,6,9a,11a-pentamethyl -2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-Tetrahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl Ester (100-1) (100 mg, 0.24 mmol, 1.0 eq.) was dissolved in dichloromethane (2.0 mL).
  • Tetrabutylammonium bromide 80mg, 0.48mmol, 2.0eq.
  • 2-methylpropan-2-yl bromoacetate 468mg, 2.40mmol, 10.0eq.
  • 40% sodium hydroxide was added at room temperature aqueous solution.
  • Stir at room temperature for 16 h, and monitor the reaction by TLC (PE:EtOAc 10:1).

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Abstract

本发明公开了一种甾类化合物、其制备方法和应用。该甾类化合物可具有如式I所示的结构。本发明的化合物具有SREBP通路抑制活性，可用于预防和/或治疗肥胖、高脂血症、脂肪肝、糖尿病、动脉粥样硬化症、心脑血管疾病、肝癌、皮肤损伤等疾病。

Description

甾类化合物、其制备方法和应用
本申请要求申请日为2022/1/28的中国专利申请2022101071901的优先权和申请日为2022/7/22中国专利申请2022108692823的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种甾类化合物、其制备方法和应用。
背景技术
随着生活方式的转变，包括高热量食物和高糖饮料摄入、缺乏运动和体力活动等，在全球范围内，以高脂血症、肥胖、2型糖尿病以及脂肪肝为代表的代谢性疾病已经成为日益严重的健康问题。其中脂肪肝已成为欧美和我国富裕地区慢性肝病的重要病因，普通成人单纯性肝脏脂质堆积患病率10％～30％，其中10％～20％为脂肪性肝炎，后者10年内肝硬化、肝癌发病率达25％。然而截止目前，脂肪肝病理生理机制尚未完全阐明，临床上仍缺乏有效而特异的治疗药物。已知血液和肝脏中胆固醇、甘油三酯等脂质累积是引起高脂血症的主要原因，而高脂血症又是引起动脉粥样硬化、脑中风和脂肪性肝疾病的重要致病因素。因此，以降低脂质为导向，研发靶向脂质代谢调控通路的新型药物，正日渐成为新型代谢性疾病药物研发的重要方向。
已知哺乳动物细胞的脂质合成途径是调控脂质代谢平衡的重要因素。调控胆固醇和脂肪酸合成的关键因子是一类转录因子蛋白甾醇反应元件结合蛋白SREBP(Sterol-Regulatory Element Binding Protein)。这一类蛋白质的前体首先在内质网(ER)上合成，前体通过SREBP切割激活蛋白(SCAP，SREBP cleavage-activating protein)转运到高尔基体，然后经过两种蛋白酶(Site-1protease(S1P)和Site-2protease(S2P))酶切，释放其N端的活性结构域，进入细胞核发挥转录因子作用，与靶基因启动子区的SREBP反应元件(SRE)结合，启动下游基因的表达。SREBP蛋白的剪切成熟严格受细胞内甾醇(如胆固醇、25-羟胆固醇)水平的调控。当细胞在内质网中积累到充足的胆固醇时，胆固醇和SCAP结合，并改变SCAP的构象，引起SCAP-SREBP复合物结合蛋白Insig(Insulin-induced gene)，从而阻断SREBP向高尔基体的转运和随后SREBP的激活。反之，核内活性形式的SREBP增多，促进细胞脂质合成。除了胆固醇，25-羟胆固醇(25-hydroxylcholesterol，25-HC)是另一个强效的SREBP通路的内源性抑制剂。和胆固醇结合SCAP不同的是，25-HC直接结合Insig，并诱导SCAP和Insig结合。
前期研究发现抑制SREBP通路是预防和/或治疗肥胖、高脂血症、脂肪肝、动脉粥样硬化、糖尿病等代谢性疾病和心脑血管疾病、皮肤损伤、肝癌等疾病的有效策略和方法。
针对高脂血症，其发病机制主要是饮食或基因突变等因素引起的脂质合成增加或者脂质转运异常导致血液胆固醇和脂肪酸等脂质的过量累积。目前临床以他汀类药物和贝特类药物为主要调脂药物，其中他汀类药物的作用机理即是通过抑制细胞胆固醇合成途径同时促进血液胆固醇逆向运输实现的。表明靶向细胞脂质合成途径关键因子是有效降低脂质水平的重要手段。
目前为止，针对脂肪性肝病还没有被批准的治疗药物，因此确定治疗靶点和开发新的有效疗法是非常重要的。已知脂肪性肝病的发病机制涉及多种危险因素，如甘油三酯以脂滴形式积累可能引发的脂肪变性，细胞中异常增加的胆固醇和脂肪酸，能引起内质网压力和线粒体功能紊乱，从而导致细胞死亡、炎症和纤维化。其中，游离胆固醇积累被报道为单纯脂肪变性向侵袭性脂肪性肝炎转变的关键驱动因素。其次，建立脂肪肝小鼠模型，简单的无胆固醇高脂饮食即使在长时间喂养后也只能诱导脂肪变性，而在饮食中添加1-2％的胆固醇是实现炎症和纤维化的必要条件因此，降低胆固醇可能成为脂肪性肝病的一种新的治疗策略。已有研究显示：在脂肪肝患者和脂肪肝小鼠模型中发现SREBP异常激活；小鼠肝脏特异性Scap的缺失或敲除，可以消除所有SREBPs的激活，从而阻止脂肪肝和高脂血症的发生。此外，最近的研究表明内质网应激诱导的SREBP异常激活促进了脂肪生成和脂肪肝。因此，这些证据表明，通过抑制SREBP通路降低肝脏的甘油本发明所要解决的技术问题是提供对SREBP通路具有抑制活性的新化合物。
发明内容
本发明提供了一种式I所示化合物或其药学上可接受的盐：
其中，R21为-L1-C(O)RA、-L1-S(O)2RA、-L1-RB、 -L2-RC或-L3-RD；
每个L1和L2独立地为单键、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分任选被-X-代替；
L3为-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分被-Y-代替；
每个X独立地为-CHR5a-、-CR5aR5b-、C3-6环烷基、C3-6氧杂环烷基、C3-6氮杂环烷基或-Y-；
每个R5a和R5b各自独立地为F或氟代C1-4烷基；
每个Y独立地为-O-、-NH-、-N(C1-4烷基)-、-CH＝CH-、 或-CHRg-；
Rg为-C1-4亚烷基-OH；
每个RA独立地为-NR21aR21b；
RB为-N(R21a)-C(O)R21b或-N(R21a)-S(O)2R21b；
RD为-OH、-CH2OH、RC、-CH(CH3)-OH或-C(CH3)2-OH；
每个RC独立地为-C(R21c)(R21d)-OH、-C(R21c)(R21d)-CN、CN、-C(O)RE、NH2、C1-4烷氧基、3-6元杂环烷基或5-10元杂芳基；所述5-10元杂芳基是未取代的或者被p个Rc取代；
RE为C1-4烷基、C3-6环烷基或3-6元杂环烷基；其中所述C1-4烷氧基、C3-6环烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
每个R21a独立地为H、C1-6烷基或3-6元杂环烷基，其中所述C1-6烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
每个R21b独立地为H、C1-6烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基独立地是未取代的或者被q个Rb取代；
或者，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成3-10元杂环烷基，其中所述3-10元杂环烷基是未取代的或者被p个Rc取代；
每个m、p和q各自独立地为1、2、3、4或5；
每个Ra、Rb和Rc各自独立地为F、Cl、OH、COOH、CN、NO2、C1-4烷基、氟代C1-4烷基、C1- 4烷氧基、
R21c为H、F、C1-4烷基、氟代C1-4烷基、C2-4烯基或C3-6环烷基；
R21d为F、C2-4烷基、氟代C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、苯基、5-6元杂芳基或-L4-R21e，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
或者，R21c和R21d以及连接它们的碳原子一起形成C3-6环烷基或3-6元杂环烷基；
L4为亚甲基或亚乙基；
R21e为OH、CN、C1-4烷氧基、苯基或5-6元杂芳基，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
每个j独立地为1、2、3或4；
每个r独立地为0、1、2、3或4；
每个Rd和Rf独立地为F、Cl、OH、CN、NO2、C1-4烷基、氟代C1-4烷基、氟代C1-4烷氧基或C1- 4烷氧基；
所述杂环烷基和杂芳基中的杂原子个数独立地为1、2、3或4个，每个杂原子独立地为N、O或S；
式I所示化合物不为：
式I中*标记的碳原子为S构型、R构型或者两者的混合。
在本发明某些优选实施方案中，所述的式I所示的化合物或其药学上可接受的盐中的某些基团如下定义，未提及的基团同本发明任一方案所述(简称“在一些实施方案中”或“在一些优选的实施方案中”)。
在一些实施方案中，如前任一方案所述的式I所示化合物中，其中，R21为-L1-C(O)RA、-L1-S(O)2RA、-L1-RB、 -L2-RC或-L3-RD；
每个L1和L2独立地为单键、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分任选被-X-代替；
L3为-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分被-Y-代替；
每个X独立地为-CHR5a-、-CR5aR5b-或-Y-；
每个R5a和R5b各自独立地为F、C1-4烷基或氟代C1-4烷基；
每个Y独立地为-O-、-NH-、-N(C1-4烷基)-、-CH＝CH-、 或-CHRg-；
Rg为-C1-4亚烷基-OH；
每个RA独立地为-NR21aR21b；
RB为-N(R21a)-C(O)R21b；
RD为-OH、-CH2OH、RC、-CH(CH3)-OH或-C(CH3)2-OH；
每个RC独立地为-C(R21c)(R21d)-OH、CN、-C(O)RE、NH2、C1-4烷氧基、 3-6元杂环烷基或5-10元杂芳基；所述5-10元杂芳基是未取代的或者被p个Rc取代；
RE为C1-4烷基、C1-4烷氧基、C3-6环烷基或3-6元杂环烷基；其中所述C1-4烷基、C1-4烷氧基、C3- 6环烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
每个R21a独立地为H、C1-6烷基、C3-6环烷基或3-6元杂环烷基，其中所述C1-6烷基、C3-6环烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
每个R21b独立地为H、C1-6烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基独立地是未取代的或者被q个Rb取代；
或者，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成3-10元杂环烷基，其中所述3-10元杂环烷基是未取代的或者被p个Rc取代；
每个m、p和q各自独立地为1、2、3、4或5；
每个Ra、Rb和Rc各自独立地为F、Cl、OH、COOH、CN、NO2、C1-4烷基、氟代C1-4烷基、C1- 4烷氧基、
R21c为H、F、C1-4烷基、氟代C1-4烷基、C2-4烯基或C3-6环烷基；
R21d为F、C2-4烷基、氟代C1-4烷基、C2-4烯基、C3-6环烷基、苯基、5-6元杂芳基或-L4-R21e，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
或者，R21c和R21d以及连接它们的碳原子一起形成C3-6环烷基或3-6元杂环烷基；
L4为C1-4亚烷基；
R21e为OH、CN、C1-4烷氧基、苯基或5-6元杂芳基，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
每个j独立地为1、2、3或4；
每个r独立地为0、1、2、3或4；
每个Rd和Rf独立地为F、Cl、OH、CN、NO2、C1-4烷基、氟代C1-4烷基或C1-4烷氧基；
所述杂环烷基和杂芳基中的杂原子个数独立地为1、2、3或4个，每个杂原子独立地为N、O或 S；
式I中*标记的碳原子为S构型、R构型或者两者的混合。
在一些实施方案中，如前任一方案所述的式I所示化合物中，其中，R21为-L1-C(O)RA、-L1-S(O)2RA、-L1-RB、 -L2-RC或-L3-RD；
每个L1和L2独立地为单键、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分任选被-X-代替；
L3为-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分被-Y-代替；
每个X独立地为-CHR5a-、-CR5aR5b-或-Y-；
每个R5a和R5b各自独立地为F、C1-4烷基或氟代C1-4烷基；
每个Y独立地为-O-、-NH-、-N(C1-4烷基)-、-CH＝CH-、 或-CHRg-；
Rg为-C1-4亚烷基-OH；
每个RA独立地为-NR21aR21b；
RB为-N(R21a)-C(O)R21b或-N(R21a)-S(O)2R21b；
RD为-OH、-CH2OH、RC、-CH(CH3)-OH或-C(CH3)2-OH；
每个RC独立地为-C(R21c)(R21d)-OH、CN、-C(O)RE、NH2、C1-4烷氧基、 3-6元杂环烷基或5-10元杂芳基；所述5-10元杂芳基是未取代的或者被p个Rc取代；
RE为C1-4烷基、C1-4烷氧基、C3-6环烷基或3-6元杂环烷基；其中所述C1-4烷基、C1-4烷氧基、C3- 6环烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
每个R21a独立地为H、C1-6烷基、C3-6环烷基或3-6元杂环烷基，其中所述C1-6烷基、C3-6环烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
每个R21b独立地为H、C1-6烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基独立地是未取代的或者被q个Rb取代；
或者，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成3-10元杂环烷基，其中所述3-10元杂环烷基是未取代的或者被p个Rc取代；
每个m、p和q各自独立地为1、2、3、4或5；
每个Ra、Rb和Rc各自独立地为F、Cl、OH、COOH、CN、NO2、C1-4烷基、氟代C1-4烷基、C1- 4烷氧基、
R21c为H、F、C1-4烷基、氟代C1-4烷基、C2-4烯基或C3-6环烷基；
R21d为F、C2-4烷基、氟代C1-4烷基、C2-4烯基、C3-6环烷基、苯基、5-6元杂芳基或-L4-R21e，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
或者，R21c和R21d以及连接它们的碳原子一起形成C3-6环烷基或3-6元杂环烷基；
L4为C1-4亚烷基；
R21e为OH、CN、C1-4烷氧基、苯基或5-6元杂芳基，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
每个j独立地为1、2、3或4；
每个r独立地为0、1、2、3或4；
每个Rd和Rf独立地为F、Cl、OH、CN、NO2、C1-4烷基、氟代C1-4烷基或C1-4烷氧基；
所述杂环烷基和杂芳基中的杂原子个数独立地为1、2、3或4个，每个杂原子独立地为N、O或S；
式I中*标记的碳原子为S构型、R构型或者两者的混合。
在一些实施方案中，如前任一方案所述的式I所示化合物中，其中，R21为-L1-C(O)RA、-L1-RB、-L2-RC或-L3-RD。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L1为单键、-CH2-、-(CH2)2-或-(CH2)3-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个R21a独立地为H或C1-6烷基，其中所述C1-6烷基是未取代的或者被m个Ra取代；每个R21b独立地为H、C1-6烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基独立地是未取代的或者被q个Rb取代；或者，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成3-10元杂环烷基，其中所述3-10元杂环烷基是未取代的或者被p个Rc取代。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个m、p和q各自独立地为1或 2。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L2为-CH2-、-(CH2)2-、-(CH2)3-或-(CH2)4-；其中所述-CH2-、-(CH2)2-、-(CH2)3-和-(CH2)4-中的一个-CH2-部分任选被-X-代替；每个X独立地为-CHR5a-，每个R5a和R5b各自独立地为F；较佳的，L2为-(CH2)3-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个RC独立地为-C(R21c)(R21d)-OH、CN、-C(O)RE、NH2、C1-4烷氧基、3-6元杂环烷基或5-10元杂芳基；所述5-10元杂芳基是未取代的或者被p个Rc取代。
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21c为H或C1-4烷基；R21d为F、C2-4烷基、氟代C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、苯基、5-6元杂芳基或-L4-R21e，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；或者，R21c和R21d以及连接它们的碳原子一起形成C3-6环烷基或3-6元杂环烷基。
在一些实施方案中，Rd独立地为F、Cl、OH、CN、C1-4烷基、氟代C1-4烷基、氟代C1-4烷氧基或C1-4烷氧基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RE为C1-4烷基或C3-6环烷基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RD为-OH、-CH2OH或-C(CH3)2-OH。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个j独立地为1或2。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个r独立地为0。
在一些实施方案中，如前所述的式I所示化合物中，每个X独立地为-CHR5a-或-CR5aR5b-，例如-CHR5a-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L1为单键。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L1为-(CH2)2-或-CH2-CHR5a-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个R5a和R5b各自独立地为F、甲基、乙基或三氟甲基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L1为-(CH2)3-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L1为-(CH2)4-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L1为-(CH2)5-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L1为-(CH2)6-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为-L1-C(O)RA。
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为-L1-S(O)2RA。
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为-L1-RB。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个R21a独立地为H、C1-6烷基或C3-6环烷基，其中所述C1-6烷基和C3-6环烷基独立地是未取代的或者被m个Ra取代。
在一些实施方案中，如前任一方案所述的式I所示化合物中，m为1、2或3。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个Ra独立地为F、OH、CN或甲氧基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个R21a独立地为H、C1-4烷基、-C1-4亚烷基-OH、-C1-4亚烷基-OC1-4烷基、氟代C1-4烷基或环丙基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个R21a独立地为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、 环丙基或三氟甲基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个R21b独立地为H、C1-6烷基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C6-10芳基和5-10元杂芳基独立地是未取代的或者被q个Rb取代。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个R21b独立地为H、-C1-4亚烷基-OH、-C1-4亚烷基-OC1-4烷基、氟代C1-4烷基、四氢吗啉基、苯基、吡啶基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噻二唑基、嘧啶基或苯并吡唑基，其中所述苯基、吡啶基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噻二唑基、嘧啶基和苯并吡唑基独立地是未取代的或者被q个Rb取代。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个R21b独立地为H、-C1-4亚烷基-OH、-C1-4亚烷基-OC1-4烷基、氟代C1-4烷基、四氢吗啉基、苯基、 其中所述苯基、 独立地是未取代的或者被q个Rb取代。
在一些实施方案中，如前任一方案所述的式I所示化合物中，q为1、2或3。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个Rb独立地为F、Cl、OH、COOH、CN、NO2、甲基、三氟甲基、甲氧基、
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个R21b独立地为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、苯基、
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个R21b独立地为
在一些实施方案中，如前任一方案所述的式I所示化合物中，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成其中所述 是未取代的或者被p个Rc取代。
在一些实施方案中，如前任一方案所述的式I所示化合物中，p为1、2或3。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个Rc各自独立地为F、OH、CN、C1-4烷基或氟代C1-4烷基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个Rc各自独立地为F、OH、CN、甲基或三氟甲基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，在-NR21aR21b中，R21a和R21b以及连 接它们的氮原子一起形成
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个RA独立地为-NH2、
在一些优选的实施方案中，如前任一方案所述的式I所示化合物中，每个RA独立地为
在一些优选的实施方案中，如前任一方案所述的式I所示化合物中，每个RA独立地
在一些优选的实施方案中，如前任一方案所述的式I所示化合物中，-L1-C(O)RA为
在一些实施方案中，如前任一方案所述的式I所示化合物中，RB为
在一些优选的实施方案中，如前任一方案所述的式I所示化合物中，RB为
在一些实施方案中，如前任一方案所述的式I所示化合物中，-L1-RB为
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为-L2-RC。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L2为单键。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L2为-CH2-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L2为-(CH2)2-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L2为-(CH2)3-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L2为-(CH2)4-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L2为-(CH2)5-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L2为-(CH2)6-。
在一些实施方案中，如前任一方案所述的式I所示化合物中，每个RC独立地为-C(R21c)(R21d)-OH。
在一些实施方案中，如前任一方案所述的式I所示化合物中，当RC为-C(R21c)(R21d)-OH时，R21c为H，R21d为C2-4烷基、氟代C1-4烷基、C3-6环烷基、苯基、氟代苯基、5-6元杂芳基或-L4-R21e。
在一些实施方案中，如前任一方案所述的式I所示化合物中，当RC为-C(R21c)(R21d)-OH时，R21c为H，R21d为C2-4烷基、氟代C1-4烷基、C3-6环烷基、苯基、5-6元杂芳基或-L4-R21e，其中，苯基任选被1个或2个Rd取代，每个Rd独立地为F、OH、CN或C1-4烷氧基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L4为亚甲基或亚乙基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21e为OH、CN、C1-4烷氧基、苯基或
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC中的-C(R21c)(R21d)-OH为
在一些实施方案中，如前任一方案所述的式I所示化合物中，当RC为-C(R21c)(R21d)-OH时，R21c为F，R21d为C2-4烷基(例如乙基)。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC中的-C(R21c)(R21d)-OH为
在一些实施方案中，如前任一方案所述的式I所示化合物中，当RC为-C(R21c)(R21d)-OH时，R21c为CH3或三氟甲基，R21d为C2-4烷基(例如乙基)或三氟甲基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC中的-C(R21c)(R21d)-OH为
在一些实施方案中，如前任一方案所述的式I所示化合物中，当RC为-C(R21c)(R21d)-OH时，R21c为C2-4烷基、C2-4烯基(例如)或C3-6环烷基(例如环丙基)，R21d为C2-4烷基、C2-4烯基(例如)或C3-6环烷基(例如环丙基)。
在一些实施方案中，如前任一方案所述的式I所示化合物中，当RC为-C(R21c)(R21d)-OH时，R21c为乙基、正丙基、异丙基、或环丙基，R21d为乙基、正丙基、异丙基、或环丙基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC中的-C(R21c)(R21d)-OH为
在一些实施方案中，如前任一方案所述的式I所示化合物中，当RC为-C(R21c)(R21d)-OH时，R21c和R21d以及连接它们的碳原子一起形成C3-6环烷基或3-6元杂环烷基(例如)。
在一些实施方案中，如前任一方案所述的式I所示化合物中，当RC为-C(R21c)(R21d)-OH时，R21c和R21d以及连接它们的碳原子一起形成环丙基、环丁基或
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC中的-C(R21c)(R21d)-OH为
在一些优选的实施方案中，如前任一方案所述的式I所示化合物中，RC中的-C(R21c)(R21d)-OH为
在一些优选的实施方案中，如前任一方案所述的式I所示化合物中，RC中的-C(R21c)(R21d)-OH为
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC为CN。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC为-C(O)RE。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RE为C1-4烷基或C3-6环烷基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RE为甲基、乙基或环己基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC为NH2。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC为C1-4烷氧基，例如甲氧基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC为例如
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC为例如
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC为例如
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC为5-10元杂芳基，所述5-10元杂芳基是未取代的或者被p个Rc取代。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC定义中的5-10元杂芳基为
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC为
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC为3-6元杂环烷基。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RC定义中的3-6元杂环烷基为
在一些优选的实施方案中，如前任一方案所述的式I所示化合物中，-L2-RC为
在一些优选的实施方案中，如前任一方案所述的式I所示化合物中，-L2-RC为
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为-L3-RD。
在一些实施方案中，如前任一方案所述的式I所示化合物中，L3为 上述结构的b端与RD连接。
在一些实施方案中，如前任一方案所述的式I所示化合物中，RD为-OH、-CH2OH、-CH(CH3)-OH或-C(CH3)2-OH。
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21中的-L3-RD为
在一些优选的实施方案中，如前任一方案所述的式I所示化合物中，R21中的-L3-RD为
在一些优选的实施方案中，如前任一方案所述的式I所示化合物中，R21中的-L3-RD为
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为
在一些实施方案中，如前任一方案所述的式I所示化合物中，R21为
在一些实施方案中，如前任一方案所述的式I所示化合物中，式I中*标记的碳原子为S构型。
在一些实施方案中，如前任一方案所述的式I所示化合物中，式I中*标记的碳原子为R构型。
在一些实施方案中，如前任一方案所述的式I所示化合物中，式I中*标记的碳原子为S构型和R构型的混合，例如S构型:R构型＝1:1。
在一些实施方案中，式I所示化合物为如下式I-1或I-2所示化合物：
其中，R21的定义如本发明任一项所述。
在一些实施方案中，式I所示化合物为如下任一化合物：













本发明的化合物可以通过已知原料(例如羊毛甾醇)经本领域各种常规反应方法(例如羟基保护、双键臭氧氧化、wittig反应、水解反应、酰胺缩合反应、格式试剂加成反应、还原反应、亲核取代反应、环氧化反应)制备获得。示例性的制备方法如本申请的制备实施例中所描述。
例如，化合物37及其类似物的制备方法可以羊毛甾醇为起始原料，经过羟基保护，双键臭氧氧化，wittig反应，水解，缩合得到化合物37及其类似物；反应路线如下所示：
例如，化合物101及其类似物的制备方法可以羊毛甾醇为起始原料，经过羟基保护，双键臭氧氧化，wittig反应，水解，格式试剂加成反应得到化合物101及其类似物；反应路线如下所示：
例如，化合物80及其类似物的制备方法可以羊毛甾醇为原料，通过羟基保护，双键臭氧化，还原，两步取代，加成反应得到化合物80及其类似物；反应路线如下所示：
例如，化合物125及其类似物的制备方法可以羊毛甾醇为原料，通过羟基保护，双键臭氧氧化，wittig反应，水解，环氧化，水解最终得到化合物125及其类似物；反应路线如下所示：
例如，化合物193及其类似物的制备方法可以以羊毛甾醇为起始原料，经过羟基保护，双键臭氧氧化，双键移位，双键臭氧氧化，还原胺化，缩合，水解，得到化合物193。所述制备方法的反应路线如下图所示：
例如，化合物199及其类似物的制备方法，以(22E,24S)-豆甾-6(5),22(23)-二烯-3β-醇为起始原料，经过羟基保护，双键臭氧氧化，Wittig反应，水解，Wittig反应，双键还原，有机锂试剂加成，环氧化得到产物199。所述制备方法的反应路线如下图所示：
本发明还提供了一种药物组合物，其包含如上所述的化合物或其药学上可接受的盐，以及至少一种药用辅料。
本发明还提供了一种如上所述的化合物或其药学上可接受的盐或如上所述的药物组合物在制备用于预防和/或治疗疾病的药物中的应用，其中所述疾病为肥胖、高脂血症、脂肪肝、糖尿病、动脉粥样硬化症、心脑血管疾病、肝癌或皮肤损伤。
本发明还提供了一种如上所述的化合物或其药学上可接受的盐或如上所述的药物组合物在制备用于抑制SREBP通路的药物中的应用。
本发明还提供了一种抑制SREBP通路的方法，其包括给予受试者有效量的如上所述的化合物或其药学上可接受的盐。
本发明还提供了一种预防和/或治疗疾病的方法，其包括给予受试者有效量的如上所述的化合物或其药学上可接受的盐，其中所述疾病为肥胖、高脂血症、脂肪肝、糖尿病、动脉粥样硬化症、心脑血管疾病、肝癌或皮肤损伤。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
在本文中，术语“取代”或“取代基”是基团中的氢原子被指定的基团所代替。当没有指明取代位置 时，取代可以在任何位置，但是只有形成一个稳定的或者是化学意义上可行的化学物才是被允许的。举例说明如下：结构表示苯环上的氢原子被q个R8所取代，当存在多个R8时，每个R8相同或不同。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本文所列举的连接基团没有指明其连接方向时，其连接方向可以是任意的，既包括从左到右连接，也包括从右到左连接。举例说明如下，-A-L-B中连接基团L为-C-D-，在没有指明L的连接方向时，-A-L-B包括-A-C-D-B和-A-D-C-B。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
在本文中，术语“烷基”是指饱和的直链或支链的一价烃基。C1-C6烷基表示具有1-6个碳原子的烷基。在一些实施方案中，C1-C6烷基可以为C1-C4烷基。C1-C4烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。
在本文中，术语“烯基”是指含有至少一个碳碳双键的直链或支链的一价烃基。当烯基中包含饱和碳原子和不饱和碳原子时，其既可以通过饱和碳原子与其他结构相连接，也可以通过不饱和碳原子与其他结构相连。C2-C4烯基表示具有2、3或4个碳原子的烯基。烯基的具体实例包括但不限于乙烯基、烯丙基。
在本文中，术语“亚烷基”是指饱和的直链或支链的二价烃基。C1-C4亚烷基是指具有1-4个碳原子的亚烷基，其具体为亚甲基、亚乙基(例如-CH2CH2-、-CH(CH3)-)、亚丙基(例如-CH2CH2CH2-、-C(CH3)2-、-CH2CH(CH3)-)、亚丁基(例如-CH2CH2CH2CH2-、-CH(CH3)CH(CH3)-、-CH2CH(CH3)CH2-)。
在本文中，术语“氟代烷基”是指烷基中的一个或多个氢原子被氟所取代形成的基团，其中烷基的定义如前所述。氟代烷基的实例包括但不限于一氟甲基、二氟甲基、三氟甲基、五氟乙基。
在本文中，术语“烷氧基”是指-O-烷基，其中烷基的定义如前所述。C1-C4烷氧基是指-O-(C1-C4烷基)，其中C1-C4烷基的定义如前所述，也即C1-C4烷氧基具体可以为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。
在本文中，术语“环烷基”是指饱和的单环或多环(例如稠环、螺环或桥环)的环状烃基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、C3-10环烷基具体可以为C3、C4、C5、C6、C7、C8、C9、C10环烷基。C3-6环烷基具体可以为C3、C4、C5、C6环烷基。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为多环的(例如稠环、螺 环或桥环)。
在本文中，术语“杂环烷基”是指由碳原子和至少一个杂原子形成的饱和的单环或多环(例如并环、螺环或桥环)环状基团，其中杂原子独立地选自N、O和S。杂环烷基可以通过环上的碳原子和杂原子与其他结构相连接。杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、四氢吡咯基、哌啶基、哌嗪基、吗啉基。3-10元杂环烷基具体可以为3、4、5、6、7、8、9或10元杂环烷基。3-6元杂环烷基具体可以为3、4、5或6元杂环烷基。在一些实施方案中，杂环烷基为单环的。在一些实施方案中，杂环烷基为多环的(例如稠环、螺环或桥环)。
在本文中，术语“C6-10芳基”是指苯基或萘基。
在本文中，术语“杂芳基”是指由碳原子和至少一个杂原子形成的芳香性的单环或稠环基团，其中杂原子独立地选自N、O和S。5-10元杂芳基具体可以为5、6、7、8、9或10元杂芳基，例如5-6元杂芳基或8-10元稠杂芳基。5-6元杂芳基是单环的，具体实例包括但不限于吡咯、呋喃、噻吩、噁唑、异噁唑、噻唑、异噻唑、吡唑、咪唑、吡啶、嘧啶、吡嗪。8-10元稠杂芳基的实例包括但不限于苯并吡咯、苯并呋喃、苯并噻吩、苯并噁唑、苯并异噁唑、苯并噻唑、苯并异噻唑、苯并吡唑、苯并咪唑、苯并吡啶、苯并嘧啶、苯并吡嗪、噻唑并噻唑、吡啶并吡啶、吡啶并吡嗪、吡啶并嘧啶。
在本文中，化学结构式中的表示连接位置。当包含于环状基团中并且没有指明所连接的环原子时，可以连接于任何环原子，但是只有形成一个稳定的或者是化学意义上可行的化学物才是被允许的。例如，包括等结构。
在本文中，术语“药学上可接受的盐”表示由适宜的非毒性有机酸、无机酸、有机碱或无机碱与化合物形成的盐，其保留化合物的生物活性。所述的有机酸可为本领域常规的能成盐的各种有机酸，优选甲磺酸、对甲苯磺酸、马来酸、富马酸、柠檬酸、酒石酸、苹果酸、乳酸、甲酸、乙酸、丙酸、三氟乙酸、草酸、丁二酸、苯甲酸、羟乙基磺酸、萘磺酸和水杨酸中的一种或多种。所述的无机酸可为本领域常规的能成盐的各种无机酸，优选盐酸、硫酸和磷酸中的一种或多种。所述的有机碱可为本领域常规的能成盐的各种有机碱，优选吡啶类、咪唑类、吡嗪类、吲哚类、嘌啉类、叔胺类和苯胺类中的一种或多种。所述的叔胺类有机碱优选三乙胺和/或N,N-二异丙基乙胺。所述的苯胺类有机碱优选N,N-二甲基苯胺。所述的吡啶类有机碱优选吡啶、甲基吡啶、4-二甲氨基吡啶和2-甲基-5-乙基吡啶中的一种或多种。所述的无机碱可为本领域常规的能成盐的各种无机碱，优选碱金属氢化物、碱金属的氢氧化物、碱金属的烷氧化物、碳酸钾、碳酸钠、碳酸锂、碳酸铯、碳酸氢钾和碳酸氢钠中的一种或多种。所述的碱金属氢化物优选氢化钠和/或氢化钾。所述的碱金属的氢氧化物优选氢氧化钠、氢氧化钾和氢氧化锂中的一种或多种。所述的碱金属的烷氧化物优选甲醇钠、乙醇钠、叔丁醇钾和叔丁醇钠中的一种或多种。
化学结构中，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型。键并未指定构型，即如果化学结构中存在构型异构，键可以为或者同时包含两种构型(例如 的比例为1:1)。碳碳双键并未指明其具体构型时，其可以为E或Z构型。立体异构体可以使用手性原料合成、手性拆分制备或者可以使用常规技术例如但不限于使用手性柱的高效液相(HPLC)拆分。
在本文中，术语“受试者”包括任何动物，优选哺乳动物，更优选人。
在本文中，术语“有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明提供了一类新化合物，其对SREBP通路具有抑制活性，可用于预防和/或治疗肥胖、高脂血症、脂肪肝、糖尿病、动脉粥样硬化症、心脑血管疾病、肝癌、皮肤损伤等疾病。
三酯和胆固醇水平是一种预防和/或治疗包括脂肪肝在内的代谢紊乱的有效策略。
附图说明
图1为25-羟羊毛甾醇抑制AMLN饮食诱导的小鼠体重增加的结果。
图2为25-羟羊毛甾醇对小鼠进食量的影响。
图3为25-羟基羊毛甾醇降低小鼠血液总胆固醇的含量。
图4为25-羟基羊毛甾醇降低小鼠血液总甘油三酯的含量。
图5为25-羟基羊毛甾醇降低小鼠肝脏总胆固醇的含量。
图6为25-羟基羊毛甾醇降低小鼠肝脏总甘油三酯的含量。
图7为25-羟基羊毛甾醇降低小鼠血液谷草转氨酶(AST)水平。
图8为25-羟基羊毛甾醇降低小鼠血液谷丙转氨酶(ALT)水平。
图9为小鼠肝脏切片HE染色结果：C57BL/6J CD组。
图10为小鼠肝脏切片HE染色结果：Ldlr-/-CD组。
图11为小鼠肝脏切片HE染色结果：Ldlr-/-AMLN组。
图12为小鼠肝脏切片HE染色结果：Ldlr-/-AMLN+25-HL组。
图13为4组小鼠肝脏切片HE染色结果和NAFLD活动度积分定量统计结果。
图14为小鼠肝脏切片油红O染色结果：C57BL/6J CD组。
图15为小鼠肝脏切片油红O染色结果：Ldlr-/-CD组。
图16为小鼠肝脏切片油红O染色结果：Ldlr-/-AMLN组。
图17为小鼠肝脏切片油红O染色结果：Ldlr-/-AMLN+25-HL组。
图18为4组小鼠肝脏切片油红O染色定量结果。
图19为小鼠肝脏切片天狼星红染色结果：C57BL/6J CD组。
图20为小鼠肝脏切片天狼星红染色结果：Ldlr-/-CD组。
图21为小鼠肝脏切片天狼星红染色结果：Ldlr-/-AMLN组。
图22为小鼠肝脏切片天狼星红染色结果：Ldlr-/-AMLN+25-HL组。
图23为4组小鼠肝脏切片天狼星红染色定量结果。
图24为小鼠肝脏切片F4/80免疫染色结果，以及偏振光成像指示胆固醇结晶的成像结果：C57BL/6J CD组。
图25为小鼠肝脏切片F4/80免疫染色结果，以及偏振光成像指示胆固醇结晶的成像结果：Ldlr-/-CD组。
图26为小鼠肝脏切片F4/80免疫染色结果，以及偏振光成像指示胆固醇结晶的成像结果：Ldlr-/-AMLN组。
图27为小鼠肝脏切片F4/80免疫染色结果，以及偏振光成像指示胆固醇结晶的成像结果：Ldlr-/-AMLN+25-HL组。
图28为4组小鼠肝脏切片F4/80免疫染色定量结果。
图29为4组小鼠肝脏切片偏振光成像指示胆固醇结晶的成像定量结果。
图30为小鼠主动脉树苏丹红IV染色结果：C57BL/6J CD组。
图31为小鼠主动脉树苏丹红IV染色结果：Ldlr-/-CD组。
图32为小鼠主动脉树苏丹红IV染色结果：Ldlr-/-AMLN组。
图33为小鼠主动脉树苏丹红IV染色结果：Ldlr-/-AMLN+25-HL组。
图34为4组小鼠主动脉树苏丹红IV染色定量结果。
图35为25-羟羊毛甾醇降低肝脏类器官中脂质生成相关基因(Hmgcs,Hmgcr和SCD1,FASN)的表达。
图36为25-羟羊毛甾醇降低肝脏类器官中和纤维化相关基因(Col1a1，αSMA)的表达。
图37为小鼠肝脏类器官的明场成像结果：溶媒对照组。
图38为小鼠肝脏类器官的明场成像结果：奥贝胆酸1μM组。
图39为小鼠肝脏类器官的明场成像结果：奥贝胆酸3μM组。
图40为小鼠肝脏类器官的明场成像结果：25-HL 1μM组。
图41为小鼠肝脏类器官的明场成像结果：25-HL 3μM组。
图42为小鼠肝脏类器官的尼罗红染色结果：溶媒对照组。
图43为小鼠肝脏类器官的尼罗红染色结果：奥贝胆酸1μM组。
图44为小鼠肝脏类器官的尼罗红染色结果：奥贝胆酸3μM组。
图45为小鼠肝脏类器官的尼罗红染色结果：25-HL 1μM组。
图46为小鼠肝脏类器官的尼罗红染色结果：25-HL 3μM组。
图47为5组小鼠肝脏类器官的尼罗红染色定量结果。
图48为小鼠肝脏类器官的纤维化标志蛋白αSMA免疫荧光染色结果：溶媒对照组。
图49为小鼠肝脏类器官的纤维化标志蛋白αSMA免疫荧光染色结果：奥贝胆酸1μM组。
图50为小鼠肝脏类器官的纤维化标志蛋白αSMA免疫荧光染色结果：奥贝胆酸3μM组。
图51为小鼠肝脏类器官的纤维化标志蛋白αSMA免疫荧光染色结果：25-HL 1μM组。
图52为小鼠肝脏类器官的纤维化标志蛋白αSMA免疫荧光染色结果：25-HL 3μM组。
图53为5组小鼠肝脏类器官的纤维化标志蛋白αSMA免疫荧光染色定量结果。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
以下实施例中，25-羟羊毛甾醇(25-HL)指的是实施例68化合物。
生物测试实施例
动物：成年雄性C57BL/6J小鼠购于上海斯莱克公司，低密度脂蛋白受体基因敲除小鼠(Ldlr-/-小鼠，T001464)购自江苏集萃药康生物科技股份有限公司。小鼠均养于无致病源的条件下，保持12小时光照/黑暗的条件，自由摄取水和饲料。灌胃液溶媒为：0.5％Tween-80，0.5％甲基纤维素，0.9％氯化钠。AMLN饲料(AMLN,Dyets)含有40％(千卡百分比)脂肪(其中80％为反式脂肪)、22％(质量比)果糖和2％(质量比)胆固醇。
试剂：甲羟戊酸(41288)，多聚甲醛(P6148)，Tween-80(P8074)，甲基纤维素(V900506),油红O(O0625),细胞核染色试剂DAPI购自Sigma-Aldrich公司。洛伐他汀(纯度≥98.5％，HPLC)购于上海药谷公司。细胞培养用的dulbecco's modified eagle medium(DMEM)培养基购自Thermo Scientific公司，胎牛血清(S1580)购于Biowest公司。去脂蛋白血清(LPDS)是本实验室通过超速离心而制备。奥贝胆酸(Obeticholic acid,OCA,CAS登录号459789-99-2，纯度98％(HPLC)。总胆固醇和总甘油三酯试剂盒购自上海科华生物工程股份有限公司。谷丙转氨酶(ALT)和谷草转氨酶(AST)试剂盒购自Lai Er Bio-tech公司。苏木精-伊红染色试剂盒(6765001、6766010)购自Thermo Scientific公司。天狼星红染色试剂盒(ab150681)购自Abcam公司。苏丹红IV(A610914)购自生工生物工程(上海)股份有限公司。尼罗红(HY-D0718)购自MCE公司。
抗体：用于免疫荧光染色分析的抗体如下：抗alpha smooth muscle Actin(αSMA，ab7817,1:500)抗体购自Abcam；二抗荧光素(FITC)偶联的山羊抗小鼠IgG(H+L)(115-095-003)购自Jackson Immunoresearch公司。抗F4/80一抗(14-4801-85，Invitrogen，1:100)、荧光二抗Alexa Fluor Plus 488-偶联的山羊抗大鼠IgG(A-11006，1:500)购自Invitrogen公司。
生物测试实施例1：细胞培养
人肝细胞癌细胞系Huh-7/SRE-Luc生长于含DMEM，10％胎牛血清，100units/ml青霉素、100 μg/ml链霉素和200μg/ml G418的培养基中。
生物测试实施例2：SREBP荧光素酶报告基因系统
Huh-7/SRE-Luc细胞系为人肝细胞癌细胞系Huh-7中稳定表达LDLR promotor-luciferase和绿荧光蛋白(GFP)。其中，LDLR promotor区域含甾醇调控元件(sterol-regulatory-element,SRE)，能够有效且灵敏地响应转录因子SREBP的调控,GFP信号作为内参，指征细胞数量的变化。因此，该细胞系可用于筛选调控SREBP信号通路的活性小分子。我们工作中，利用该细胞系筛选能够有效抑制SREBP信号通路的抑制剂。将细胞孵育于固醇缺乏的培养基中(5％去脂蛋白血清，2μM洛伐他汀，10μM甲羟戊酸)同时添加相应浓度的化合物处理16小时。化合物处理结束后，细胞用裂解液(E397A，Promega)裂解，添加荧光素酶底物(E1500，Promega)后，SRE驱动的荧光素酶的活性通过BioTek Synergy HTX酶标仪(包含但不限于此一类的仪器)测量。绿色荧光蛋白(EGFP)的荧光强度也是通过上述的BioTek酶标仪(包含但不限于此一类的仪器)测量，并作为内参。SRE驱动的荧光素活性除以绿色荧光蛋白的荧光强度后得到的比值作为SREBP通路活性的指标。每一个受试化合物的测试数据经prism软件分析后得到该化合物的IC50参数。
生物测试实施例3：实时荧光定量PCR
肝脏或者肝脏类器官样品在TRI Reagent(T9424，Sigma)中匀浆，根据制造商提供的操作手册提取总RNA。等量的RNA模板以oligo dT引物和MLV逆转录酶(Promega)用于合成cDNA，基因的定量数据通过Bio-Rad CFX96real-time PCR System采集，基因mRNA的相对量是通过相对CT方法来定量。所用引物序列如下表所示：

生物测试实施例4血清和肝脏代谢参数的测量
小鼠药物处理后，移去饲料饥饿4小时后处死小鼠，收集血液和肝脏。血液凝固后于4℃ 1500g离心10分钟，上清即为血清。肝脏中的脂质通过氯仿/甲醇的方法提取，先用匀浆仪Precelly 24匀浆破碎，于4℃ 16000g离心10分钟，有机相转移到新管中，用氮气吹干，之后用乙醇溶解。血液和肝脏中的总胆固醇和甘油三酯水平分别通过胆固醇和甘油三酯试剂盒(上海科华生物工程有限公司)测量。血清中的ALT(LE-M0477，Lai Er Bio-tech)，AST(LE-M0568，Lai Er Bio-tech)，分别根据相应制造商的手册，采用希森美康医用电子(上海)有限公司的分析系统进行测量。
生物测试实施例5：肝脏的组织切片分析
苏木精-伊红染色：摘取后的肝脏用4％多聚甲醛4℃固定过液，石蜡包埋，用石蜡切片机(Leica RM2235)切片，切片厚度为7μm，脱蜡复水后用苏木精-伊红染色试剂盒(6765001，6766010，Thermo Scientific)染色，图像用Olympus VS 120玻片显微镜拍摄，用ImageJ软件定量。油红O染色：肝脏用OCT包埋剂(Leica)包埋，用冰冻切片机(Leica CM1950)切为7μm厚，并用Oil Red O(O0625，Sigma)染色，图像用Olympus VS120玻片显微镜拍摄，并用ImageJ软件定量。天狼星红(Sirius Red)胶原染色：肝脏的石蜡切片脱蜡复水后，按照厂家说明书用天狼星红染色试剂盒(ab150681,Abcam)进行染色。免疫荧光染色：肝脏用OCT包埋剂(Leica)包埋，用冰冻切片机(Leica CM1950)切为7μm厚，冰冻切片用抗F4/80大鼠单克隆抗体(14-4801-85,Invitrogen,1:100),Alexa Fluor 488偶联的山羊抗大鼠IgG二抗(A-11006,Invitrogen,1:500)染色，DAPI(Sigma)30特异染色细胞核。染色封片后，用转盘共聚焦显微镜(Nikon CSU-W1SoRa)拍照，并用ImageJ软件进行定量分析。胆固醇晶体的偏振光成像：冰冻切片F4/F80和DAPI染色后，用配置有偏振光滤光片的转盘共聚焦显微镜(Nikon CSU-W1SoRa)进行拍照，并用ImageJ软件定量。
生物测试实施例6小鼠动脉树分离和动脉粥样硬化斑块苏丹红IV染色
小鼠给药实验结束后，主动脉被分离并固定在4％的PFA中，在体视显微镜下用眼科钳取出血管周围脂肪组织后，用苏丹IV染色，用70％乙醇清洗动脉粥样硬化斑块。染色后，用ZEISS Axio Zoom.V16立体显微镜对主动脉树进行成像。用ImageJ软件对动脉粥样硬化病变进行量化。
生物测试实施例7小鼠肝脏类器官的制备和培养
C57BL/6N小鼠在12周龄时投喂脂肪肝诱导饲料(TrophicDiet，TP2630052A，含有10.2％kcal蛋白质、37.3％kcal碳水化合物，52.6％kcal脂肪)和含果糖的饮用水(23.1g果糖和18.9g葡萄糖溶解在1L水中，然后过滤灭菌)共16周，生成脂肪肝模型。为了生成脂肪肝肝脏类器官，将脂肪肝小鼠的肝脏组织切碎，在37℃的消化缓冲液中消化30-60分钟。消化缓冲液包括DMEM/F-12(Cytiva,SH30023.01)和2.5mg/mL胶原酶D(罗氏，COLLD-RO)，0.1mg/mL DNaseI(Sigma-Aldrich,DN25)。分离的单个肝细胞，经70μm滤膜过滤，洗涤1次。离心收集细胞，将培养基与基底膜提取物(BME)(R&D Systems,3533-010-02)按1:3的比例混合重悬。培养基包括AdDMEM/F12,10mM Hepes,1x Glutamax,1％pen/strep,1x B27,1x N2,NAC(1mM),NIC(10mM),Gastrin(10nM),EGF(50ng/mL), FGF10(100ng/mL),A83-01(5μM),Rki(10μM),10％RSPO1条件培养基,30％Wnt3a条件培养基,5％Noggin条件培养基的培养条件中。给药前，类器官经胰酶(Gibco,Cat#25200072)消化后重悬。24小时后，以DMSO作为空白对照，给类器官换液含有不同浓度OCA或25-HL的培养基。将脂肪肝肝脏类脏器分为5组(1‰DMSO、1μM OCA、3μM OCA、1μM 25-HL和3μM 25-HL)，分别给予72小时药物治疗。
生物测试实施例8小鼠肝脏类器官的组织化学染色
免疫细胞化学:将类器官固定在免疫染色固定液(Beyotime Biotechnology,P0098)中，4℃过夜。然后在PBS中洗涤，然后用含0.5％Triton X-100的PBS在室温下处理20分钟。然后将类器官用含10％山羊血清的PBS封闭溶液在室温下处理1小时，并与一抗(Anti-alpha smooth muscle Actin,ab7817,Abcam,1:500稀释)在4℃下孵育一夜。第二天，将类器官洗净，与第二抗体荧光素(FITC)偶联的山羊抗小鼠IgG(H+L)共孵育(Jackson Immunoresearch,115-095-003)。细胞核用荧光盾TM与DAPI(Sigma-Aldrich,F6057)复染。
为了观察脂滴，类器用4％多聚甲醛(PFA)固定1小时，室温下用250nmol/L尼罗红(MCE,HY-D0718)染色3分钟。成像前用PBS冲洗两次类器官。染色的类器官在Dragonfly高速共聚焦显微镜系统(Andor,Dragonfly 200)下观察。
生物测试实施例9本发明化合物对SREBP通路抑制效果
通过生物测试实施例2的方法测试本发明化合物对SREBP通路的抑制效果，每个化合物浓度梯度设计为0.01、0.03、0.1、0.3、1.0、3.0、10μM，对照为溶媒DMSO。部分化合物的IC50值如表1中所示。
表1：部分实施例的化合物的活性数据






















生物测试实施例10 25-羟羊毛甾醇降低血脂水平、缓解脂肪肝和肝脏损伤
已知血液脂质水平升高和肝脏脂质蓄积是脂肪肝的高危因素，本发明进而分析了25-羟羊毛甾醇是否能减缓饮食诱导的小鼠脂肪肝的典型症状：脂质蓄积、肝损伤、炎症和纤维化。
购买8周龄的雄性C57BL/6J小鼠和雄性Ldlr-/-小鼠(T001464,江苏集萃药康生物科技股份有限公司)，分组并投喂不同的饲料以及给予不同药物处理，小鼠随机分成4组，每组8-9只小鼠：1组为C57BL/6J野生型小鼠投喂基础饲料(chow diet，CD)溶媒对照组。其它3组均为Ldlr-/-基因敲除小鼠，分别为基础饲料(CD)溶媒对照组,AMLN饲料(AMLN diet,含20％脂肪，22％果糖，2％胆固醇)溶媒对照组，AMLN饲料25-羟羊毛甾醇给药组(25-羟羊毛甾醇的给药浓度为30mg/kg/day)。4组小鼠每天灌胃一次，期间统计不同处理组小鼠的进食和体重变化。8周后收集小鼠的血液和肝脏，分析血脂、肝脂和肝脏损伤的表型。
结果如图1-8所示，其中，图1为各组小鼠每周称重的统计结果，图2为各组小鼠进食量累积统计，图3为25-羟基羊毛甾醇降低小鼠血液总胆固醇的含量，图4为25-羟基羊毛甾醇降低小鼠血液总甘油三酯的含量，图5为25-羟基羊毛甾醇降低小鼠肝脏总胆固醇的含量，图6为25-羟基羊毛甾醇降低小鼠肝脏总甘油三酯的含量，图7为25-羟基羊毛甾醇降低小鼠血液谷草转氨酶(AST)水平，图8为25-羟基羊毛甾醇降低小鼠血液谷丙转氨酶(ALT)水平。
图1和图2中，P值采用统计学双因素two-way ANOVA(Dunnett's multiple comparisons test)方差分析计算；*表示P<0.05；ns表示无统计学差异。图3-图8中，数据以平均值±标准偏差表示。P值采用单因素one-way ANOVA方差分析*表示P<0.05,**表示P<0.01,***表示P<0.001。
结果显示，连续给药8周后，Ldlr-/-小鼠在投喂AMLN饲料同时给药25-羟羊毛甾醇组，其体重增加显著低于AMLN饲料溶媒对照组。说明25-羟羊毛甾醇对AMLN饮食诱导的体重增加有很好的抑制效果。脂肪性肝病的病理特征主要包括肝脏的脂肪变性、肝脏损伤、炎症浸润和纤维化。4组小鼠给药8周后，我们首先检测了小鼠血液总胆固醇，总甘油三酯等脂质水平的变化以及肝脏总胆固醇和总甘油三酯脂质水平的变化。如图3-4所示：与对照组相比，25-羟羊毛甾醇显著减低血清中总胆固醇和总甘油三酯水平。同时如图5-6所示25-羟羊毛甾醇显著减低小鼠肝脏总胆固醇和总甘油三酯水平。表明25-羟羊毛甾醇具有良好的降低血脂和肝脂的效果。从图7-8中可以看出，血清中的肝损伤标志分子谷草转氨酶AST和丙氨酸转氨酶ALT都被25-羟羊毛甾醇显著降低。表明25-羟羊毛甾醇具有良好的改善肝脏损伤的效果。
生物测试实施例11 25-羟羊毛甾醇减缓脂肪肝和动脉粥样硬化
进一步，我们对各组小鼠的肝脏组织切片进行多种染色或者免疫组化操作，分析其肝脏脂质蓄积和脂肪肝的表型变化。结果如图9-29所示，其中，图9-13为小鼠肝脏切片HE染色结果和NAFLD活动度积分定量结果：25-羟羊毛甾醇减少肝脏的脂肪变性并显著降低NAFLD活动度积分；图14-18为小鼠肝脏切片油红O染色和定量结果：25-羟羊毛甾醇减少肝脏中的脂滴；图19-23为小鼠肝脏切片天狼星红染色和定量结果：25-羟羊毛甾醇减少肝脏中的纤维化；图24-29为小鼠肝脏切片F4/80免疫染色和定量结果，以及偏振光成像指示胆固醇结晶的成像和定量结果：25-羟羊毛甾醇减少肝脏中Kupffer细胞的聚集和胆固醇结晶的形成。
图9-29定量分析采用Image J软件进行，数据以平均值±标准偏差表示。P值采用单因素one-way ANOVA方差分析*表示P<0.05,**表示P<0.01,***表示P<0.001。
结果如图9-13苏木精－伊红染色所示：雄性Ldlr-/-小鼠在AMLN饲料喂养8周后肝脏中含有明显的大泡状脂滴、气泡状变性肝细胞。和对照组相比，25-羟羊毛甾醇显著减少所述表型。同时，图14-18肝脏组织切片的油红O染色结果显示：和对照组相比，25-羟羊毛甾醇显著减少肝脏中包括胆固醇和脂肪酸在内的中性脂类的脂滴堆积。这些结果和图1-8中25-羟羊毛甾醇降低肝脏脂质含量的结果相一致，表明25-羟羊毛甾醇有效改善AMLN饮食诱导的肝脏脂质堆积表型。此外，本发明进一步分析了肝脏中脂肪肝相关的炎症和纤维化表型的变化。图24-29免疫荧光染色结果显示溶媒对照Ldlr- /-AMLN饲料喂养小鼠中，F4/80特异性染色显示Kupffer细胞聚集在一起并在胆固醇结晶周围形 成皇冠状结构(图24-27放大图)。25-羟羊毛甾醇显著减少Kupffer细胞形成的皇冠状结构，说明25-羟羊毛甾醇可显著减少肝脏的炎症浸润。肝脏切片中胆固醇晶体的偏振光成像结果显示在溶媒对照小鼠中，Kupffer细胞形成的皇冠状结构内部含有大量的胆固醇晶体。与单纯脂肪变性相比，这些胆固醇晶体和Kupffer细胞形成的皇冠状结构是脂肪肝的标志性特征，巨噬细胞被胆固醇晶体吸引并试图清除这些残留的脂滴，与动脉粥样硬化中描述的现象相似。更为重要的是，25-羟羊毛甾醇明显减少了皇冠状结构和胆固醇晶体的数量(图24-29)。同时，图19-23天狼星红染色结果显示25-羟羊毛甾醇显著减少小鼠肝脏组织切片胶原纤维形成的纤维化表型。以上结果提示25-羟羊毛甾醇缓解肝脏脂肪蓄积和脂肪肝的症状，可用于预防和/或治疗高血脂和脂肪肝等疾病。
AMLN喂养的Ldlr-/-小鼠也是动脉粥样硬化的常用模型，因此我们可以同时研究脂肪肝和动脉粥样硬化。8周龄雄性Ldlr-/-小鼠，投喂AMLN饲料，同时灌胃给药，每日1次，共8周。处死小鼠后，分离主动脉并用4％多聚甲醛固定。在体视显微镜下去除血管周围脂肪组织，经苏丹红IV染色，70％乙醇漂洗。用体视显微镜(德国蔡司，Axio Zoom Vl6)对主动脉树进行成像。并用ImageJ软件对动脉粥样硬化病变斑块进行定量分析。
结果如图30-34所示，图30-34为小鼠主动脉树苏丹红IV染色和定量结果：25-羟羊毛甾醇减少动脉粥样硬化斑块的形成。
结果显示，连续给药8周后，分离各组小鼠的主动脉树，进行主动脉苏丹红IV脂质特异性染色，如图30-34所示与对照组小鼠相比25-羟羊毛甾醇显著减少动脉粥样硬化斑块的形成和数量。25-羟羊毛甾醇对动脉粥样硬化的形成具有减缓作用。
图1-8至图9-34这些数据表明25-羟羊毛甾醇减少血液脂质水平升高，减少肝脏的脂肪蓄积、胆固醇结晶、肝细胞损伤、炎症浸润和纤维化，减少动脉粥样硬化斑块的形成和数量。说明25-羟羊毛甾醇针对高血脂、脂肪肝、动脉粥样硬化具有良好疗效。
生物测试实施例12利用体外肝脏类器官证明25-羟羊毛甾醇对脂肪肝的脂质生成和纤维化具有抑制效果
为了区分25-羟羊毛甾醇的抑制效果是直接基于对肝脏的影响还是全身系统性效应。我们利用3D肝脏类器官作为一种体外的脂肪肝的研究模型，分析25-羟羊毛甾醇对肝脏类器官脂质生成和纤维化标志分子表达的影响。我们给C57BL/6N小鼠在12周龄时投喂脂肪肝诱导饲料(TrophicDiet，TP2630052A，含有10.2％kcal蛋白质、37.3％kcal碳水化合物，52.6％kcal脂肪)和含果糖的饮用水(23.1g果糖和18.9g葡萄糖溶解在1L水中，然后过滤灭菌)共16周，生成脂肪肝模型。从该模型鼠肝脏器官分离并制备肝脏类器官进行体外培养。同时对类器官进行体外给药处理，奥贝胆酸(Obeticholic acid,OCA)是farnesoid X receptor(FXR)的激动剂，该药物在临床三期试验中表现了良好的抗脂肪肝的效果，本实施例采用此药物作为对照药物。类器官分组并给予相同浓度梯度的奥贝胆酸和25-羟羊毛甾醇处理3天，收集类器官RNA并采用荧光实时定量PCR分析脂质合成相关基因(Hmgcs,Hmgcr,SCD1,FASN)以及纤维化标志分子(αSMA,Col1α1)的表达差异。
结果如图35-53所示，其中，图35为25-羟羊毛甾醇降低肝脏类器官中脂质生成相关基因(Hmgcs, Hmgcr和SCD1,FASN)的表达，且效果优于相同浓度的对照药物奥贝胆酸；图36为25-羟羊毛甾醇降低肝脏类器官中和纤维化相关基因(Col1a1，αSMA)的表达，且效果优于相同浓度的对照药物奥贝胆酸；图37-53为肝脏类器官的明场成像结果，尼罗红染色和定量结果和纤维化标志蛋白αSMA免疫荧光染色和定量结果：25-羟羊毛甾醇降低肝脏类器官中脂质蓄积同时降低肝脏类器官中纤维化标志蛋白αSMA表达。
图35，图36数据以平均值±标准偏差表示。P值采用单因素one-way ANOVA方差分析ns表示无统计学差异，*表示P<0.05,**表示P<0.01,***表示P<0.001。图47和图53的定量分析采用Image J软件进行。数据以平均值±标准偏差表示。P值采用单因素one-way ANOVA方差分析*表示P<0.05,**表示P<0.01,***表示P<0.001。
结果显示，相较于奥贝胆酸未能抑制脂质合成基因表达，25-羟羊毛甾醇能显著抑制脂质合成相关基因(图35)和纤维化相关基因(图36)的表达水平。同时，尼罗红染色实验检测类器官中性脂质的蓄积情况，如图37-53结果显示25-羟羊毛甾醇和OCA使类器官的脂质积累减少，纤维化标志蛋白αSMA的染色数据显示纤维化蛋白αSMA表达显著减少。图35-53结果说明25-羟羊毛甾醇通过抑制脂肪生成和纤维化基因的表达，直接减少肝脏脂质积累和纤维化，而OCA可能通过促进脂质氧化，间接抑制肝脏脂质积累。这些数据证明了25-羟羊毛甾醇直接靶向对肝脏脂质合成途径和纤维化基因的调控。
效果实施例13：肝微粒体代谢稳定性实验
分别配置PBS溶液(100mM)，MgCl2溶液(100mM)和NADPH溶液(20mM)，然后分别用二甲基亚砜(DMSO)配置化合物和睾酮(阳性对照)储备液，用甲醇稀释至100μM用于样品孵育，-10～-30℃保存。分别取12.5μL大鼠肝微粒体(购自XenoTech，货号：R1000，批号：1310030，规格：20mg/ml)、432.5μL PBS溶液(100mM)、25μL NADPH溶液(20mM)及25μL MgCl2溶液(100mM)加入96孔板中混匀后于37℃预孵育5分钟；加入5μL底物(待测化合物)溶液启动反应；分别于各设定时间点0、5、15、30、45、60分钟(阴性组为0、60分钟)，取50μL孵育样品置于加好100μL冰终止液的终止板中，涡旋1分钟灭活，-60～-90℃保存，待后续分析。待测化合物和对照化合物睾酮的样品分析采用LC-MS/MS方法进行。使用Analyst软件对色谱峰进行积分、计算和处理。待测化合物和对照化合物睾酮均采用半定量分析法，以峰面积比进行计算。
表2：部分实施例的化合物的大鼠肝脏微粒体稳定性结果
与对照化合物68相比，本发明化合物在大鼠肝脏微粒体代谢稳定性明显提高，显著优于68化合物。
关键中间体的制备
中间体II乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯的制备
第一步 (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-6-甲基庚-5-烯-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(10.00g,23.4mmol,1.0eq)溶解于DCM(250mL)中，完全溶解后依次向反应体系中加入乙酸酐(6.7mL,71.0mmol，3.0eq)，DMAP(0.57g,4.7mmol,0.2eq)和TEA(16.3mL,117.2mmol,5.0eq)，加料完毕后在室温下搅拌2小时。TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应完全后，用甲醇(10mL)萃灭，反应液用饱和碳酸氢钠(～100mL)和水(～100mL)各洗涤一次，无水硫酸钠干燥，浓缩，在浓缩快干时，加入甲醇(～100mL)，冰浴下搅拌30分钟，抽滤，滤饼用少量甲醇淋洗，滤饼干燥得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-6-甲基庚-5-烯-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(I)(9.00g，17.3mmol，纯度90.0％，收率82.54％)。1H NMR(400MHz,CDCl3):δ4.50(dd,J＝11.5,4.5Hz,1H),2.69(s,1H),2.09-1.87(m,8H),1.77-1.24(m,26H),1.15(d,J＝11.4Hz,3H),1.00(s,3H),0.93-0.85(m,12H),0.69(d,J＝2.7Hz,3H).13CNMR(400MHz,CDCl3):δ203.21,171.00,134.37,134.32,99.99,80.90,77.34,77.02,76.71,50.50,50.30,49.82,44.54,41.14,37.81,36.90,36.08,36.03,35.27,30.95,30.78,28.24,28.15,27.91,26.38,24.23,24.17,21.33,20.98,19.19,18.46,18.40,18.11,16.53,15.78.
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-6-甲基庚-5-烯-2-基]- 2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(I)(15.00g,32.0mmol,1.0eq)溶于DCM(二氯甲烷)(300mL)中，氮气置换，体系冰浴下降温到0℃，通入臭氧，鼓气10min。TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应，点板产物点明显比原料点浓，停止通气，体系用氮气置换后直接浓缩至干，粗产物用快速色谱法分离纯化(PE:EtOAc＝95:5to 90:10,磷钼酸烤板)纯化，得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(II)(6.50g,13.2mmol,纯度95.5％,收率41.3％)。1H NMR(400MHz,CDCl3)：δ9.77(t,J＝1.9Hz,1H),4.50(dd,J＝11.6,4.5Hz,1H),2.51-2.30(m,2H),2.09-1.88(m,8H),1.86-1.24(m,17H),1.23-1.12(m,2H),0.99(d,J＝11.2Hz,3H),0.93-0.84(m,12H)。
中间体VI(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸的制备
第一步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(II)(1.50g,3.4mmol，1.0eq)溶解在二氯甲烷(50mL)中，0℃下依次加入三乙胺(1.41mL,10.2mmol，3.0eq)和叔丁基二甲硅基三氟甲磺酸酯(1.30g,5.1mmol，1.5eq)。反应液0℃搅拌2小时，TLC(PE：DCM＝3:1，磷钼酸烤板)显示原 料点消失，反应液浓缩至干，加入正已烷(50mL)搅拌10分钟，过滤，滤液旋干，加入DCM(50mL)，反应液冷却到-78℃,通入臭氧，鼓泡10分钟，TLC(PE：DCM＝3:1)监测原料点消失，加入PPh3(0.89g,3.4mmol，1.0eq)搅拌30分钟，反应液直接浓缩，柱层析纯化(PE:EtoAc＝90:10)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(III)(300mg,0.560mmol,16.52％)。1H NMR(400MHz,CDCl3)δ9.76(dd,J＝3.3,1.1Hz,1H),4.50(dd,J＝11.6,4.5Hz,1H),2.47(dd,J＝16.4,2.5Hz,1H),2.17(m,1H),2.04(m,7H),1.92(m,1H),1.43(m,18H),0.99(dd,J＝9.3,2.8Hz,5H),0.90(m,12H),0.74(s,2H).
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(III)(300mg,0.700mmol,1.0eq)溶解在二氯甲烷(10mL)中，加入乙基(三苯基膦)乙酸酯(243.81mg,0.700mmol,1.0eq)，反应液室温搅拌2小时。TLC(PE:DCM＝3：1,磷钼酸烤板)监测反应完全，反应液直接浓缩，硅胶柱层析(PE:EtOAc＝95:5)得到白色固体(2E,5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己-2-烯酸乙酯(IV)(250mg,0.401mmol,57.30％)。1H NMR(400MHz,CDCl3)δ6.96(m,1H),5.81(d,J＝15.5Hz,1H),4.50(dd,J＝11.5,4.5Hz,1H),4.19(q,J＝7.1Hz,2H),1.99(m,8H),1.63(m,12H),1.31(m,6H),1.17(m,3H),1.00(s,3H),0.92(t,J＝5.3Hz,4H),0.87(m,10H),0.69(m,3H).13C NMR(101MHz,CDCl3)δ171.01,148.45,134.35,122.47,80.90,77.33,77.21,77.01,76.69,60.12,50.50,50.24,49.86,44.60,39.33,37.81,36.91,36.38,35.26,30.80,28.22,27.91,26.92,26.38,24.25,24.17,21.33,20.96,19.19,18.96,18.11,16.53,15.78,14.29,-0.01.
第三步 (2E,5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己-2-烯酸乙基酯(IV)(250mg,0.55mmol,1.0eq)溶解在甲醇(10mL)中，加入钯(钯炭)(30mg,0.282mmol)，氢气氛围下，搅拌3小时，TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应,反应完全后，硅藻土滤掉钯碳，滤液浓缩至干，硅胶柱层析纯化(PE:EtOAc＝80:20,磷钼酸烤板)得到白色固体(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸乙基酯(V)(200mg,0.392mmol,71.68％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.5,4.5Hz,1H),4.13(q,J＝7.1Hz,2H),2.26(dd,J＝15.5,8.6Hz,2H),2.04(m,8H),1.68(m,7H),1.50-1.37(m,9H),1.26(t,J＝7.1Hz,3H),1.15(m,3H),1.00(s,3H),0.90(m,12H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ173.95,171.03,80.95,77.33,77.22,77.02,76.70,60.16,50.52,50.26,49.82,44.49,37.82,36.91,36.21,35.69,35.28,34.82,30.96,30.80,28.16,27.92,26.39,24.25,24.18,21.85,21.34,21.00,19.19,18.61,18.13,16.54,15.75,14.28,
第四步 (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸乙酯(V)(200mg,0.40mmol)溶解在乙醇(2mL)中，加入氢氧化钠溶液(2mL,4mol/L)，反应液加热到回流，搅拌过夜。TLC(PE: EtOAc＝5:1,磷钼酸烤板)监测反应。反应完全后，反应液降温到室温，用1N的盐酸调pH＝1，乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝90:10to 50:50)得到白色固体(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸(VI)(150mg,0.331mmol,82.84％)。1H NMR(400MHz,CDCl3)δ3.24(dd,J＝11.6,4.5Hz,1H),2.33(m,2H),2.04(d,J＝8.2Hz,4H),1.91(dd,J＝13.4,7.5Hz,1H),1.70(m,6H),1.50(m,7H),1.19(m,7H),0.99(d,J＝7.8Hz,5H),0.91(t,J＝5.9Hz,3H),0.87(s,3H),0.81(s,3H),0.69(s,3H).
中间体VII(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸的制备
将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(II)(3.00g,6.78mmol，1.0eq.)溶于丙酮(50.0mL)中(溶不清，浑浊)，置换氮气三次后，降温至0℃，缓慢滴加琼斯试剂(7.8mL,2.0M,2.0eq.)反应5分钟后,TLC监测(PE:EA＝5:1,磷钼酸显色,Rf1＝0.72,Rf2＝0.34)。反应完，低温滴加15.0mL异丙醇淬灭,搅拌30分钟,浓缩后用50.0ml二氯甲烷溶解,分别用30.0mL 1.5N NaHSO3和30.0mL H2O洗一次干燥浓缩之后，得到粗品白色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VII)(3.00g,4.56mmol,67.56％).1H NMR(400MHz,Chloroform-d)δ4.48(dd,J＝11.6,4.6Hz,1H),2.40(ddd,J＝15.4,9.9,5.0Hz,2H),2.25(ddd,J＝15.9,9.5,6.4Hz,1H),2.08–1.92(m,7H),1.84–1.56(m,8H),1.45(td,J＝13.6,12.0,7.2Hz,3H),1.31(dt,J＝11.8,4.3Hz,2H),1.23–1.07(m,3H),0.98(s,3H),0.88(q,J＝4.7,3.8Hz,12H),0.67(s,3H).13C NMR(100MHz,Chloroform-d)δ179.93,171.11,134.35,134.23,80.94,50.44,50.18,49.78,44.49,37.77,36.86,35.98,35.22,31.14,30.99,30.92,30.74,28.04,27.88,26.33,24.20,24.13,21.32,20.95,19.17,18.24,18.08,16.51,15.75.
中间体VIII(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸的制备
称取(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(500mg,1.09mmol,1.0eq.),加入四氢呋喃(20.0mL),甲醇(20.0mL),1M氢氧化锂水溶液(20.0mL),室温下搅拌过夜，点板监测，反应结束后，浓缩除去四氢呋喃和甲醇，随后浓缩液中加入水(30.0mL),再以乙酸乙酯(30.0mL*3)萃取，有机相合并，干燥，浓缩得(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VIII)(350mg,77.1％).1HNMR(400MHz,DMSO-d6)δ11.99(s,1H),4.35(d,J＝5.1Hz,1H),3.07–2.96(m,1H),2.18(dddd,J＝22.7,15.9,9.3,6.2Hz,2H),2.04–1.84(m,5H),1.73–1.06(m,16H),0.92(ddd,J＝30.4,18.0,4.7Hz,12H),0.70(s,3H),0.65(s,3H).
中间体IX(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁酸的制备
化合物乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(III)(2.30g,5.2mmol,1.0eq)溶解于t-BuOH(叔丁醇)(60mL)中，冰浴下加入2-甲基-2-丁烯(2.19g,31.2mmol,6.0eq)以及磷酸二氢钠(2.1g,15.6mmol,3.0eq)和亚氯酸钠(1.41g,15.6mmol,3.5eq)的水溶液(15mL)，反应液在室温下搅 拌2hrs。TLC(PE:EtOAc＝5:1，磷钼酸显色剂)显示反应已经完成。反应液浓缩后，用EtOAc(50mL)萃取，用饱和碳酸氢钠(50mL×2)洗涤。有机层用无水硫酸钠干燥，粗品用PE:EtOAc＝3:1过柱，得到固体(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁酸(IX)(1.6g,纯度90％,收率60.42％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.6,4.5Hz,1H),2.40(dd,J＝10.2,5.2Hz,1H),2.29(dd,J＝9.5,6.5Hz,1H),2.11–1.87(m,8H),1.83(dd,J＝10.0,3.5Hz,1H),1.77–1.54(m,7H),1.53–1.44(m,2H),1.43–1.22(m,4H),1.22–1.10(m,2H),1.00(s,3H),0.97–0.81(m,12H),0.69(s,3H).
制备实施例
实施例1
化合物1(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酰胺的制备
(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸VI(50mg,0.116mmol,1.0eq)溶解在无水四氢呋喃(5mL)中，依次加入DCC(二环己基碳二亚胺)(72mg,0.35mmol,3.0eq)和N-羟基丁二酰亚胺(40mg,0.35mmol,3.0eq)，反应搅拌过夜。体系有固产生，过滤除去固体，滤液旋干，剩余物溶解在DMF(3mL)中，加入氨水(25％)(0.05mL,1.298mmol，11eq)，反应加热到50℃，搅拌过夜，TLC监测反应(PE:EtOAc＝1:1,磷钼酸烤板)，反应完全后，反应液用水(30mL)稀释，分出有机相，有机相用饱和盐水洗涤，无水硫酸钠干燥，硅胶柱层析(PE:EtOAc＝50:50)得到白色固体(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酰胺(1)(30 mg,0.052mmol,45.10％)。1H NMR(400MHz,CDCl3)δ5.31(d,J＝44.1Hz,2H),3.23(dd,J＝11.5,4.5Hz,1H),2.30-2.10(m 2H),2.09-1.96(m,4H),1.95-1.85(m,1H),1.75-1.65(m,5H),1.60-1.38(m,10H),1.35-1.27(m,1H),1.24-1.05(m,4H),1.01(dd,J＝16.9,5.1Hz,6H),0.93(d,J＝6.5Hz,2H),0.87(s,3H),0.81(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ175.45,134.54,79.00,77.34,77.22,77.02,76.70,50.42,38.90,36.27,35.79,35.60,30.98,30.83,29.71,28.21,27.97,27.86,26.51,24.27,21.00,19.15,18.65,18.26,15.75,15.42.LC-MS:[M+H]+＝530.10
实施例2
化合物2(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,1 0,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-丙基戊酰胺的制备
第一步 将(4R)-4-[(1R,3aR,5aR,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸VII(100mg,0.22mmol)溶于DMF(N,N-二甲基甲酰胺)(5.0mL)中，加入N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(99.47mg,0.26mmol)和二异丙基乙基胺(0.04mL,0.26mmol)，室温搅拌0.5h后加入丙胺(29.06mg,0.24mmol)，室温下反应4h，TLC监测(PE:EtOAc＝3:1,磷钼酸显色,Rf1＝0.52,Rf2＝0.62)反应完后，反应液加水和EtOAc洗萃，有机相盐水洗一次合并干燥浓缩得黄色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-氧亚基-5-(丙基氨基)戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(2-1)(100mg,0.167mmol,83.33％),直接用于下一步。
第二步 将(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-丙基戊酰胺(100mg,0.167mmol)溶解在四氢呋喃(2.0mL)和甲醇(2.0mL)中,加入1M氢氧化锂水溶液(2.0mL,2.00mmol)，室温过夜搅拌。TLC监测(PE:EtOAc＝3:1,磷钼酸显色,Rf1＝0.62,Rf2＝0.24)反应完后，将反应液浓缩送制备分离得到白色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,1 0,11,11a-十 四氢-1H-环戊并[1,2-a]菲-1-基]-N-丙基戊酰胺(2)(37.63mg,0.08mmol,40.43％)。1H NMR(399MHz,CDCl3)δ5.57(1H,s)3.19(3H,d,J＝3.5),2.24(1H,s)2.00(6H,s),1.80(3H,s),1.80(3H,s),1.67(4H,m),1.47(5H,m),1.34(3H,d,J＝23.5),1.18(3H,dd,J＝27.9,10.4),0.96(7H,t,J＝8.2),0.85(3H,s)0.78(3H,d,J＝23.5)0.66(3H,s).13C NMR(101MHz,CDCl3)δ173.73,134.38,78.94,77.32,77.00,76.69,50.36,50.28,49.79,44.50,41.35,38.86,36.99,36.20,35.55,34.04,32.22,30.97,30.79,28.19,27.94,27.80,26.46,24.24,22.93,20.96,19.12,18.48,18.21,15.77,15.40,11.42.LC-MS:[M+H]+＝458.60
实施例3
化合物3(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(3,4,5,6-四氢-2H-吡喃-4-基)戊酰胺的制备
参照实施例2，将第一步的胺换为四氢吡喃-4-胺，最终得到(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(3,4,5,6-四氢-2H-吡喃-4-基)戊酰胺(3)。1H NMR(399MHz,CDCl3)δ5.30(s,1H),3.93(d,J＝11.5Hz,2H),3.45(t,J＝11.4Hz,2H),3.21(d,J＝11.2Hz,1H),2.22(s,1H),2.00(s,5H),1.87(d,J＝12.9Hz,3H),1.81–1.5 9(m,6H),1.58(s,2H),1.42(d,J＝9.8Hz,5H),1.31(s,2H),1.27–1.11(m,3H),0.98(t,J＝10.3Hz,6H),0.89(d,J＝5.3Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ172.86,134.38,134.28,78.95,77.31,76.99,76.67,66.78,50.35,50.25,49.78,45.51,44.50,38.86,36.98,36.13,35.55,33.94,33.22,32.02,30.96,30.77,28.15,27.93,27.79,26.45,24.21,20.95,19.12,18.41,18.21,15.74,15.39.LC-MS:[M+H]+＝500.60。
实施例4
化合物4(4R)–4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-甲基苯基)戊酰胺的制备
参照实施例2，将第一步的胺换为2-甲基苯胺，最终得到(4R)–4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-甲基苯基)戊酰胺(4)。1H NMR.(399MHz,CDCl3)δ7.80(s,1H),7.17(s,2H),7.05(s,1H),6.89(m,1H),3.22(d,J＝11.1Hz,1H),2.47(m,1H),2.29(s,1H),2.25(s,3H),2.01(s,5H),1.71(s,4H),1.49(s,3H),1.41(s,2H),1.22(d,J＝12.0Hz,4H),1.05(s,1H),0.97(d,J＝7.8Hz,9H),0.87(s,3H),0.79(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ171.72,135.65,134.38,134.29,130.41,126.79,125.09,123.16,78.97,77.31,76.99,76.67,50.35,49.80,44.53,38.87,37.00,36.16,35.55,34.75,32.07,30.98,30.79,28.15,27.94,27.80,26.46,24.23,20.96,19.13,18.43,18.21,17.80,15.78,15.40,1.00.LC-MS:[M+H]+＝506.65
实施例5
化合物5(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例2，将第一步的胺换为2-氟苯胺，最终得到(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(5).1H NMR(399MHz,CDCl3)δ8.31(s,1H),7.30(s,1H),7.08(m,3H),3.22(dd,J＝11.5,4.4Hz,1H),2.47(s,1H),2.29(s,1H),2.02(s,4H),1.91(m,1H),1.68(dd,J＝27.2,10.4Hz,5H),1.47(t,J＝20.3Hz,6H),1.20(dd,J＝20.5,10.9Hz,3H),1.03(d,J＝12.4Hz,1H),0.97(d,J＝7.6Hz,6H),0.94(d,J＝4.9Hz,3H),0.87(s,3H),0.79(s,3H),0.68(s,3H).13C NMR(101MHz,Chloroform-d)δ134.29,124.59,121.66,78.97,77.18,50.36,50.28,49.80,44.53,38.86,36.99,36.12,35.55,34.90,31.72, 30.97,30.79,28.12,27.93,27.80,26.46,24.22,20.96,19.12,18.42,18.21,15.76,15.39.LC-MS:[M+H]+＝510.40
实施例6
化合物6(4R)-N-(2-氯苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例2，将第一步的胺换为2-氯苯胺，最终得到(4R)-N-(2-氯苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(6).1H NMR(399MHz,CDCl3)δ8.36(s,1H),7.59(s,1H),7.34(d,J＝8.0Hz,1H),7.01(t,J＝7.9Hz,1H),3.22(dd,J＝11.6,4.5Hz,1H),2.49(s,1H),2.37–2.27(m,1H),2.01(s,6H),1.69(t,J＝16.6Hz,6H),1.41(s,2H),1.27–1.07(m,4H),1.03(d,J＝12.1Hz,1H),0.98(s,3H),0.95(d,J＝8.3Hz,6H),0.89–0.86(m,3H),0.79(s,3H),0.69(s,3H).13C NMR(101MHz,Chloroform-d)δ134.62,128.90,127.73,124.40,121.53,78.95,77.19,50.36,50.28,49.80,44.54,38.87,37.00,36.10,35.55,31.77,30.97,30.79,28.13,27.94,27.81,26.46,24.24,20.97,19.13,18.43,18.22,15.78,15.40.LC-MS:[M+1]+＝526.40.
实施例7
化合物7(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基乙基)戊酰胺的制备
参照实施例2，将第一步的胺换为2-{[二甲基(2-甲基丙-2-基)甲硅基]氧基}乙-1-胺，最终得到(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环 戊并[1,2-a]菲-1-基]-N-(2-羟基乙基)戊酰胺(7).1H NMR(399MHz,CDCl3)δ5.94(s,1H),3.73(s,2H),3.43(s,2H),3.35–3.11(m,1H),2.30(s,1H),2.11(s,1H),2.01(s,5H),1.74–1.62(m,5H),1.55(s,2H),1.45(d,J＝8.0Hz,2H),1.33(s,2H),1.21(d,J＝24.4Hz,4H),1.03(d,J＝11.2Hz,1H),0.97(d,J＝8.3Hz,6H),0.90(d,J＝6.0Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H).LC-MS:[M+H]+＝460.50
实施例8
化合物8(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基乙基)丙酰胺的制备
第一步 将(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VII)(3.00g,6.54mmol，1.0eq.)溶于苯(40.00mL)，加入吡啶(20.00mL),Cu(OAc)2(醋酸铜,0.47g,2.62mmol,0.4eq.),置换氩气3次；升温至90℃,分批加入Pb(OAc)4(四醋酸高铅,8.98g,20.28mmol,3.1eq.)，回流12h后自然降至室温,TLC监测(PE:EtOAc＝2:1,磷钼酸显色,Rf1＝0.42,Rf2＝0.89)。反应完,将反应液浓缩除去苯,用200.0mL二氯甲烷溶解后，依次用100.0mL 5％HCl(乳化严重，垫硅藻土过滤),饱和100.0mL NaHCO3,100.0mL饱和食盐水洗，干燥浓缩柱层析PE-PE：EtOAc＝30:1(出产品)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-丁-3-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四 氢-1H-环戊并[2,1-i]菲-7-基酯(8-1)(1.50g,2.91mmol,44.46％).1H NMR(399MHz,CDCl3)δ5.71–5.59(m,1H),4.95–4.76(m,2H),4.48(dd,J＝11.5,4.7Hz,1H),2.08–1.98(m,7H),1.79–1.59(m,7H),1.59–1.42(m,4H),1.28(dtd,J＝19.3,8.8,5.2Hz,3H),1.18–1.09(m,2H),0.99(d,J＝5.9Hz,5H),0.86(d,J＝1.5Hz,9H),0.70(s,3H).13C NMR(100MHz,Chloroform-d)δ170.99,145.50,134.44,134.17,111.52,80.89,50.46,49.83,49.74,44.45,41.82,37.77,36.88,35.23,30.90,30.81,28.22,27.88,26.35,24.23,24.14,21.31,20.96,20.05,19.16,18.08,16.51,15.97.
第二步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-丁-3-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(8-1)(1.50g,3.64mmol,1.0eq.)溶于二氯甲烷(30.0mL)中,置换氮气三次,降温至0℃。缓慢通臭氧,10分钟后,TLC监测(PE:EtOAc＝10:1,磷钼酸显色,Rf1＝0.84,Rf2＝0.51反应完全；然后通N2赶走臭氧后，加入PPh3(2.86g,10.90mmol,3.0eq),升至室温反应30分钟,TLC监测(PE:EtOAc＝10:1,磷钼酸显色,Rf1＝0.85,Rf2＝0.49),浓缩反应液，柱层(PE-PE:EtOAc＝20:1)纯化，浓缩得到乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-甲酰基乙基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(8-2)(800mg,1.54mmol,42.46％).1H NMR(399MHz,Chloroform-d)δ9.55(d,J＝3.3Hz,1H),4.47(dd,J＝11.6,4.5Hz,1H),2.35(dqd,J＝10.1,6.8,3.2Hz,1H),2.08–1.99(m,7H),1.93–1.81(m,2H),1.71–1.60(m,6H),1.53–1.33(m,3H),1.32–1.17(m,3H),1.12–1.05(m,3H),0.98(s,3H),0.87(d,J＝9.5Hz,9H),0.72(s,3H).13C NMR(101MHz,Chloroform-d)δ205.34,170.99,134.28,80.80,77.17,50.40,50.15,49.27,45.54,45.14,37.77,36.90,35.21,31.13,30.77,27.88,26.95,26.38,24.17,24.13,24.11,21.32,20.90,19.18,19.16,18.04,16.51,16.25,13.46.
第三步 将(1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-甲酰基乙基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(8-2)(100mg,0.24mmol，1.0eq.)溶于水(1.0mL)和叔丁醇(5.0mL)混合溶液中(溶不清，浑浊)，置换氮气三次后，降温至0℃，分别加入2-甲基-2-丁烯(168mg,2.40mmol,10.0eq.),亚氯酸钠(65mg,0.72mmol,3.0eq.),磷酸二氢钠(158mg,1.31mmol,5.5eq.),室温反应30分钟后,TLC监测(PE:EtOAc＝3:1,磷钼酸显色,Rf1＝0.8,Rf2＝0.4)。反应完，浓缩后用10.0ml乙酸乙酯溶解,再加入10.0mL水，有机相分离后，水相再分别以乙酸乙酯5.0mL萃取两次，合并有机相，加入无水硫酸钠干燥，过滤，浓缩后得到粗品白色固体123mg，最后经柱层析纯化(PE:EtOAc＝10：1～5：1～3：1),得白色固体(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丙酸(8-3)(73mg,0.17mmol,64.68％)。1HNMR(399MHz,CDCl3)δ4.48(dd,J＝11.6,4.5Hz,1H),2.41(dd,J＝15.3,8.5Hz,1H),2.08–2.00(m,7H),2.00–1.92(m,2H),1.71(d,J＝13.7Hz,2H),1.68–1.59(m,2H),1.56(d,J＝9.7Hz,3H),1.35–1.27(m,3H),1.25–1.10(m,2H),0.96(d,J＝16.0Hz,3H),0.94–0.76(m,12H),0.76–0.63(m,3H).
第四步 将(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丙酸(8-3)(130mg,0.30mmol,1.0eq.) 溶于DMF(N,N-二甲基甲酰胺)(4.0mL)中，再加入HATU(N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲)(137.74mg,0.36mmol,1.2eq.),二异丙基乙基胺(46.82mg,0.36mmol,1.2eq.),室温下搅拌30分钟，随后在室温下加入2-{[二甲基(2-甲基丙-2-基)甲硅基]氧基}乙-1-胺(68.82mg,0.39mmol,1.3eq.),随后继续在室温下搅拌2小时，TLC监测(PE:EtOAc＝3:1,磷钼酸显色,Rf1＝0.5,Rf2＝0.6)，反应结束后，加入20.0mL水，在以乙酸乙酯30mL*3萃取，有机相合并，干燥，浓缩得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(9S)-2,2,3,3-四甲基-8-氧亚基-7-氮杂-4-氧杂-3-硅杂癸-9-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(8-4)(200mg),黄色油状物粗品直接投至下一步反应中。
第五步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(9S)-2,2,3,3-四甲基-8-氧亚基-7-氮杂-4-氧杂-3-硅杂癸-9-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(8-4)(200mg,0.34mmol,1.0eq.),加入四氢呋喃(10.0mL),甲醇(10.0mL),1M氢氧化锂水溶液(5.0mL),室温下搅拌过夜，TLC监测(PE:EtOAc＝3:1,磷钼酸显色,Rf1＝0.6,Rf2＝0.2)，反应结束后，浓缩出去四氢呋喃和甲醇，随后浓缩液中加入水(30.0mL),再以乙酸乙酯(20mL*3)萃取，有机相合并，干燥，浓缩经制备HPLC纯化得(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基乙基)丙酰胺(8)(5.8mg,0.012mmol,4.54％)。1HNMR(399MHz,CDCl3)δ3.60(s,1H),3.38–3.12(m,3H),2.11(d,J＝6.5Hz,1H),1.97(s,5H),1.80(s,2H),1.70–1.40(m,7H),1.19(dd,J＝27.0,14.9Hz,3H),1.15–1.05(m,3H),0.99(d,J＝11.9Hz,1H),0.93(d,J＝5.3Hz,6H),0.86(s,3H),0.75(s,3H),0.65(s,3H).
LC-MS[M+1]+＝432.35
实施例9
化合物9(4R)-N-(2,6-二甲基苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例2，将第一步的胺换为2,6-二甲基苯胺，最终得到(4R)-N-(2,6-二甲基苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(9).1H NMR(399MHz,CDCl3)δ7.06(d,J＝3.7Hz,2H),6.66(s,1H),3.22(dd,J＝11.5,4.7Hz,1H),2.49(s,1H),2.32(s,1H),2.25(s,1H),2.21(s,5H),2.01(s,7H),1.72(s,2H),1.57(d,J＝12.5Hz,3H),1.51(s,3H),1.40(s,2H),1.28–1.09(m,5H),1.03(d,J＝12.1Hz,1H),1.01–0.95(m,9H),0.88(s,3H),0.79(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ135.46,128.19,127.36,78.97, 77.20,76.95,50.40,50.36,38.87,36.22,35.55,34.04,32.41,31.00,30.93,30.79,28.16,27.94,27.80,26.46,24.25,20.97,19.13,18.56,18.21,15.80,15.41.LC-MS:[M+H]+＝520.50
实施例10
化合物10(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-[2-(丙-2-基)苯基]戊酰胺的制备
参照实施例2，将第一步的胺换为2-异丙基苯胺，最终得到(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-[2-(丙-2-基)苯基]戊酰胺(10).1H NMR(399MHz,CDCl3)δ7.63(s,1H),7.18(s,2H),6.97(s,1H),3.22(dd,J＝11.5,4.5Hz,1H),3.00(s,1H),2.47(s,1H),2.31(s,1H),2.06–1.92(m,8H),1.67(d,J＝16.4Hz,5H),1.57(d,J＝12.6Hz,2H),1.50(s,3H),1.41(s,3H),1.24(s,3H),1.22(s,3H),1.03(d,J＝12.4Hz,2H),0.97(d,J＝7.3Hz,9H),0.87(s,3H),0.79(s,3H),0.69(s,3H).13C NMR(101MHz,Chloroform-d)δ134.38,133.90,126.38,126.08,125.55,125.00,78.98,77.19,50.35,38.86,36.99,36.16,35.55,34.66,32.08,30.98,30.91,30.78,28.14,28.02,27.93,27.78,26.45,24.23,23.03,20.95,19.12,18.41,18.21,15.76,15.39.LC-MS:[M+H]+＝534.50
实施例11
化合物11(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-甲氧基乙基)戊酰胺的制备
参照实施例2，将第一步的胺换为2-甲氧基乙胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-甲 氧基乙基)戊酰胺(11).1H NMR(399MHz,CDCl3)δ5.76(s,1H),3.43(s,3H),3.34(s,3H),3.20(s,1H),2.25(s,0.5H),2.06(s,0.5H),2.01(s,5H),1.69(dd,J＝20.7,12.6Hz,6H),1.56(s,1H),1.44(d,J＝9.0Hz,4H),1.22(dd,J＝30.2,17.4Hz,6H),1.03(d,J＝12.1Hz,1H),0.97(d,J＝8.4Hz,6H),0.89(d,J＝5.9Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(100MHz,CDCl3)δ173.51,134.38,134.34，78.93,77.29,76.97,76.65,71.29,58.72,50.36,50.27,49.78,44.49,39.07,38.86,36.99,36.14,35.55,33.78,31.97,30.96,30.78,28.10,27.93,27.81,26.46,24.21,20.95,19.11,18.38,18.21,15.73,15.38.LC-MS:[M+H]+＝474.40
实施例12
化合物12(4R)-N-(3-氰基苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例2，将第一步的胺换为3-氰基苯胺，最终得到化合物(4R)-N-(3-氰基苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(12)。1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.65(d,J＝7.8Hz,1H),7.40–7.26(m,2H),3.17(dd,J＝11.5,4.5Hz,1H),2.39(ddd,J＝15.0,10.2,4.9Hz,1H),2.26–2.18(m,1H),2.01–1.82(m,6H),1.67–1.35(m,13H),1.17(ddd,J＝22.0,12.4,6.0Hz,3H),0.90(dd,J＝16.2,6.7Hz,8H),0.81(d,J＝5.2Hz,3H),0.74(s,3H),0.61(d,J＝19.3Hz,3H).13C NMR(101MHz,CDCl3)δ138.78,134.47,134.31,129.87,113.08,78.99,77.33,77.22,77.01,76.70,50.40,50.31,49.85,44.57,38.90,37.04,36.16,35.59,31.67,31.02,30.81,28.19,27.97,27.84,26.49,24.25,20.99,19.16,18.47,18.24,15.81,15.42.LC-MS:[M+H]+＝517.4
实施例13
化合物13(4R)-N-(3-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例12，将第一步的胺换为3-氟苯胺,最终得到化合物(4R)-N-(3-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(13).1H NMR(400MHz,CDCl3)δ7.43(d,J＝10.8Hz,1H),7.09(dd,J＝27.5,16.0Hz,2H),6.73(t,J＝7.4Hz,1H),3.17(dd,J＝11.5,4.5Hz,1H),2.37(ddd,J＝15.0,10.3,4.9Hz,1H),2.24–2.14(m,1H),1.99–1.84(m,5H),1.70–1.52(m,6H),1.47–1.29(m,8H),1.15(dd,J＝21.6,11.6Hz,2H),1.00–0.86(m,9H),0.83–0.79(m,3H),0.74(s,3H),0.60(d,J＝19.3Hz,3H).13C NMR(101MHz,CDCl3)δ134.45,134.33,78.99,77.33,77.22,77.01,76.69,50.40,50.32,49.84,44.57,38.90,37.03,36.17,35.59,31.75,31.02,30.81,28.18,27.97,27.85,26.49,24.25,20.99,19.15,18.47,18.25,15.80,15.42.LC-MS:[M+H]+＝510.4
实施例14
化合物14(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(吡啶-2-基)戊酰胺的制备
参照实施例2，将第一步的胺换为2-氨基吡啶，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(吡啶-2-基)戊酰胺(14).1H NMR(399MHz,CDCl3)δ8.23(dd,J＝14.5,6.8Hz,2H),7.73(t,J＝7.8Hz,1H),7.07–7.02(m,1H),3.22(dd,J＝11.6,4.4Hz,1H),2.53–2.42(m,1H),2.32(dd,J＝15.0,8.9Hz,1H),1.96–1.86(m,2H),1.72–1.63(m,10H),1.52(dd,J＝35.3,9.9Hz,8H),1.23–1.13(m,3H),1.03(d,J＝12.4Hz,1H),0.98(s,3H),0.96(s,3H),0.93(d,J＝4.8Hz,3H),0.86(s,3H),0.79(s,3H),0.68(s,3H).13C NMR(101MHz,Chloroform-d)δ172.31,151.30,147.24,138.72,134.38,134.27,119.60,114.03,78.95,77.20,50.34,50.25,49.79,44.51,38.87,36.99,36.15,35.55,34.95,31.68,30.95,30.79,28.15,27.94,27.81,26.46,24.22,20.96,19.14,18.43,18.22,15.77,15.41.LC-MS:[M+H]+＝493.65
实施例15
化合物15(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(吡啶-3-基)戊酰胺的制备
参照实施例2，将第一步的胺换为吡啶-3-胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(吡啶-3-基)戊酰胺(15).1H NMR(399MHz,CDCl3)δ8.25(dd,J＝48.5,40.7Hz,3H),7.23(d,J＝13.2Hz,1H),3.31(s,1H),2.37(d,J＝10.6Hz,1H),2.21(s,1H),1.89(m,6H),1.60(dd,J＝38.4,14.0Hz,6H),1.40(dd,J＝25.4,17.7Hz,3H),1.14(m,4H),0.96(d,J＝12.6Hz,1H),0.90(m,9H),0.80(s,3H),0.73(s,3H),0.62(s,3H).13CNMR(101MHz,CDCl3)δ173.53,143.74,140.22,134.34,134.21,127.50,123.86,78.73,77.36,77.04,76.72,50.31,50.24,49.72,49.54,49.33,49.11,48.90,48.68,48.47,44.44,38.75,36.90,36.16,35.52,34.20,31.73,30.91,30.71,29.59,28.02,27.79,27.42,26.38,24.09,20.88,19.01,18.25,18.14,15.65,15.31,0.88.LC-MS:[M+H]+＝493.60.
实施例16
化合物16(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(吡啶-4-基)戊酰胺的制备
参照实施例2，将第一步的胺换为吡啶-4-胺，最终得到化合(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(吡啶-4-基)戊酰胺(16).1HNMR(399MHz,CDCl3)δ8.32(d,J＝6.0Hz,2H),7.48(d,J＝6.2Hz,2H),3.15(dd,J＝11.4,4.8Hz,1H),2.38(m,1H),2.24(m,1H),1.90(m,6H),1.57(m,6H),1.40(dd,J＝32.1,23.5Hz,4H),1.15(dd,J＝22.5,10.3Hz,4H),0.98(d,J＝11.6Hz,1H),0.92(d,J＝5.0Hz,6H),0.88(d,J＝5.6Hz, 3H),0.81(s,3H),0.74(s,3H),0.63(s,3H).13CNMR(101MHz,CDCl3)δ149.80,134.35,134.21,113.56,78.77,77.35,77.04,76.72,50.31,50.27,49.74,49.68,49.47,49.26,49.04,48.83,44.46,38.78,36.92,36.14,35.52,34.49,31.52,30.92,30.72,28.05,27.82,27.47,26.40,24.11,20.90,19.05,18.28,18.16,15.68,15.34,0.92.LC-MS:[M+H]+＝493.55.
实施例17
化合物17(4R)-N-(4-氰基苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例12，将第一步的胺换为4-氰基苯胺,最终得到化合物(4R)-N-(4-氰基苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(17).1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.8Hz,2H),7.53(d,J＝8.7Hz,2H),7.30(s,1H),3.17(dd,J＝11.5,4.4Hz,1H),2.40(ddd,J＝15.0,10.3,4.9Hz,1H),2.28–2.18(m,1H),2.01–1.83(m,6H),1.60(dd,J＝22.2,9.3Hz,8H),1.44–1.30(m,4H),1.15(dd,J＝21.3,11.5Hz,3H),0.90(dd,J＝17.2,6.9Hz,8H),0.81(d,J＝4.3Hz,3H),0.74(s,3H),0.60(d,J＝19.4Hz,3H).13C NMR(101MHz,CDCl3)δ141.99,134.48,134.29,133.31,119.39,118.83,78.99,77.33,77.22,77.02,76.70,50.39,50.30,49.84,44.57,38.90,37.03,36.14,35.59,34.93,31.60,31.02,30.81,28.19,27.97,27.84,26.49,24.25,20.98,19.16,18.48,18.24,15.80,15.42.LC-MS:[M-17]+＝499.
实施例18
化合物18(4R)-N-(2,6-二氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例12，将第二步的胺换为2,6-二氟苯胺，最终得到化合物(4R)-N-(2,6-二氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(18).1H NMR(400MHz,CDCl3)δ7.24–7.15(m,1H),6.95(t,J＝8.1Hz,2H),6.70(s,1H),3.24(dd,J＝11.5,4.5Hz,1H),2.49(d,J＝12.1Hz,1H),2.40–2.30(m,1H),2.07–1.93(m,6H),1.82(s,2H),1.77–1.58(m,8H),1.50(t,J＝10.9Hz,3H),1.41(d,J＝7.2Hz,2H),1.23–1.14(m,2H),1.05(dd,J＝12.6,1.9Hz,1H),1.00(s,3H),0.98(s,3H),0.96(s,3H),0.88(s,3H),0.81(s,3H),0.70(s,3H).13C NMR(101MHz,CDCl3)δ134.4,111.579.00,77.34,77.02,76.71,50.39,50.35,49.84,44.56,38.90,37.03,36.08,35.59,31.00,30.83,28.15,27.97,27.84,26.49,24.25,21.00,19.16,18.41,18.25,15.77,15.43.
实施例19
化合物19(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-[3-(三氟甲基)苯基]戊酰胺的制备
参照实施例12，将第二步的胺换为3-三氟甲基苯胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-[3-(三氟甲基)苯基]戊酰胺(19).1H NMR(400MHz,CDCl3)δ7.81(s,1H),7.73(d,J＝8.1Hz,1H),7.43(t,J＝7.9Hz,1H),7.35(d,J＝7.7Hz,1H),7.24(s,1H),3.24(dd,J＝11.5,4.5Hz,1H),2.45(td,J＝10.0,4.9Hz,1H),2.33–2.24(m,1H),2.07–1.87(m,6H),1.62(dddd,J＝34.6,25.4,14.3,7.8Hz,12H),1.31–1.14(m,3H),1.04–0.91(m,9H),0.88(s,3H),0.81(s,3H),0.70(s,3H).13C NMR(101MHz,CDCl3)δ134.46, 134.32,129.55,78.99,77.33,77.01,76.70,50.40,50.32,49.84,44.57,38.90,37.03,36.16,35.59,31.72,31.02,30.81,28.18,27.97,27.85,26.49,24.25,20.99,19.15,18.48,18.25,15.80,15.42.LC-MS:[M+H]+＝560.45
实施例20
化合物20(4R)-N-(2-氰基苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例12，将第二步的胺换为2-氰基苯胺，最终得到化合物(4R)-N-(2-氰基苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(20).1H NMR(400MHz,CDCl3)δ8.43(d,J＝8.6Hz,1H),7.66–7.48(m,2H),7.16(t,J＝7.6Hz,1H),3.24(dd,J＝11.5,4.4Hz,1H),2.53(ddd,J＝14.8,10.1,4.6Hz,1H),2.39–2.26(m,1H),2.11–1.87(m,6H),1.60(dddd,J＝21.5,17.4,12.4,4.6Hz,13H),1.32–1.14(m,3H),1.07–0.94(m,9H),0.88(d,J＝5.0Hz,3H),0.83(d,J＝12.7Hz,3H),0.69(dd,J＝12.1,7.4Hz,3H).13C NMR(101MHz,CDCl3)δ172.08,140.60,134.46,134.32,134.24,133.45,132.16,123.95,121.62,121.15,116.44,78.99,77.33,77.22,77.02,76.70,50.41,50.34,50.27,49.84,44.59,38.90,37.03,36.10,35.59,34.91,31.58,31.00,30.82,28.15,27.97,27.85,26.50,24.27,21.00,19.15,18.46,18.25,15.80,15.42.LC-MS:[M+H]+＝517.40
实施例21
化合物21(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-苯基戊酰胺的制备
参照实施例2，将第一步的胺换为苯胺，最终得到化合物4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-苯基戊酰胺(21).1H NMR(399MHz,CDCl3)δ7.49(d,J＝7.9Hz,2H),7.32–7.26(m,2H),7.18(s,1H),7.08(d,J＝7.4Hz,1H),3.22(dd,J＝11.7,4.4Hz,1H),2.40(dt,J＝10.1,4.3Hz,1H),2.30–2.19(m,1H),1.90(dd,J＝17.1,9.5Hz,2H),1.75–1.55(m,10H),1.53–1.29(m,7H),1.20(tt,J＝12.5,6.8Hz,2H),1.03(dd,J＝12.6,2.2Hz,1H),0.97(dd,J＝8.2,1.8Hz,6H),0.95–0.90(m,3H),0.86(s,3H),0.79(d,J＝1.8Hz,3H),0.68(s,3H).13C NMR(101MHz,Chloroform-d)δ171.75,144.87,134.33,128.96,124.12,119.71,78.96,50.35,50.29,49.79,38.87,36.99,36.16,35.55,34.86,31.84,30.97,30.79,28.15,27.94,27.80,26.46,24.24,20.96,19.13,18.46,18.22,15.77,15.41.LC-MS:[M+H]+＝492.55
实施例22
化合物22(4R)-N-(4-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例2，将第一步的胺换为对氟苯胺，最终得到化合物(4R)-N-(4-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(22).1H NMR(399MHz,CDCl3)δ7.44(s,2H),7.06(s,1H),6.99(t,J＝8.6Hz,2H),3.20(s,1H),2.41(s,1H),2.23(s,1H),2.01(s,5H),1.69(m,4H),1.36(s,4H),1.21(m,6H),1.03(d,J＝11.4Hz,1H),0.97(d,J＝7.9Hz,6H),0.93(d,J＝5.2Hz,3H),0.86(s,3H),0.79(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ171.85,134.41,134.29,133.88,121.59,121.52,115.71,115.48,78.95,77.30,76.98,76.67,50.28,49.79,44.52,38.86,36.99,36.16,35.55,34.70,31.81,30.97,30.77,28.15,27.93,27.80,26.45,24.21,20.95,19.12,18.44,18.20,15.76,15.38,0.99.LC-MS:[M+H]+＝510.60
实施例23
化合物23 2-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基]氨基}苯甲酸的制备
参照实施例12，将第二步的胺换为2-氨基苯甲酸甲酯，最终得到化合物2-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基]氨基}苯甲酸(23).1H NMR(400MHz,DMSO)δ11.52(s,1H),8.48(d,J＝8.3Hz,1H),7.97(d,J＝7.7Hz,1H),7.53(t,J＝7.5Hz,1H),7.10(t,J＝7.6Hz,1H),4.34(s,1H),3.03–2.97(m,1H),2.32–2.23(m,1H),2.07–1.88(m,5H),1.85–1.75(m,1H),1.74–1.59(m,4H),1.53–1.29(m,8H),1.23(s,3H),1.19–1.08(m,2H),0.91(d,J＝6.2Hz,8H),0.84(s,3H),0.68(d,J＝17.2Hz,6H).13C NMR(101MHz,DMSO)δ182.46,172.15,142.13,139.93,134.79,134.00,131.56,122.74,113.41,77.23,50.51,50.19,49.86,44.52,39.00,37.02,35.98,35.67,35.25,34.28,31.92,30.97,30.87,28.73,28.58,28.04,26.46,24.50,20.98,19.47,18.72,16.31,16.05.LC-MS:[M+H]+＝536.35.
实施例24
化合物24(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-{2-[(1-氧亚基丙-2-烯基)氨基]苯基}戊酰胺的制备

第一步 将邻苯二胺(1g,9.25mmol,1.0eq.)溶于二氯甲烷(15.0mL)中，加入三乙胺(2.6mL,18.5mmol,2.0eq.),氮气置换后，冰浴冷却，滴加丙烯酰氯(0.84g,9.25mmol,1.0eq.),继续在0℃下反应一小时，TLC监测(PE:EA＝10:1,磷钼酸显色,Rf1＝0.3,Rf2＝0.4)，反应结束后，加入10mL水淬灭，以二氯甲烷20mL*3萃取，有机相干燥，浓缩，柱层析(PE:EA＝50：1～10：1)得N-(2-氨基苯基)丙-2-烯酰胺(24-1)(120mg，0.66mmol)白色固体。1H NMR(399MHz,CDCl3)δ7.48(s,1H),7.21(d,J＝7.9Hz,1H),7.05(t,J＝7.6Hz,1H),6.78(d,J＝7.5Hz,2H),6.39(d,J＝16.8Hz,1H),6.27(dd,J＝16.8,10.1Hz,1H),5.74(d,J＝10.0Hz,1H).
第二步 称取(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VIII)(50mg,0.19mmol，1.0eq.)溶于N,N’-二甲基甲酰胺(2.0mL)中,室温下加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(54.76mg,0.144mmol,1.2eq.),滴入二异丙基乙基胺(24-1)(0.03mL,0.18mmol,1.5eq.),室温下搅拌30分钟，接着加入N-(2-氨基苯基)丙-2-烯酰胺(25mg,0.12mmol),随后室温下搅拌，TLC监测(PE:EA＝3：1)，反应结束后，加入水8mL稀释，接着以二氯甲烷10mL*3萃取，有机相合并干燥，浓缩经制备HPLC纯化得(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-{2-[(1-氧亚基丙-2-烯基)氨基]苯基}戊酰胺(24)(12mg,0.02mmol,17.47％)。1H NMR(399MHz,CDCl3)δ8.55(s,1H),8.25(s,1H),7.38(d,J＝6.8Hz,1H),7.24(s,1H),7.14(d,J＝3.5Hz,2H),6.39(d,J＝17.1Hz,1H),6.21(dd,J＝17.1,10.1Hz,1H),5.76(d,J＝10.1Hz,1H),3.22(dd,J＝11.3,4.2Hz,1H),2.37(s,1H),2.30–2.10(m,1H),2.02(s,5H),1.71(dd,J＝31.4,14.8Hz,7H),1.47(d,J＝7.5Hz,3H),1.38(d,J＝21.9Hz,3H),1.20(dd,J＝20.9,10.7Hz,3H),1.03(d,J＝12.6Hz,1H),0.99(t,J＝10.6Hz,6H),0.93(d,J＝5.4Hz,3H),0.87(s,3H),0.79(s,3H),0.68(s,3H).13C NMR(100MHz,CDCl3)δ173.51,164.49,134.42,134.24,130.90,130.44,130.36,127.85,126.19,125.50,125.39,78.96,77.30,76.98,76.66,50.35,50.28,49.80,44.52,38.86,36.99,36.19,35.54,34.20,31.93,30.97,30.91,30.78,28.16,27.93,27.79,26.46,24.22,20.96,19.12,18.40,18.21,15.78,15.39,0.99.LC-MS:[M+H]+＝561.60
实施例25
化合物25丙-2-烯酸-2-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基]氨基}苯基酯的制备
第一步 将2-氨基苯酚(1g,9.16mmol,1.0eq.)溶于四氢呋喃(20.0mL)中，室温下加入二碳酸二叔丁酯(4.2g,18.33mmol,2.0eq.),室温下搅拌16小时，TLC监测(PE:EA＝10:1,磷钼酸显色,Rf1＝0.3,Rf2＝0.5)，反应结束后，浓缩，柱层析(PE:EA＝30：1～20：1)得[(2-羟基苯基)氨基]甲烷酸-2-甲基丙-2-基酯(25-1)(800mg，3.44mmol)白色固体。
第二步 称取[(2-羟基苯基)氨基]甲烷酸-2-甲基丙-2-基酯(800mg,3.82mmol,1.0eq.)溶于二氯甲烷(15.0mL)中,加入三乙胺(1.063mL,7.65mmol),氮气置换，降温至0℃，滴加丙烯酰氯(346.04mg,3.823mmol),随后室温下搅拌过夜，TLC监测(PE:EA＝10：1)，反应结束后，加入水15mL淬灭，随后以二氯甲烷10mL*3萃取，有机相合并干燥，浓缩经柱层(PE:EA＝30:1～20:1～15:1)纯化，浓缩得丙-2-烯酸-2-({[(2-甲基丙-2-基)氧基]羰基}氨基)苯基酯(25-2)(600mg,2.05mmol,53.65％)。1H  NMR(399MHz,CDCl3)δ8.04(d,J＝8.1Hz,1H),7.22–7.15(m,1H),7.11(dd,J＝8.2,1.5Hz,1H),7.08–7.00(m,1H),6.65(dd,J＝17.3,1.3Hz,1H),6.47(s,1H),6.37(dd,J＝17.3,10.5Hz,1H),6.07(dd,J＝10.4,1.2Hz,1H),1.49(d,J＝2.2Hz,9H).
第三步 称取丙-2-烯酸-2-({[(2-甲基丙-2-基)氧基]羰基}氨基)苯基酯(25-2)(300mg,2.05mmol，1.0eq.)溶于二氯甲烷(1.0mL)中,氮气置换，降温至0℃，滴加三氟乙酸(2mL,0.76mmol),随后室温下搅拌，TLC监测(PE:EA＝10：1)，反应结束后，25℃浓缩除去二氯甲烷，加入水5mL稀释，接着以饱和碳酸氢钠水溶液调节pH＝7～8，随后以乙酸乙酯10mL*3萃取，有机相合并干燥，浓缩经制备TLC(PE:EA＝3：1)纯化得丙-2-烯酸-2-氨基苯基酯三氟乙酸盐(25-3)(30mg,0.16mmol,14.52％)。LCMS:164.20
第四步 参照实施例24，将胺换为丙-2-烯酸-2-氨基苯基酯三氟乙酸盐，最终得到化合物丙-2-烯酸-2-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基]氨基}苯基酯(25).1H NMR(399MHz,CDCl3)δ8.23(s,1H),7.24(s,2H),7.13(s,2H),6.40(d,J＝16.8Hz,1H),6.20(dd,J＝16.7,9.9Hz,1H),5.77(d,J＝10.0Hz,1H),3.26–3.18(m,1H),2.66(s,1H),2.59–2.47(m,1H),2.01(s,6H),1.76–1.61(m,6H),1.49(s,5H),1.37(s,1H),1.26–1.16(m,3H),1.03(d,J＝13.2Hz,1H),0.98(d,J＝6.5Hz,9H),0.88(s,3H),0.79(s,3H),0.69(s,3H).13C NMR(100MHz,CDCl3)δ171.90,134.46,134.21,129.48,126.41,78.93,77.29,76.97,76.66,50.35,50.25,49.81,44.56,38.86,37.00,36.13,35.54,31.56,31.38,30.98,30.90,30.76,28.16,27.93,27.79,26.46,24.21,20.95,19.13,18.32,18.20,15.79,15.39.LC-MS:[M+H]+＝562.60
实施例26
化合物26(4R)-N-(3-氟吡啶-4-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例2，将第一步的胺换为3-氟-4-氨基吡啶，最终得到化合物(4R)-N-(3-氟吡啶-4-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(26).1H NMR(399MHz,CDCl3)δ8.47–8.22(m,3H),7.53(s,1H),3.21(d,J＝7.8Hz,1H),2.50(s,1H),2.34(s,1H),2.01(s,4H),1.96–1.85(m,2H),1.66(d,J＝15.3Hz,4H), 1.61–1.52(m,2H),1.49(s,2H),1.36(s,2H),1.28–1.16(m,4H),1.03(d,J＝12.3Hz,1H),0.99–0.91(m,9H),0.86(s,3H),0.79(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ172.23,146.86,136.91,136.70,134.43,134.23,114.45,78.91,77.30,77.19,76.99,76.67,50.35,50.22,49.80,44.53,38.86,36.99,36.05,35.55,34.88,31.33,30.97,30.77,28.13,27.94,27.79,26.45,24.23,20.95,19.13,18.42,18.21,15.76,15.39.LC-MS:[M+H]+＝511.60
实施例27
化合物27(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-甲基吡唑-3-基)戊酰胺的制备
参照实施例2，将第一步的胺换为1-甲基-5-氨基吡唑，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-甲基吡唑-3-基)戊酰胺(27).1H NMR(400MHz,Methanol-d4)δ7.38(s,1H),6.20(d,J＝1.7Hz,1H),3.69(s,3H),3.18–3.10(m,1H),2.55–2.29(m,2H),2.06(s,5H),1.90(s,1H),1.83–1.58(m,8H),1.58–1.47(m,3H),1.39(s,2H),1.31–1.15(m,3H),1.04(d,J＝12.5Hz,1H),1.01–0.95(m,9H),0.91(s,3H),0.79(s,3H),0.75(s,3H).13C NMR(101MHz,DMSO)δ172.02,137.71,136.90,134.74,133.95,99.11,77.20,50.48,50.20,49.83,44.48,40.54,40.33,40.12,39.91,39.70,39.50,39.29,38.97,36.98,36.02,35.93,35.64,32.79,31.80,30.96,30.83,28.54,28.01,26.45,24.48,20.96,19.43,18.72,18.33,16.27,16.01.LC-MS:[M+H]+＝496.35
实施例28
化合物28(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(异恶唑-3-基)戊酰胺的制备
参照实施例2，将第一步的胺换为异恶唑-3-胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(异恶唑-3-基)戊酰胺(28).1H NMR(400MHz,CDCl3)δ8.38(d,J＝30.0Hz,1H),7.22(s,1H),3.24(dd,J＝11.5,4.4Hz,1H),2.55–2.25(m,2H),2.07–1.99(s,3H),1.95–1.89(s,1H),1.76–1.58(s,10H),1.55–1.45(m,3H),1.30–1.17(s,4H),0.99(d,J＝8.3Hz,6H),0.95(d,J＝4.8Hz,3H),0.88(s,3H),0.81(s,3H),0.70(s,3H).13CNMR(101MHz,CDCl3)δ184.86,146.42,137.97,134.46,134.29,124.83,78.99,50.38,50.24,49.83,44.56,38.90,37.03,36.12,35.58,34.33,31.47,30.99,30.81,28.17,27.97,27.84,26.49,24.25,20.99,19.16,18.43,18.25,15.80,15.43.LC-MS[M+H]+＝546.40
实施例29
化合物29(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(1,4-氧杂氮杂环己-4-基)己-1-酮的制备
(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸(VI)(75mg,0.174mmol,1.0eq)溶解在DMF(3mL)中，加入HATU(2-(7-偶氮苯并三氮唑)-N,N,N\',N\'-四甲基脲六氟磷酸酯)(66mg,0.174mmol)和DIPEA(N,N-二异丙基乙胺)(0.03mL,0.17mmol,1.0eq)，搅拌30分钟后加入吗啡啉(0.011mL,0.174mmol，1.0eq)，室温搅拌2小时。TLC(PE:EtOAc＝1:1,磷钼酸烤板)监测反应完全后，反应液加入乙酸乙酯(20mL)稀释，用水洗涤2次，合并有机相，无水硫酸钠干燥，硅胶柱层析纯化(PA:EA＝80:20to 50:50)得到白色固体(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(1,4-氧杂氮杂环己-4-基)己-1-酮(29)(25mg,0.048mmol,27.29％)。1H NMR(400MHz,DMSO)δ4.31(d,J＝5.1Hz,1H),3.52(dd,J＝10.9,4.9Hz,4H),3.42(d,J＝4.5Hz,4H),2.05-2.30(m,2H),2.05-1.95(m,4H),1.86(m,1H),1.61(m,6H),1.54-1.22(m,9H),1.13(m,2H),1.03(m,1H),0.98-0.94(m,1H),0.91(d,J＝7.5Hz,5H),0.88(d,J＝6.3Hz,3H),0.84(s,3H),0.70(s,3H),0.66(s,3H).13C NMR(101MHz,DMSO)δ171.33,134.82,134.02,77.24,66.64,50.53,50.35,49.86,44.48,41.84,39.01,37.03,36.22,32.93,31.02,30.85,28.58,28.16,28.05,26.48,24.51,20.98,19.47,18.98,18.36,16.30,16.05.LC-MS:[M+H]+＝500
实施例30
化合物30(4R)-1-(六氢吡啶-1-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮的制备
参照实施例2，第二步的胺换为哌啶，最终得到化合物(4R)-1-(六氢吡啶-1-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮(30).1H NMR(399MHz,CDCl3)δ3.52(s,1H),3.37(s,1H),3.20(s,1H),2.35(d,J＝11.3Hz,1H),2.21(m,5H),2.01(s,4H),1.67(m,6H),1.48(d,J＝8.7Hz,5H),1.25(m,9H),1.03(d,J＝13.1Hz,1H),0.97(d,J＝Hz,6H),0.91(d,J＝6.1Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ171.97,134.33,78.96,77.30,76.98,76.66,50.35,49.79,46.74,44.50,42.58,38.86,36.99,36.47,35.55,31.87,30.95,30.81,28.16,27.93,27.81,26.57,26.46,25.55,24.58,24.22,20.96,19.12,18.51,18.22,15.75,15.40,1.00.LC-MS:[M+H]+＝484.55
实施例31
化合物31(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(1,4-氧杂氮杂环己-4-基)戊-1-酮的制备
参照实施例2，第二步的胺换为吗啡啉，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(1,4-氧杂氮杂环己-4-基)戊-1-酮(31).1H NMR(400MHz,CDCl3)δ3.69–3.58(m,6H),3.46(d,J＝5.1Hz,2H),3.22(dd,J＝11.5,4.4Hz,1H),2.43–2.32(m,1H),2.25–2.16(m,1H),2.01(s,4H),1.67(d,J＝12.8Hz,5H),1.51–1.39(m,5H),1.33(d,J＝11.5Hz,2H),1.23(d,J＝12.8Hz,3H),0.98(d,J＝8.3Hz,6H),0.91(d,J＝5.9Hz,3H),0.86(s,4H),0.80(s,3H),0.68(s,3H).13CNMR(100MHz,Chloroform-d)δ172.32,78.94,66.93,66.66,50.35,50.31,49.79,46.06,44.50,41.85,38.86,36.36,35.55,31.61,30.94,30.79,30.38,28.18,27.93,27.80,26.45,24.22,20.95,19.12,18.51,18.21,15.75,15.39.LC-MS:[M+H]+＝486.50
实施例32
化合物32(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(四氢-1H-吡咯-1-基)戊-1-酮的制备
参照实施例2，第二步的胺换为四氢吡咯，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(四氢-1H-吡咯-1-基)戊-1-酮(32).1H NMR(399MHz,CDCl3)δ3.44(s,4H),3.22(dd,J＝11.4,4.4Hz,1H),2.36(s,1H),2.20(s,1H),2.01(s,4H),1.90(s,3H),1.73(s,1H),1.66(d,J＝13.5Hz,5H),1.56(d,J＝17.0Hz,2H),1.47 (s,4H),1.35(s,2H),1.20(d,J＝26.1Hz,3H),1.03(d,J＝12.5Hz,1H),0.97(d,J＝8.1Hz,6H),0.91(d,J＝5.6Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ134.37,78.96,77.19,50.36,50.30,44.52,38.87,36.99,36.43,35.56,31.45,30.96,30.81,28.16,27.94,27.81,26.46,24.24,20.97,19.13,18.51,18.22,15.76,15.40.LC-MS:[M+H]+＝470.50
实施例33
化合物33(4R)-1-(氮杂环丁-1-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮的制备
参照实施例2，第二步的胺换为氮杂环丁烷，最终得到化合物(4R)-1-(氮杂环丁-1-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮(33).1H NMR(399MHz,CDCl3)δ4.08(s,4H),3.22(dd,J＝11.5,4.5Hz,1H),2.26(s,2H),2.13(s,1H),2.00(s,6H),1.73(s,1H),1.70–1.61(m,5H),1.58(s,2H),1.32(d,J＝69.1Hz,7H),1.22–1.11(m,2H),1.03(d,J＝12.8Hz,1H),0.97(d,J＝8.3Hz,6H),0.89(d,J＝5.9Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ134.31,78.96,77.18,50.35,50.25,49.78,38.86,36.99,36.31,35.55,30.96,30.78,28.13,27.93,27.80,26.45,24.23,20.95,19.12,18.21,15.75,15.39.LC-MS:[M+H]+＝456.50
实施例34
化合物34(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(哌嗪-1-基)戊-1-酮的制备
参照实施例2，第二步的胺换为哌嗪,最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基- 3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(哌嗪-1-基)戊-1-酮(34).1H NMR(399MHz,CDCl3)δ3.56(t,J＝5.1Hz,2H),3.41(t,J＝5.0Hz,2H),3.20(dd,J＝11.5,4.5Hz,1H),2.82(dt,J＝13.6,5.1Hz,4H),2.42–2.29(m,1H),2.21(dd,J＝10.4,5.4Hz,1H),1.97(dt,J＝25.9,9.4Hz,5H),1.83–1.72(m,1H),1.61–1.53(m,2H),1.46(dt,J＝15.0,8.1Hz,3H),1.37–1.28(m,2H),1.23–1.10(m,2H),1.02(dd,J＝12.5,2.2Hz,1H),0.96(d,J＝7.9Hz,6H),0.90(d,J＝6.0Hz,3H),0.85(s,3H),0.78(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ78.93,76.92,50.35,50.32,49.79,46.87,46.39,45.87,44.50,42.58,38.86,36.99,36.41,35.55,31.74,30.95,30.80,30.58,28.18,27.94,27.80,26.46,24.22,20.96,19.12,18.52,18.22,15.75,15.40.LC-MS:[M+H]+＝485.50
实施例35
化合物35(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N,N-二丙基戊酰胺的制备
参照实施例2，第二步的胺换为二丙胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N,N-二丙基戊酰胺(35).1H NMR(399MHz,CDCl3)δ3.30–3.11(m,5H),2.40–2.29(m,1H),2.25–2.14(m,1H),2.00(s,5H),1.72(dd,J＝27.7,18.5Hz,7H),1.52(ddd,J＝27.0,17.8,10.5Hz,9H),1.30–1.12(m,3H),1.02(d,J＝12.6Hz,1H),0.97(d,J＝7.8Hz,6H),0.90(d,J＝5.9Hz,6H),0.85(s,6H),0.79(s,3H),0.67(s,3H).13C NMR(100MHz,CDCl3)δ173.38,134.34,78.92,77.29,76.98,76.66,50.36,49.78,47.57,44.49,38.85,36.99,36.33,35.56,32.01,30.97,30.80,30.25,28.14,27.93,27.81,26.45,24.19,20.96,19.11,18.52,18.21,15.74,15.38,11.29.LC-MS:[M+H]+＝500.65
实施例36
化合物36(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(4-甲基哌嗪-1-基)戊-1-酮的制备
将(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(哌嗪-1-基)戊-1-酮(34)(100mg,0.206mmol)和甲醛(24.75mg,0.825mmol)溶于四氢呋喃中(5.0ml),常温搅拌0.5h后加入氰基硼氢化钠(64.81mg,1.031mmol),室温反应过夜。TLC监测(PE:EtOAc＝3:1,磷钼酸显色,Rf1＝0.18,Rf2＝0.29)反应完后，反应液加水和EtOAc洗萃，有机相盐水洗一次合并干燥浓缩送制备分离得到白色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(4-甲基哌嗪-1-基)戊-1-酮(36)(5.3mg,0.01mmol,3.80％).1H NMR(399MHz,Chloroform-d)δ4.75(s,1H),3.96(s,2H),3.24(dd,J＝11.5,4.5Hz,1H),2.84(s,3H),2.74(s,2H),2.38(s,2H),1.76–1.64(m,7H),1.57(d,J＝14.7Hz,2H),1.44(dt,J＝17.4,8.4Hz,4H),1.36–1.17(m,7H),1.05(s,1H),1.02(s,1H),0.98(s,3H),0.96(s,3H),0.90(d,J＝5.8Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(100MHz,Chloroform-d)δ79.02,50.34,49.80,38.85,36.25,35.53,30.95,30.76,30.24,28.20,27.92,27.74,26.45,24.21,20.94,19.12,18.51,18.20,15.76,15.39.LC-MS:[M+H]+＝499.50
实施例37
化合物37(5R)-1-(六氢吡啶-1-基)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己-1-酮的制备
第一步 将(甲氧基甲基)三苯基氯化磷(7.5g,23mmol,2.0eq.)溶于四氢呋喃(50.0mL)中，氮气保护下，冰浴降温至0℃，随后滴加加入双(三甲基硅基)氨基钠(10.0mL,23mmol,2.0eq.),滴加完后继续在冰浴下搅拌30分钟，另称取乙酸(3aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(II)(5.0g,11.6mol，1.0eq.)溶于四氢呋喃(30.0mL)中，在0℃下滴加至上述反应液中，滴加完毕后，缓慢升至室温，继续在室温下搅拌2.0小时，TLC监测(PE:EA＝10:1,磷钼酸显色,Rf1＝0.6,Rf2＝0.8)，反应结束后，加入30.0mL饱和氯化铵水溶液，在以乙酸乙酯70mL*3萃取，有机相合并，干燥，浓缩得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,5E)-6-甲氧基己-5-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-1)的11g白色固体粗品直接投至下一步反应中。
第二步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,5E)-6-甲氧基己-5-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-1)(3.5g,4.46mmol,1.0eq.),加入四氢呋喃(60.0mL)，5M盐酸水溶液(9.0mL),50℃下搅拌2个小时，TLC监测(PE:EA＝10:1,磷钼酸显色,Rf1＝0.7,Rf2＝0.6)，反应结束后，浓缩除去四氢呋喃，随后浓缩液中加入饱和碳酸氢钠水溶液(100.0mL),再以乙酸乙酯(50.0mL*3)萃取，有机相合并，干燥，浓缩经柱层析纯化(PE:EA＝50：1～20：1)得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基- 2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(930mg,1.934mmol,43.36％)。1H NMR(399MHz,CDCl3)δ9.75(s,1H),4.48(dd,J＝11.5,4.4Hz,1H),2.38(dd,J＝13.6,6.8Hz,2H),2.03(s,4H),1.98(s,2H),1.89(dt,J＝17.1,9.3Hz,1H),1.77–1.56(m,8H),1.49(dd,J＝14.5,9.2Hz,3H),1.34(ddd,J＝27.1,24.4,13.2Hz,5H),1.15(dd,J＝17.5,11.1Hz,2H),1.04(dd,J＝12.3,7.3Hz,1H),0.98(s,3H),0.90(d,J＝6.2Hz,3H),0.86(d,J＝4.6Hz,9H),0.67(s,3H).
第三步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(830mg,1.82mmol,1.0eq.),加入水(14.0mL)，叔丁醇(90mL),室温下依次加入2-甲基-2-丁烯(2.5g，36.35mmol，20.0eq.),磷酸二氢钠(2.4g,20.0mmol,10.0eq.),亚氯酸钠(493mg,5.4mmol,3.0eq.),室温下搅拌2个小时，TLC监测(PE:EA＝3:1,磷钼酸显色,Rf1＝0.8,Rf2＝0.4)，反应结束后，浓缩除去叔丁醇，随后浓缩液中加入水(10.0mL),再以乙酸乙酯(10.0mL*3)萃取，有机相合并，干燥，浓缩得(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸(37-3)(1.05g,1.77mmol,97.78％)。1H NMR(399MHz,CDCl3)δ4.48(dd,J＝11.6,4.5Hz,1H),2.42–2.22(m,2H),2.03(s,4H),1.98(s,2H),1.94–1.85(m,1H),1.76–1.63(m,8H),1.51(dd,J＝20.7,7.5Hz,4H),1.41(s,2H),1.32–1.24(m,3H),1.13(d,J＝14.2Hz,3H),0.98(s,3H),0.90(d,J＝6.3Hz,3H),0.86(d,J＝4.8Hz,9H),0.67(s,3H).
第四步 将(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸(37-3)(120mg,0.27mmol,1.0eq.)溶于DMF(N,N-二甲基甲酰胺)(5.0mL)中，再加入HATU(N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲)(123.13mg,0.32mmol,1.2eq.),二异丙基乙基胺(41.85mg,0.32mmol,1.2eq.),室温下搅拌30分钟，随后在室温下加入哌啶(25.28mg,0.30mmol,1.3eq.),随后继续在室温下搅拌2小时，TLC监测(PE:EA＝3:1,磷钼酸显色,Rf1＝0.5,Rf2＝0.6)，反应结束后，加入15.0mL水，在以乙酸乙酯10mL*3萃取，有机相合并，干燥，浓缩得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(六氢吡啶-1-基)-6-氧亚基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-4)260mg黄色油状物粗品直接投至下一步反应中。
第五步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(六氢吡啶-1-基)-6-氧亚基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-4)(260mg,0.25mmol,1.0eq.),加入四氢呋喃(6.0mL),甲醇(6.0mL),1M氢氧化锂水溶液(3.5mL),室温下搅拌过夜，TLC监测(PE:EA＝3:1,磷钼酸显色,Rf1＝0.6,Rf2＝0.5)，反应结束后，浓缩出去四氢呋喃和甲醇，随后浓缩液中加入水(15.0mL),再以乙酸乙酯(15.0mL*3)萃取，有机相合并，干燥，浓缩经制备HPLC纯化得(5R)-1-(六氢吡啶-1-基)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己-1-酮(37)(4.11mg,0.01mmol,3.7％)。
1H NMR(399MHz,CDCl3)δ3.53(s,2H),3.37(s,2H),3.21(d,J＝7.3Hz,1H),2.26(s,2H),1.94(d,J＝46.1Hz,6H),1.70(s,1H),1.54(s,9H),1.39(s,4H),1.32–1.12(m,7H),1.03(d,J＝12.3Hz,2H),0.97(d,J＝7.8Hz,6H),0.90(d,J＝5.7Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(101MHz,dmso)δ166.89,129.58,74.22,72.55,72.24,71.92,45.02,42.00,39.70,34.11,32.24,29.21,26.12,23.18,21.25,19.99,17.45,16.14,13.49,10.17.LC-MS:[M+H]+＝498.70
实施例38
化合物38(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(1,4-氧杂氮杂环己-4-基)丁-1-酮的制备
第一步 将化合物(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁酸III(60mg,0.14mmol，1.0eq)溶解DMF(N,N二甲基甲酰胺)(2mL)在中，依次加入HATU(61.57mg,0.16mmol，1.2eq)，N，N二异丙基乙胺(26.16g,0.20mmol，1.5eq)，室温下搅拌半小时。点板监测原料消失，再加入吗菲林(87.12g,0.14mmol，1.3eq)，反应3小时。TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应完全，加水稀释，乙酸乙酯萃取，浓缩溶剂得乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(1,4-氧杂氮杂环己-4-基)-4-氧亚基丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯IX(60mg,010.mmol,纯度80％，收率77.90％)，粗品直接投下一步。
第二步 化合物乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(1,4-氧杂氮杂环己-4-基)-4-氧亚基丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(IX)溶解于EtOH(乙醇)(4mL)中，加入氢氧化钠水溶液(4mol/L,0.5mL)，室温反应16小时。TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应完全，反应液浓缩去除乙醇，加水稀释，用乙酸乙酯(20mL)萃取两次，合并有机相，盐水洗涤两次，无水硫酸钠干燥，硅胶柱层析(PE:EtOAc＝50:10),(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(1,4-氧杂氮杂环己-4-基)丁-1-酮(38)(44.99mg,纯度92.43％，收率88.2％)。1H  NMR(400MHz,CDCl3)δ3.61–3.59(m,4H),3.50(s,4H),3.16(dd,J＝11.6,4.5Hz,1H),2.32(d,J＝12.2Hz,1H),2.05–1.79(m,7H),1.70–1.47(m,10H),1.31–1.07(m,4H),0.91(dd,J＝9.9,6.8Hz,8H),0.81(s,3H),0.74(s,3H),0.65(d,J＝18.9Hz,3H).13C NMR(101MHz,CDCl3)δ171.70,134.57,134.17,78.97,77.33,77.22,77.01,76.70,50.95,50.41,49.91,44.72,39.81,38.90,37.04,35.59,34.50,30.92,30.82,28.32,27.97,27.85,26.49,24.23,20.98,19.63,19.15,18.24,15.85,15.42
实施例39
化合物39(3R)-1-(六氢吡啶-1-基)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁-1-酮的制备
参照实施例38，将第一步的胺换为六氢吡啶，最终得到化合物(3R)-1-(六氢吡啶-1-基)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁-1-酮(39).1H NMR(400MHz,CDCl3)δ3.42(s,4H),3.16(dd,J＝11.5,4.5Hz,1H),2.33(d,J＝13.8Hz,1H),2.06–1.81(m,7H),1.69–1.44(m,14H),1.31(dd,J＝21.5,11.2Hz,2H),1.14(dd,J＝22.0,12.0Hz,3H),0.94(ddd,J＝20.1,12.3,3.9Hz,9H),0.81(s,3H),0.74(s,3H),0.65(d,J＝18.7Hz,3H).13C NMR(101MHz,CDCl3)δ171.40,134.53,134.23,78.99,77.33,77.22,77.01,76.70,51.05,50.41,49.89,44.72,38.90,37.04,35.59,34.58,30.92,30.84,28.25,27.97,27.85,26.49,24.61,24.25,20.99,19.56,19.15,18.24,15.86,15.42.
实施例40
化合物40(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N,N-二甲基戊酰胺的制备
参照实施例12，将胺换为二甲胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N,N-二甲基戊 酰胺(40).1H NMR(400MHz,CDCl3)δ3.17(dd,J＝11.5,4.5Hz,1H),2.92(s,6H),2.35(ddd,J＝15.9,11.1,5.1Hz,1H),2.23–2.14(m,1H),1.98–1.89(m,5H),1.81–1.71(m,3H),1.66–1.57(m,4H),1.55–1.35(m,5H),1.20(dddd,J＝15.7,11.3,5.9,2.8Hz,4H),0.92(d,J＝8.3Hz,6H),0.86(d,J＝6.0Hz,3H),0.81(s,3H),0.74(s,3H),0.60(d,J＝19.3Hz,3H).13C NMR(101MHz)δ134.41,134.38,78.98,77.34,77.23,77.02,76.70,50.40,49.83,44.54,38.90,37.03,36.41,35.59,31.58,31.00,30.84,30.49,28.18,27.97,27.85,26.49,24.25,21.00,19.15,18.52,18.25,15.78,15.42.LC-MS:[M+H]+＝444.35
实施例41
化合物41(4R)-N,N-二乙基-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
参照实施例12，将胺换为二乙胺，最终得到化合物(4R)-N,N-二乙基-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(41).1H NMR(400MHz,CDCl3)δ3.28(s,4H),3.17(dd,J＝11.5,4.5Hz,1H),2.33(ddd,J＝15.7,11.0,5.0Hz,1H),2.22–2.13(m,1H),2.01–1.84(m,7H),1.80–1.58(m,6H),1.41(dddd,J＝25.1,21.0,10.4,5.2Hz,6H),1.20–1.04(m,8H),0.92(d,J＝8.3Hz,6H),0.86(d,J＝6.0Hz,3H),0.81(s,3H),0.74(s,3H),0.60(d,J＝19.3Hz,3H).13C NMR(101MHz,CDCl3)δ134.41,78.98,77.34,77.23,77.02,76.71,50.43,50.40,49.83,44.54,38.90,37.03,36.45,35.59,32.02,31.00,30.84,30.19,28.20,27.97,27.85,26.49,24.24,21.00,19.15,18.55,18.25,15.78,15.42.LC-MS:[M+H]+＝472.45
实施例42
化合物42(4R)-1-(4-氟六氢吡啶-1-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮的制备
参照实施例12，将胺换为4-氟哌啶，最终得到化合物(4R)-1-(4-氟六氢吡啶-1-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮(42).1H NMR(400MHz,CDCl3)δ4.93–4.86(m,1H),4.81–4.74(m,1H),3.55(s,2H),3.51(s,2H),3.20(dd,J＝11.5,4.5Hz,1H),2.45–2.32(m,1H),2.27–2.16(m,1H),2.04–1.91(m,4H),1.89–1.71(m,5H),1.71–1.53(m,10H),1.45(ddd,J＝17.7,13.6,5.9Hz,3H),1.33–1.12(m,4H),1.05–0.93(m,6H),0.90(d,J＝6.0Hz,3H),0.86–0.81(m,3H),0.78(s,3H),0.64(d,J＝19.4Hz,3H).13C NMR(101MHz,CDCl3)δ134.35,78.98,77.33,77.01,76.70,50.40,49.84,44.55,38.90,37.03,36.46,35.59,31.00,30.83,28.22,27.96,27.85,26.49,24.27,20.99,19.15,18.25,15.79,15.42.LC-MS:[M+H]+＝502.45
实施例43
化合物43(4R)-1-(4-氟六氢吡啶-1-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮的制备
参照实施例12，将胺换为4，4-二氟哌啶，最终得到化合物(4R)-1-(4-氟六氢吡啶-1-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮(43).1H NMR(400MHz,CDCl3)δ3.58(s,4H),3.17(dd,J＝11.5,4.5Hz,1H),2.41–2.30(m,1H),2.25–2.14(m,1H),1.93(ddd,J＝20.6,11.9,7.5Hz,7H),1.69–1.50(m,11H),1.41(dt,J＝12.9,8.0Hz,3H),1.28–1.08(m,4H),0.94(dd,J＝17.3,4.9Hz,6H),0.86(d,J＝6.0Hz,3H),0.82(d,J＝5.1Hz,3H),0.74(s,3H),0.60(d,J＝19.4Hz,3H).13C NMR(101MHz,CDCl3)δ172.17,134.46,134.33,78.98,77.33,77.01,76.70,50.40,50.37,49.84,44.56,38.90,37.03,36.41,35.59,31.74,30.99,30.82,30.54,28.21,27.96,27.84,26.49,24.24,20.99,19.15,18.54,18.24,15.78,15.42.LC-MS:[M+H]+＝520.50
实施例44
化合物44(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-[4-(三氟甲基)六氢吡啶-1-基]戊-1-酮的制备
参照实施例2，将胺换为4-三氟甲基哌啶，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-[4-(三氟甲基)六氢吡啶-1-基]戊-1-酮(44).1H NMR(400MHz,CDCl3)δ4.73(d,J＝14.3Hz,1H),3.94(d,J＝12.8Hz,1H),3.22(d,J＝7.0Hz,1H),3.00(t,J＝13.0Hz,1H),2.48(d,J＝12.2Hz,1H),2.38(s,1H),2.23(d,J＝5.0Hz,2H),2.01(s,4H),1.92(d,J＝14.6Hz,3H),1.69(m,6H),1.48(d,J＝8.2Hz,5H),1.21(m,7H),1.03(d,J＝12.6Hz,1H),0.97(d,J＝7.8Hz,6H),0.91(d,J＝5.9Hz,3H),0.86(s,3H),0.79(s,3H),0.68(s,3H).13CNMR(100MHz,CDCl3)δ172.05,134.30,109.99,78.93,77.30,76.98,76.66,50.31,49.80,44.49,40.42,38.85,36.98,36.38,35.54,31.69,30.95,30.80,30.63,28.18,27.93,27.79,26.45,24.21,20.95,19.12,18.51,18.21,15.74,15.39.19F NMR(376MHz,CDCl3)δ-73.89,-73.92.LC-MS:[M+H]+＝552.50
实施例45
化合物45(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(4-甲基六氢吡啶-1-基)戊-1-酮的制备
参照实施例2，将胺换为4-甲基哌啶，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(4-甲基六氢吡啶-1-基)戊-1-酮(45).1H NMR(399MHz,CDCl3)δ4.54(d,J＝12.7Hz,1H),3.78(d,J＝12.9Hz, 1H),3.21(dd,J＝11.4,4.2Hz,1H),2.96(t,J＝12.3Hz,1H),2.50(t,J＝12.4Hz,1H),2.36(t,J＝10.4Hz,1H),2.19(m,1H),1.97(d,J＝26.1Hz,5H),1.68(dt,J＝27.2,14.0Hz,12H),1.32(m,7H),1.03(m,3H),0.96(d,J＝7.9Hz,6H),0.91(dd,J＝9.1,6.3Hz,6H),0.85(s,3H),0.78(s,3H),0.67(s,3H).13CNMR(100MHz,CDCl3)δ171.95,134.37,98.57,78.92,77.30,76.98,76.66,50.36,49.78,46.02,44.50,41.95,38.85,36.99,36.44,35.56,34.74,33.79,31.86,31.10,30.96,30.80,28.15,27.93,27.80,26.45,24.21,21.71,20.96,19.11,18.50,18.21,15.74,15.38,0.98.LC-MS:[M+H]+＝498.65
实施例46
化合物46(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(2-氮杂螺[3.3]庚-2-基)戊-1-酮的制备
参照实施例2，将胺换为2-氮杂螺[3.3]庚烷，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(2-氮杂螺[3.3]庚-2-基)戊-1-酮(46).1H NMR(399MHz,CDCl3)δ4.02(s,2H),3.91(s,2H),3.66(s,0.16H),3.21(dd,J＝11.5,4.4Hz,1H),2.14(t,J＝7.2Hz,4H),2.07(m,1H),1.96(m,5H),1.84(m,2H),1.68(m,6H),1.47(m,5H),1.26(m,3H),1.17(m,2H),1.02(m,1H),0.96(d,J＝8.4Hz,6H),0.87(m,6H),0.79(s,3H),0.66(s,3H).13CNMR(101MHz,CDCl3)δ173.72,134.34,134.32,78.93,77.31,77.00,76.68,62.44,60.01,50.35,50.25,49.77,44.47,38.86,37.45,36.98,36.26,35.55,33.08,31.20,30.95,30.79,29.67,28.64,28.09,27.93,27.80,26.45,24.21,20.95,19.12,18.44,18.21,16.03,15.74,15.40LC-MS:[M+H]+＝496.65
实施例47
化合物47(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N,N-双(2-甲基丙基)戊酰胺的制备
参照实施例2，将胺换为二异丁胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N,N-双(2-甲基丙基)戊酰胺(47).1H NMR(399MHz,CDCl3)δ3.21(d,J＝8.8Hz,1H),3.16(d,J＝7.3Hz,2H),3.06(d,J＝7.4Hz,2H),2.35(m,1H),2.22(m,1H),1.93(m,7H),1.85(s,1H),1.68(m,6H),1.48(m,3H),1.21(dt,J＝21.2,20.7Hz,6H),1.03(d,J＝12.7Hz,1H),0.97(d,J＝7.8Hz,6H),0.90(d,J＝6.7Hz,9H),0.85(m,9H),0.79(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ173.98,134.34,78.95,77.31,76.99,76.67,55.63,53.07,50.35,49.78,44.48,38.86,36.98,36.29,35.55,32.09,30.96,30.80,30.57,28.14,27.98,27.93,27.80,26.50,26.45,24.20,20.96,20.18,20.11,19.12,18.53,18.22,15.74,15.40,1.00.LC-MS:[M+H+＝528.70
实施例48
化合物48 1-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基]六氢吡啶-4-甲腈的制备
参照实施例12，将胺换为4-氰基哌啶，最终得到化合物1-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基]六氢吡啶-4-甲腈(48).1H NMR(400MHz,CDCl3)δ3.73(d,J＝35.0Hz,2H),3.50(d,J＝34.4Hz,2H),3.23(dd,J＝11.5,4.4Hz,1H),2.88(dt,J＝11.6,3.8Hz,1H),2.44–2.33(m,1H),2.28–2.18(m,1H),2.07–1.85(m,8H),1.75–1.58(m,8H),1.53–1.15(m,8H),1.02(dd,J＝23.5,9.5Hz,7H),0.93(d,J＝6.0Hz, 3H),0.88(s,3H),0.81(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ172.09,134.45,134.32,120.75,78.96,77.35,77.03,76.71,50.40,50.37,49.83,44.55,38.90,37.03,36.41,35.59,31.70,30.99,30.82,30.57,28.22,27.97,27.84,26.49,26.41,24.25,20.99,19.15,18.54,18.25,15.79,15.42.LC-MS:[M+H]+＝509.45.
实施例49
化合物49(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基戊酰胺的制备
参照实施例2，将胺换为(2-氟苯基)(甲基)胺,最终得到化合物((4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基戊酰胺(49).1H NMR(399MHz,CDCl3)δ7.32(s,1H),7.18(dd,J＝18.6,11.2Hz,3H),3.21(d,J＝8.6Hz,4H),2.09(s,1H),1.95(s,4H),1.79(s,1H),1.72–1.60(m,6H),1.50(d,J＝26.5Hz,6H),1.33(d,J＝8.5Hz,1H),1.21(d,J＝13.4Hz,3H),1.18–1.09(m,1H),1.02(d,J＝12.8Hz,1H),0.96(d,J＝13.8Hz,6H),0.79(d,J＝5.8Hz,6H),0.66(d,J＝5.3Hz,3H),0.60(s,3H).13CNMR(101MHz,CDCl3)δ173.99,145.24,134.29,129.71,125.01,117.01,116.81,78.95,77.31,77.20,76.99,76.68,50.33,49.73,44.38,38.85,36.96,36.45,36.06,35.53,30.86,30.76,27.93,27.79,26.43,24.14,20.92,19.11,18.20,15.67,15.39.LC-MS:[M+H]+＝524.40
实施例50
化合物50(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N,N-二(丙-2-基)戊酰胺的制备
参照实施例2，将胺换为二异丙胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N,N-二(丙-2-基)戊酰胺(50).1H NMR(399MHz,CDCl3)δ3.94(s,1H),3.45(s,1H),3.22(dd,J＝11.2,4.2Hz,1H),2.31(d,J＝10.1Hz,1H),2.15(s,1H),2.01(s,4H),1.69(dd,J＝20.1,12.6Hz,7H),1.49(m,7H),1.35(d,J＝6.7Hz,5H),1.25(d,J＝11.5Hz,4H),1.18(d,J＝6.6Hz,6H),1.03(d,J＝13.0Hz,1H),0.97(d,J＝8.3Hz,6H),0.91(d,J＝6.1Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(100MHz,CDCl3)δ172.41,134.34,78.96,77.30,77.18,76.99,76.67,75.96,50.37,49.78,48.36,45.53,44.49,38.86,36.98,36.42,35.55,32.72,31.92,30.95,30.81,28.20,27.93,27.80,26.45,24.21,21.05,20.70,19.12,18.57,18.22,15.74,15.39,1.00.LC-MS:[M+H]+＝500.70
实施例51
化合物51(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基乙基)-N-丙基戊酰胺的制备
参照实施例2，将胺换为2-(丙基氨基)乙-1-醇，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基乙基)-N-丙基戊酰胺(51).1H NMR(399MHz,CDCl3)δ8.32(d,J＝6.0Hz,2H),7.48(d,J＝6.2Hz,2H),3.15(dd,J＝11.4,4.8Hz,1H),2.38(m,1H),2.24(m,1H),1.90(m,6H),1.57(m,6H),1.40(dd,J＝32.1,23.5Hz,4H),1.15(dd,J＝22.5,10.3Hz,4H),0.98(d,J＝11.6Hz,1H),0.92(d,J＝5.0Hz,6H),0.88(d,J＝5.6Hz,3H),0.81(s,3H),0.74(s,3H),0.63(s,3H).13C NMR(101MHz,CDCl3)δ149.80,134.35,134.21,113.56,78.77,77.35,77.04,76.72,50.31,50.27,49.74,49.68,49.47,49.26,49.04,48.83,44.46,38.78,36.92,36.14,35.52,34.49,31.52,30.92,30.72,28.05,27.82,27.47,26.40,24.11,20.90,19.05,18.28,18.16,15.68,15.34,0.92.LC-MS:[M+H]+＝502.60
实施例52
化合物52(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基乙基)戊酰胺的制备
参照实施例12，将胺换为(2-氟苯基)(4,4,5,5-四甲基-3-氧杂-4-硅杂己-1-基)胺，最终得到化合物(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基乙基)戊酰胺(52).1H NMR(400MHz,CDCl3)δ7.44–7.34(m,1H),7.33–7.27(m,1H),7.25–7.16(m,2H),4.05–3.94(m,1H),3.85–3.64(m,3H),3.23(dd,J＝11.5,4.4Hz,1H),2.18–2.09(m,1H),1.93–2.05(m,5H),1.80–1.64(m,11H),1.30–1.20(m,4H),1.18–1.10(m,1H),1.06–1.02(m,1H),0.98(d,J＝14.3Hz,6H),0.81(d,J＝6.2Hz,6H),0.69(d,J＝4.7Hz,3H),0.62(s,3H).13C NMR(101MHz,CDCl3)δ176.20,134.35,134.32,130.36,130.30,125.23,125.19,117.10,116.90,78.96,61.96,52.76,50.35,50.21,50.16,49.76,44.42,38.87,36.99,35.55,31.70,31.64,31.24,31.10,30.89,30.76,27.95,27.81,26.45,24.15,20.94,19.13,18.22,15.69,15.41.LC-MS:[M+H]+＝554.00
实施例53
化合物53(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-苯基戊酰胺的制备
参照实施例2，将胺换为N-甲基苯胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-苯基戊酰胺(53).1H NMR(400MHz,CDCl3)δ7.43(t,J＝7.5Hz,2H),7.35(t,J＝7.3Hz,1H),7.19(d,J＝7.6Hz,2H),3.27(s,3H),3.23(dd,J＝11.5,4.4Hz,1H),2.06–1.88(m,8H),1.86–1.74(m,2H),1.72–1.48(m,7H),1.34–1.10(m,6H),1.03(dd,J＝12.6,1.8Hz,1H),0.99(s,3H),0.96(s,3H),0.81(d,J＝5.0Hz,6H),0.72–0.64(m,3H),0.62(s,3H).13C NMR(101MHz,CDCl3)δ173.92,144.29,134.34,129.70,127.35, 78.96,77.33,77.22,77.01,76.69,50.36,50.21,49.76,44.41,38.87,36.98,36.16,35.56,31.29,30.89,30.78,28.03,27.95,27.82,26.45,24.17,20.94,19.12,18.22,15.70,15.70,15.41.LC-MS:[M+H]+＝507.4
实施例54
化合物54 2-氟-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-N-甲基苯甲酰胺的制备
第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(III)(50mg,0.12mmol)溶于甲醇(5.0mL)中，再加入甲胺的甲醇溶液(0.1mL,3.2mmol,27eq.),室温下搅拌30分钟，随后在室温下加入钯碳(1.25mg,0.012mmol),氢气置换，随后继续在室温下搅拌2小时，TLC监测(PE:EA＝10:1,磷钼酸显色,Rf1＝0.8,Rf2＝0.6)，反应结束后，过滤除去钯碳，滤液浓缩得90mg白色固体乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(甲基氨基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(54-1)，粗品直接投至下一步反应中。
第二步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(甲基氨基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(54-1)(90mg,0.142mmol,1.0eq.),加入二氯甲烷(5.0mL),三乙胺(0.02mL,0.142mmol),接着冰浴下加入邻氟苯甲酰氯(22.51mg,0.142 mmol),随后室温下搅拌过夜，LC-MS监测，反应结束后，浓缩除去二氯甲烷，随后浓缩液中加入饱和碳酸氢钠水溶液(10.0mL),再以乙酸乙酯(10.0mL*3)萃取，有机相合并，干燥，浓缩经制备制备TLC纯化得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{[(2-氟苯基)羰基](甲基)氨基}丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(54-2)(80mg,0.134mmol,94.61％).1H NMR(399MHz,CDCl3)δ7.37–7.29(m,2H),7.15(dd,J＝21.3,13.9Hz,1H),7.08(t,J＝8.7Hz,1H),4.55–4.39(m,1H),3.78–3.68(m,0.3H),3.47–3.35(m,0.4H),3.15(d,J＝7.2Hz,1H),3.07(s,2H),2.86(s,1H),2.03(s,5H),1.98–1.91(m,2H),1.68(d,J＝19.3Hz,6H),1.54(d,J＝19.5Hz,4H),1.40–1.24(m,4H),1.13(d,J＝10.3Hz,3H),1.01–0.92(m,5H),0.86(d,J＝3.5Hz,7H),0.79(s,2H),0.70–0.67(m,1H),0.66–0.54(m,3H).
第三步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{[(2-氟苯基)羰基](甲基)氨基}丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(54-2)(80mg,0.141mmol)溶于四氢呋喃(3.0mL)和甲醇(3.0mL)的混合溶剂中，室温搅拌下加入1M氢氧化锂水溶液(1.5mL),随后室温下搅拌，LCMS监测，反应结束后，浓缩除去反应溶剂，随后加入10mL水，再以乙酸乙酯(10.0mL*3)萃取，有机相合并，干燥，浓缩经制备制备HPLC纯化得2-氟-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-N-甲基苯甲酰胺(54)(15.41mg,0.029mmol,20.24％)白色固体。1H NMR(400MHz,CDCl3)δ7.42–7.28(m,2H),7.17(t,J＝7.4Hz,1H),7.07(q,J＝8.6Hz,1H),3.24–3.15(m,1H),3.07(s,1.8H),2.82(d,J＝35.9Hz,1.4H),1.98(d,J＝20.3Hz,5H),1.69(dd,J＝24.3,14.3Hz,8H),1.54(d,J＝7.8Hz,3H),1.42–1.29(m,2H),1.26–1.12(m,4H),1.07–1.02(m,1H),0.98(dd,J＝7.1,4.1Hz,6H),0.95(s,2H),0.88(s,1.3H),0.79(d,J＝3.7Hz,5H),0.71(s,1.3H),0.61(d,J＝8.4Hz,3H).13CNMR(101MHz,CDCl3)δ166.74,166.38,144.85,134.42,134.28,134.14,130.85,130.78,128.89,128.65,124.53,124.40,115.87,115.75,115.66,115.53,78.95,78.91,77.31,76.99,76.67,50.40,50.37,50.34,49.94,49.82,49.76,48.61,45.09,44.56,44.42,38.85,36.97,36.14,35.53,34.38,34.34,34.01,33.08,32.72,30.96,30.82,30.70,28.27,28.05,27.93,27.82,27.78,26.47,26.43,24.23,24.12,20.97,20.89,19.11,18.78,18.47,18.22,18.19,15.68,15.58,15.39.LC-MS:[M+H]+＝524.35.
实施例55
化合物55(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1,3-硫杂氮杂环戊熳-2-基)戊酰胺的制备
参照实施例2，将胺换为N-甲基-2-噻唑胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1,3-硫杂氮杂环戊熳-2-基)戊酰胺(55).1H NMR(399MHz,CDCl3)δ7.48(d,J＝3.5Hz,1H),6.96(d,J＝3.3Hz,1H),3.72(s,3H),3.21(dd,J＝11.5,4.4Hz,1H),2.67(dd,J＝10.7,5.8Hz,1H),2.57–2.47(m,1H),2.07–1.90(m,6H),1.75–1.62(m,6H),1.62–1.34(m,6H),1.25–1.17(m,2H),1.03(d,J＝11.8Hz,1H),0.96(t,J＝7.5Hz,9H),0.86(s,3H),0.79(s,3H),0.69(s,3H).13CNMR(101MHz,CDCl3)δ172.80,160.29,136.58,134.40,134.26,114.77,78.91,77.31,76.99,76.67,50.33,49.80,44.53,38.86,36.99,36.14,35.54,34.89,32.08,30.96,30.88,30.79,28.16,27.93,27.80,26.45,24.21,20.95,19.12,18.54,18.21,15.77,15.40.LC-MS:[M+H]+＝513.60.
实施例56
化合物56(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(2-甲基吡唑-3-基)戊酰胺的制备

第一步 称取(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VII)(100mg,0.218mmol)溶于二氯甲烷(10.0mL)中，加入N,N’-二甲基甲酰胺(1d)，置换N2，置冰浴。将草酰氯(36.89mg,0.291mmol)溶于二氯甲烷(3.0mL)中缓慢滴加至反应体系中，冰浴下搅拌半小时后TLC(石油醚：乙酸乙酯＝10:1)监测，反应完毕，旋干，加入二氯甲烷(10.0mL)稀释，在冰浴下缓慢滴加到1-甲基-5-氨基吡唑(10.59mg,0.109mmol)和4-二甲氨基吡啶(106.54mg,0.872mmol)的DCM溶液中，滴加完毕后于冰浴反应0.5h，升到室温反应。TLC(PE：EtOAc＝3:1)监测反应完毕，LCMS确认产物。经柱层析(PE:EtOAc＝30:1～20:1～15:1)纯化得乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-[(2-甲基吡唑-3-基)氨基]-5-氧亚基戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(56-1)(60mg，0.11mmol，46.06％)。1H NMR(400MHz,Methanol-d4)δ7.38(s,1H),6.20(d,J＝1.7Hz,1H),3.69(s,3H),3.18–3.10(m,1H),2.55–2.29(m,2H),2.06(s,5H),1.90(s,1H),1.83–1.58(m,8H),1.58–1.47(m,3H),1.39(s,2H),1.31–1.15(m,3H),1.04(d,J＝12.5Hz,1H),1.01–0.95(m,9H),0.91(s,3H),0.79(s,3H),0.75(s,3H).
第二步 称取(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-甲基吡唑-3-基)戊酰胺(56-1)(10mg,0.019mmol)溶于N,N’-二甲基甲酰胺(1.0mL)中，加入碳酸钾(7.71mg,0.056mmol),接着在室温下加入碘甲烷(15.83mg,0.112mmol),TLC(PE:EtOAc＝1:1)监测，反应完毕，LCMS确认产物，加入水5.0mL和乙酸乙酯3.0mL*3，有机相分出后，合并，干燥，浓缩粗品经制备TLC(PE:EtOAc＝1:1)纯化得乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-[甲基(2-甲基吡唑-3-基)氨基]-5-氧亚基戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(56-2)(6.0mg，0.01mmol，48.64％).1H NMR(400MHz,Methanol-d4)δ7.50(d,J＝2.0Hz,1H),6.27(s,1H),4.43(t,J＝8.3Hz,1H),3.70(s,3H),3.15(s,3H),2.03(d,J＝14.7Hz,8H),1.82–1.50(m,13H),1.39(t,J＝8.8Hz,6H),1.17(dd,J ＝24.7,12.2Hz,4H),1.02(s,3H),0.87(d,J＝2.4Hz,9H),0.76(d,J＝5.9Hz,4H),0.68(s,3H).
第三步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-[甲基(2-甲基吡唑-3-基)氨基]-5-氧亚基戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(56-2)(114mg,0.21mmol)溶于四氢呋喃(5.0mL)，加入甲醇(3.00mL)，最后加入氢氧化锂(8.91mg,0.372mmol)的水(1M,2.0mL)溶液，加完后于室温搅拌18h。TLC(EA)监测反应完毕，制备HPLC得(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(2-甲基吡唑-3-基)戊酰胺(56)(19.32mg，0.038mmol，18.41％)1H NMR(399MHz,Methanol-d4)δ7.49(s,1H),6.26(d,J＝2.0Hz,1H),3.69(s,3H),3.14(s,4H),2.06(d,J＝30.0Hz,7H),1.84(s,1H),1.72(d,J＝13.5Hz,5H),1.60(s,6H),1.34(dt,J＝32.2,11.1Hz,4H),1.16(d,J＝10.2Hz,1H),1.02(d,J＝13.4Hz,2H),0.96(s,3H),0.85(s,3H),0.78(s,3H),0.75(d,J＝5.9Hz,3H),0.67(s,3H).13C NMR(101MHz,CD3OD)δ175.21,140.83,138.54,134.56,134.15,78.19,50.50,49.57,48.20,47.98,47.84,47.77,47.61,47.56,47.49,47.35,47.13,46.92,44.23,38.52,36.76,35.52,33.95,31.43,30.77,27.17,27.04,26.20,23.14,20.59,18.17,17.98,17.37,14.84,14.71.LC-MS:[M+H]+＝510.40
实施例57
化合物57 N-乙基-2-氟-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]苯甲酰胺的制备

第一步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯III(100mg,0.233mmol)，钛酸四乙酯(106.42mg,0.467mmol),乙基胺(45.09mg,0.7mmol)溶于四氢呋喃(10.0mL)中，接着升温至80℃下搅拌，TLC(DCM:MeOH＝20:1)监测，反应完毕，冷却至室温，加入15mL水稀释后，再加入乙酸乙酯10mL*3萃取，有机相合并，干燥，浓缩得粗品后经柱层析(二氯：甲醇＝100:1～30:1)纯化得乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(乙基氨基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(57-1)(65mg，0.13mmol，54.79％)。
第二步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(乙基氨基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(57-1)(50mg,0.11mmol)溶于二氯甲烷(5.0mL)，氮气置换，冰浴降温，加入二异丙基乙基胺(19.4mg,0.15mmol),接着再滴入邻氟苯甲酰氯(19.0mg,0.12mmol),滴加完毕后，渐渐升至室温搅拌，TLC(PE:EA＝3：1)监测反应完毕，加入饱和碳酸氢钠水溶液10mL,随后加入乙酸乙酯6mL*3,有机相分离，干燥，浓缩所得粗品经制备TLC(展开剂：PE:EtOAc＝1：1)得乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{乙基[(2-氟苯基)羰基]氨基}丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(57-2)(39.6mg，0.07mmol，62.18％).1H NMR(399MHz,Chloroform-d)δ7.31(dt,J＝14.4,7.1Hz,2H),7.16(t,J＝7.5Hz,1H),7.07(t,J＝8.9Hz,1H),4.53–4.43(m,1H),3.55(s,2H),3.18(q,J＝7.6Hz,2H),2.03(d,J＝2.1Hz,8H),1.68(q,J＝18.6,14.1Hz,6H),1.53(d,J＝17.7Hz,7H),1.42–1.21(m,6H),1.20–0.91(m,11H),0.91–0.82(m,8H),0.79(s,2H),0.70(s,1H),0.63–0.55(m,3H).
第三步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{乙基[(2-氟苯基)羰基]氨基}丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(57-2)(39.6mg,0.07mmol,1.0eq.),加入四氢呋喃(4.0mL),甲醇(4.0mL),1M氢氧化锂水溶液(2.5mL),室温下搅拌过夜，LCMS监测，反应结束后，浓缩除去四氢呋喃和甲醇，随后浓缩液中加入水(10.0mL),再以 乙酸乙酯(8.0mL*3)萃取，有机相合并，干燥，浓缩经制备HPLC纯化得N-乙基-2-氟-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]苯甲酰胺(57)(11.90mg,0.022mmol,31.6％)。1H NMR(400MHz,CD3OD)δ7.45(s,1H),7.36–7.22(m,2H),7.19(t,J＝8.7Hz,1H),3.54(s,2H),3.17(ddd,J＝22.8,15.0,7.2Hz,3H),2.09–1.97(m,4H),1.73(ddd,J＝30.2,17.9,10.2Hz,5H),1.63–1.49(m,5H),1.40–1.31(m,1H),1.29–1.09(m,6H),1.00(ddd,J＝34.8,17.9,11.4Hz,12H),0.78(dd,J＝13.9,7.6Hz,6H),0.64(d,J＝5.3Hz,3H).13C NMR(400MHz,CD3OD)δ167.16,134.56,134.08,131.10,131.08,131.04,128.12,127.83,124.47,115.61,115.57,115.40,115.36,78.17,50.48,50.33,49.74,49.64,49.54,48.19,47.98,47.76,47.55,47.34,47.12,46.91,44.35,44.20,38.51,36.74,35.49,34.59,34.47,34.10,33.37,30.86,30.69,30.35,27.88,27.57,27.16,27.02,26.17,23.22,23.12,20.55,18.16,17.95,17.61,14.86,14.70,12.62,11.62.LC-MS:[M+H]+＝538.45
实施例58
化合物58(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(4-羟基六氢吡啶-1-基)戊-1-酮的制备
参照实施例2，将胺换为4-羟基-哌啶，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-(4-羟基六氢吡啶-1-基)戊-1-酮(58).1H NMR(400MHz,DMSO)δ4.71(d,J＝4.1Hz,1H),4.32(d,J＝5.0Hz,1H),3.89(s,1H),3.71–3.62(m,2H),3.14–3.07(m,1H),3.03–2.87(m,2H),2.37–2.10(m,4H),2.03–1.85(m,5H),1.75–1.57(m,8H),1.49–1.40(m,4H),1.27–1.21(m,3H),1.18–1.10(m,3H),0.93–0.83(m,12H),0.70(s,3H),0.66(s,3H).13C NMR(101MHz,CDCl3)δ182.82,134.40,78.77,78.71,62.50,44.47,43.17,42.49,38.78,36.93,36.43,35.54,33.60,32.82,31.84,30.90,30.75,28.10,27.81,27.44,26.41,25.37,24.13,20.91,19.04,18.72,18.39,18.17,17.70,15.67,15.33.LC-MS[M+H]+＝500.00
实施例59
化合物59(4R)-N-乙基-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺的制备
第一步 称取(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸VII(200mg,0.44mmol,1.0eq.)和邻氟苯胺(72.68mg,0.65mmol),溶于二氯甲烷(4mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(331.59mg，0.872mmol),二异丙基乙基胺(0.288mL,1.744mmol)，室温下搅拌过夜，TLC(PE:EA＝10：1)监测，反应结束后，加入水(30.0mL),再以乙酸乙酯(30.0mL*3)萃取，有机相合并，干燥，浓缩粗品经柱层析(PE:EA＝50：1～30：1)得淡黄色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-氟苯基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(59-1)(85mg,0.15mmol,33.50％)。
第二步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-氟苯基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(59-1)(80mg,0.15mmol,1.0eq.)溶于DMF(N,N-二甲基甲酰胺)(8.0mL)中，氮气置换后，冰浴降温，然后称取氢化钠(34.8mg,1.45mmol)加至反应体系中，搅拌半小时，随后加入溴乙烷(0.011mL,0.145mmol),接着升至室温下搅拌2小时，TLC监测(PE:EA＝10:1,磷钼酸显色,Rf1＝0.57,Rf2＝0.7)，反应结束后，加入10.0mL饱和氯化铵水溶液，再以乙酸乙酯10mL*3萃取，有机相合并，干燥，浓缩制备TLC得白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[乙基(2-氟苯基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a, 11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(59-2)(50mg,0.078mmol,53.53％)。1H NMR(399MHz,CDCl3)δ7.33(s,1H),7.18(d,J＝7.6Hz,3H),4.47(dd,J＝11.0,4.5Hz,1H),3.70(dd,J＝14.2,7.2Hz,2H),1.98(d,J＝34.5Hz,8H),1.64(d,J＝8.4Hz,5H),1.54–1.46(m,2H),1.23(s,6H),1.07(t,J＝7.3Hz,3H),0.96(s,3H),0.85(s,6H),0.79(s,3H),0.66(s,3H),0.60(s,3H).
第三步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[乙基(2-氟苯基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(59-2)(50mg,0.086mmol)溶于四氢呋喃(3mL)中，加入甲醇(3mL),室温搅拌下加入1M氢氧化锂水溶液(3.62mg,0.086mmol),随后继续在室温下搅拌16小时，反应结束后，加入5mL水稀释后，再加入乙酸乙酯5mL*3萃取，干燥，浓缩后粗品经制备HPLC得白色固体(4R)-N-乙基-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(59)(25mg,0.048mmol,60％)。1H NMR(399MHz,CDCl3)δ7.33(s,1H),7.21–7.13(m,3H),3.78–3.63(m,2H),3.25–3.16(m,1H),2.06–1.87(m,6H),1.69–1.45(m,9H),1.33–1.15(m,7H),1.07(t,J＝7.1Hz,3H),0.98(d,J＝9.2Hz,4H),0.93(s,3H),0.78(d,J＝5.2Hz,6H),0.65(d,J＝4.5Hz,3H),0.60(s,3H).13C NMR(100MHz,CDCl3)δ173.38,159.75,159.67,157.26,157.18,134.31,130.67,130.61,130.15,130.01,129.72,129.64,124.87,116.89,116.68,78.93,77.31,76.99,76.68,50.33,50.21,50.17,49.72,44.38,43.51,38.85,36.96,36.06,36.03,35.53,31.74,31.67,31.29,31.14,30.86,30.75,27.95,27.93,27.79,26.43,24.14,20.92,19.10,18.21,15.66,15.39,12.91,1.00.LC-MS:[M+H]+＝538.65.
实施例60
化合物60(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基-2-甲基丙基)戊酰胺的制备

第一步 将原料2-溴乙-1-醇(6mL,88.02mmol,1.1eq)和2,2-二甲基氧杂环丙烷(100mg,1.387mmol,1.0eq)溶解乙醚(10mL)中，加入高氯酸锂(147.54mg,1.387mmol,10eq)，将反应体系置换成氮气氛围，室温搅拌18hr。TLC(PE:EtOAc＝10:1,磷钼酸烤板)显示反应已经完成，停止反应。将水(20mL)加入到反应体系中，用DCM(二氯甲烷)(3×25mL)萃取，合并的有机相用饱和食盐水(20mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(PE:EtOAc＝94:6to 92:)得到褐色油状1-[(2-氟苯基)氨基]-2-甲基丙-2-醇(60-1)(40mg,纯度95％，收率14.95％)。1H NMR(400MHz,CDCl3)δ7.02–6.94(m,2H),6.82–6.76(m,1H),6.68–6.61(m,1H),3.14(s,2H),1.32(s,6H).
第二步和第三步 参照实施例2，将第一步的胺换为60-1，最终得到化合物(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基-2-甲基丙基)戊酰胺(60).1H NMR(400MHz,CDCl3)δ7.39–7.28(m,2H),7.24–7.16(m,2H),3.91(dd,J＝14.4,7.8Hz,1H),3.54(dd,J＝14.4,9.5Hz,1H),3.23(dd,J＝11.5,4.4Hz,1H),2.35(s,2H),2.20–2.09(m,1H),2.06–1.93(m,5H),1.89–1.24(m,15H),1.22(d,J＝1.8Hz,3H),1.20(s,3H),1.16–1.09(m,1H),1.03(d,J＝11.0Hz,1H),0.99(s,3H),0.96(s,3H),0.81(d,J＝6.0Hz,6H),0.72–0.64(m,3H),0.62(s,3H).13CNMR(101MHz,CDCl3)δ176.90,134.40,130.08,129.97,129.77,129.69,125.04,117.15,116.95,78.97,71.78,50.41,50.25,50.21,49.79,48.24,44.46,38.89,37.02,36.03,35.59,31.71,31.66,31.14,30.98,30.94,30.77,27.95,27.85,27.70,26.47,24.15,20.95,19.12,18.24,15.70,15.39.LC-MS[M+H]+＝582.5
实施例61
化合物61(4R)-N-(3-氟吡啶-4-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基戊酰胺的合成

第一步 参照实施例2，将胺换为3-氟-4-氨基-吡啶，得到化合物乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(3-氟吡啶-4-基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(61-1)(300mg)。
第二步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(3-氟吡啶-4-基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(61-1)(300mg,0.54mmol,1.0eq.)溶于N,N’-二甲基甲酰胺(7.0mL)中，氮气置换，冰浴降温后，加入氢化钠(65.13mL,1.63mmol)，随后将碘甲烷(80.89mg,0.57mmol)溶于N,N’-二甲基甲酰胺(3.0mL)中，加至上述反应体系中，随后反应体系升至室温搅拌，TLC(DCM:MeOH＝20：1)监测,反应结束后，加入水(10.0mL),再以乙酸乙酯(8.0mL*3)萃取，有机相合并，干燥，浓缩粗品经柱层析(DCM:MeOH＝100：1～30：1)得乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(3-氟吡啶-4-基)(甲基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(61-2)(120mg,0.20mmol,37.06％)白色固体。1H NMR(399MHz,CDCl3)δ8.57(s,1H),8.46(d,J＝4.5Hz,1H),7.22(d,J＝5.1Hz,1H),4.47(d,J＝7.8Hz,1H),3.25(s,3H),2.22(s,2H),2.03(s,3H),1.96(s,3H),1.79(s,3H),1.67(d,J＝8.9Hz,3H),1.62(s,3H),1.53(s,2H),1.37(d,J＝9.1Hz,2H),1.28(s,3H),1.13(t,J＝13.0Hz,2H),0.97(s,3H),0.85(s,6H),0.81(s,3H),0.74(s,3H),0.62(s,3H).
第三步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(3-氟吡啶-4-基)(甲基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(61-2)(70mg,0.12mmol)溶于四氢呋喃(5.0mL)和甲醇(5.0mL)中，室温搅拌下加入1M氢氧化锂水溶液(2.0mL),随后继续在室温下搅拌3小时，TLC(DCM:MeOH＝20:1)监测(乙酰基水解同时存在酰胺键的水解)，反应结束后，加入10mL水稀释后，再加入乙酸乙酯10mL*3萃取，干燥，浓缩后粗品经制备TLC(DCM:MeOH＝20:1)纯化后得(4R)-N-(3-氟吡啶-4-基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基戊酰胺(61)(6.0mg,0.011mmol,8.8％)白色固体。1H NMR(399MHz,CDCl3)δ8.58(s,1H),8.47(s,1H),7.21(s,2H),3.26(s,3H),3.20(m,1H),2.22(s,2H),1.99(s,5H),1.79(s,3H),1.66(d,J＝14.9Hz,4H),1.50(m,4H),1.28(s,4H),1.17(s,2H),0.96(d,J＝11.9Hz,6H),0.80(d,J＝13.2Hz,6H),0.74(s,3H),0.63(s,3H).13C NMR(101MHz,CDCl3)δ173.09,145.45,145.42,134.34,134.25,78.92,77.31,77.00,76.68,50.32,50.25,49.75,44.43,38.85,36.96,36.06,35.53,31.59,30.94,30.88,30.74,28.03,27.93,27.79,26.43,24.16,20.92,19.11,18.27,18.20,15.69,15.40,1.00.
LC-MS[M+1]+＝525.4
实施例62
化合物62(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(丙-2-基)戊酰胺的制备
称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-氟苯基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(61-1)(100mg,0.181mmol)溶于N,N’-二甲基甲酰胺(3mL)中，氮气置换三次后，冰浴降至0℃，接着加入氢化钠(21.75mg,0.544mmol),继续在0℃下搅拌30分钟，随后将碘代异丙烷(61.61mg,0.36mmol)溶于N,N’-二甲基甲酰胺(2mL)后加至上述反应体系中，加完后升至室温，在室温搅拌1小时后，TLC(PE:EA＝5:1)检测，原料大量剩余，随后升至80℃搅拌1小时，TLC(PE:EA＝5:1)检测，反应结束，随后冷却至室温，加入10mL水稀释后，再加入乙酸乙酯10mL*3萃取，干燥，浓缩后粗品经制备TLC(DCM:EA＝50:1)纯化后得(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(丙-2-基)戊酰胺(62)(30mg,0.052mmol,28.5％)白色固体。1H NMR(399MHz,CDCl3)δ7.36(s,1H),7.15(m,3H),4.99(s,1H),3.21(m,1H),1.97(d,J＝17.9Hz,5H),1.81(m,2H),1.73(d,J＝18.5Hz,2H),1.65(d,J＝14.8Hz,4H),1.56(m,3H),1.50(s,3H),1.31(dd,J＝16.1,7.7Hz,2H),1.19(m,3H),1.09(d,J＝6.7Hz,3H),0.97(s,6H),0.94(s,3H),0.78(s,6H),0.64(d,J＝5.5Hz,3H),0.60(s,3H).13C NMR(100MHz,CDCl3)δ173.17,134.32,134.29,132.23,130.03,130.03,124.49,124.45,116.76,116.55,78.93,77.30,76.98,76.66,50.34,50.25,50.20,49.73,46.54,44.38,38.85,36.96,36.07,36.02,35.54,31.94,31.76,31.68,31.65,30.87,30.76,27.98,27.93,27.80,26.43,24.13,21.46,21.41,20.92,19.75,19.10,18.24,18.21,15.66,15.38.LC-MS:[M+H]+＝552.4
实施例63
化合物63(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1,3,4-硫杂二氮杂环戊烷-2-基)戊酰胺的制备
第一步 将1(4R)-4-[(1R,3aR,5aR,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(100mg,0.22mmol,1.0eq.)溶于二氯甲烷(5.0mL)中，加入N,N’-二甲基甲酰胺(1滴),氮气置换后，冰浴冷却至0℃，滴加草酰氯(166.67mg,1.3mmol)的二氯甲烷(2.0mL)溶液，滴完后继续在冰浴下搅拌30分钟，TLC(PE:EA＝3:1)监测反应完全，浓缩除去二氯甲烷，随后加入二氯甲烷(3.0mL)稀释,在冰浴下滴加至1,3,4-硫杂二氮杂环戊熳-2-胺(48mg,0.47mmol)和二异丙基乙基胺(133.3mg,1.03mmol)的二氯甲烷(5.0mL)反应液中，滴加完毕后，继续在冰浴下搅拌30分钟，随后升至室温搅拌2小时，TLC监测(PE:EA＝1:1,磷钼酸显色,Rf1＝0.8,Rf2＝0.4)，反应结束后，浓缩，柱层析(PE:EA＝100：1～5：1)得酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-氧亚基-5-(1,3,4-硫杂二氮杂环戊熳-2-基氨基)戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(63-1)(50mg，0.083mmol，45％)白色固体。LC-MS:[M+H]+＝542.50
第二步 称取酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-氧亚基-5-(1,3,4-硫杂二氮杂环戊熳-2-基氨基)戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(63-1)(20mg,0.037mmol,1.0eq.)溶于四氢呋喃(2.0mL)中,加入甲醇(2.0mL),室温下加入氢氧化锂(0.04mL,0.04mmol),室温搅拌16小时，TLC监测(PE:EA＝1：1)，反应结束后，加入水5mL淬 灭，随后以乙酸乙酯5mL*3萃取，有机相合并干燥，浓缩经柱层析(PE:EA＝100：1～2:1)纯化得(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(1,3,4-硫杂二氮杂环戊熳-2-基)戊酰胺(63-2)((10mg,0.02mmol,48.79％)。LC-MS:[M+H]+＝500.50
第三步 称取(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(1,3,4-硫杂二氮杂环戊烷-2-基)戊酰胺(63-2)(10mg,0.02mmol，1.0eq.)溶于N,N’-二甲基甲酰胺(3.0mL)中,氮气置换，加入碳酸钾(2.77mg,0.02mmol),碘甲烷(2.84mmol,0.02mmol),升温至60℃搅拌2小时，TLC监测(PE:EA＝1：1)，反应结束后，加入水5mL稀释，接着以乙酸乙酯5mL*3萃取，有机相合并干燥，浓缩经制备TLC(PE:EA＝1：1)纯化得(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1,3,4-硫杂二氮杂环戊烷-2-基)戊酰胺(63)(3mg,0.005mmol,23.34％)。1HNMR(399MHz,CDCl3)δ8.83(s,1H),3.83(s,3H),3.23(s,1H),2.65(d,J＝59.7Hz,2H),2.01(s,6H),1.61(dd,J＝47.5,22.0Hz,11H),1.22(s,3H),1.05(s,1H),0.98(d,J＝7.3Hz,9H),0.87(s,3H),0.79(s,3H),0.69(s,3H).13CNMR(101MHz,CDCl3)δ172.82,160.34,145.43,134.43,134.21,78.92,77.31,77.00,76.68,50.33,49.80,44.54,38.86,36.99,36.11,35.53,35.40,31.66,30.94,30.78,28.18,27.93,27.79,26.45,24.21,20.95,19.13,18.53,18.20,15.77,15.40.LC-MS[M+1]+＝514.45。
实施例64
化合物64(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1-甲基咪唑-2-基)戊酰胺的制备

第一步 将原料(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸VII(100mg,0.22mmol,1.0eq)溶解DCM(二氯甲烷)(5mL)中，滴加草酰氯(138mg,1.09mmol,5eq)，反应混合物在氮气环境，25℃搅拌1hrs。浓缩除去溶剂和未反应的草酰氯，得到粗品。将粗品溶于DCM(5mL)，加入1-甲基咪唑-2-胺(63.52mg,0.65mmol,1.2eq)并将反应体系置换成氮气氛围，室温搅拌18hr。TLC(DCM:MeOH＝20:1,磷钼酸烤板)监测反应。将水(20mL)加入到反应体系中，用DCM(二氯甲烷)(3×25mL)萃取，合并的有机相用饱和食盐水(20mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(DCM:MeOH＝96：4to 94:6)得到橙色固体乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-[(1-甲基咪唑-2-基)氨基]-5-氧亚基戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(64-1)(92mg,纯度85％，收率66.70％)。1H NMR(400MHz,CDCl3)δ6.81(s,1H),6.73(s,1H),4.50(dd,J＝11.5,4.5Hz,1H),3.59(s,3H),2.59–2.33(m,2H),2.05(s,3H),2.03–1.84(m,5H),1.77–1.62(m,6H),1.62–1.44(m,4H),1.43–1.25(m,4H),1.23–1.11(dd,J＝16.6,11.7Hz,2H),1.00(s,3H),0.93(d,J＝4.8Hz,3H),0.87(d,J＝4.4Hz,9H),0.69(d,J＝4.6Hz,3H).
第二步 将原料(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(64-1)(200mg,0.372mmol,1.0eq)溶于DMF(20mL)中，并将反应体系置换成氮气氛围。将反应体系冷却至0℃后，缓慢加入氢化钠(60％,石蜡)(11.60mg,0.483mmol,1.3eq)，接下来将反应室温搅拌30min后,加入碘甲烷(68.62mg,0.483mmol,1.3eq),反应体系在室温搅拌2h。TLC(DCM:MeOH＝20:1，磷钼酸烤板)监测反应完全，停止反应。体系中加入水(20mL)稀释，用EA(乙酸乙酯)(20mL×3)萃取，合并的有机相用饱和食盐水(20mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(PE：EtOAC＝40:60to 30：70)得到橙固体乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基 -1-[(2R)-5-[甲基(1-甲基咪唑-2-基)氨基]-5-氧亚基戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(64-2)(130mg,纯度90％，收率57.01％)。1HNMR(400MHz,CDCl3)δ7.01(s,1H),6.90(s,1H),4.49(dd,J＝11.5,4.4Hz,1H),3.53(s,3H),3.19(s,2H),2.05(s,3H),1.98(s,4H),1.85(d,J＝32.9Hz,3H),1.76–1.61(m,6H),1.61–1.46(m,4H),1.43–1.10(m,8H),0.99(s,3H),0.88(s,7H),0.83(s,3H),0.75(s,3H),0.64(s,3H).
第三步 将原料乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(异恶唑-3-基氨基)-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(150mg,0.27mmol,1eq)溶解于THF(四氢呋喃)(1mL)和MeOH(甲醇)(1mL)中，滴加1N氢氧化锂(0.6mL)，反应混合物在50℃搅拌2hrs。TLC(DCM:MeOH＝20:1，磷钼酸烤板)监测反应完全，反应液降到室温，反应液使用1N HCl酸化至PH＝3～4后，浓缩掉乙醇后用EA(乙酸乙酯)(20mL×3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(DCM:MeOH＝95:5to 94:6)得到黄色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1-甲基咪唑-2-基)戊酰胺(64)(138.26mg,纯度98.03％，收率97.81％)。1HNMR(400MHz,DMSO)δ7.44(s,1H),7.18(s,1H),3.58(s,3H),3.07(s,3H),3.00(dd,J＝9.8,5.5Hz,1H),1.98(s,5H),1.84(s,2H),1.73-1.40(m,10H),1.23(s,4H),1.12(s,3H),0.90(s,7H),0.81(s,3H),0.70(s,4H),0.61(s,2H).
13CNMR(101MHz,DMSO)δ181.72,138.05,134.81,133.99,132.82,77.21,50.53,49.85,44.50,39.00,37.02,35.84,35.69,34.88,34.85,30.95,30.86,28.60,28.04,27.94,26.48,24.47,21.82,20.97,19.47,19.34,18.93,18.63,18.36,16.31,16.06.LCMS[M+H]+＝510.40
实施例65
化合物65(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(甲氧基甲基)戊酰胺的制备
参照实施例64，将第一步的胺换为溴甲氧基甲醚，最终得到化合物(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(甲氧基甲基)戊酰胺(65).1H NMR(400MHz,CDCl3)δ7.40-7.32(m,1H),7.28-7.31 (m,1H),7.20(dd,J＝15.6,7.7Hz,2H),5.25(dd,J＝10.1,5.2Hz,1H),4.89-4.81(m,1H),3.43(s,3H),3.23(dd,J＝11.5,4.3Hz,1H),2.21-2.08(m,1H),2.07-1.91(m,5H),1.90–1.77(m,2H),1.75-1.61(m,4H),1.51(dd,J＝27.4,12.9Hz,3H),1.37–1.10(m,7H),1.04(d,J＝11.1Hz,1H),0.98(d,J＝13.9Hz,6H),0.87–0.77(m,6H),0.69(d,J＝5.6Hz,3H),0.62(s,3H).13C NMR(101MHz,CDCl3)δ174.74,158.68,134.38,134.35,130.76,130.66,130.13,130.04,78.98,78.56,56.60,50.33,50.30,49.78,44.38,41.13,38.89,37.01,35.58,30.92,30.79,28.01,27.96,27.84,26.47,24.17,20.96,19.14,18.24,15.71,15.42.LCMS[M+H]+＝554.5
实施例66
化合物66(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1,3-硫杂氮杂环戊烷-5-基)戊酰胺的制备
参照实施例63，将第一步的胺换为1,3-噻唑-5-胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1,3-硫杂氮杂环戊烷-5-基)戊酰胺(66).1HNMR(400MHz,DMSO)δ8.59(s,1H),7.69(s,1H),6.87(s,1H),6.65(s,1H),4.32(d,J＝5.1Hz,1H),3.50(s,2H),2.03–1.85(m,6H),1.64(d,J＝13.1Hz,4H),1.54–1.42(m,5H),1.23(s,10H),0.96–0.82(m,10H),0.69(d,J＝12.6Hz,4H).13CNMR(101MHz,CDCl3)δ1.81,190.70,157.30,152.65,135.56,135.46,127.84,127.44,100.11,100.01,72.49,72.39,72.29,26.60,24.55,18.57,9.12.LC-MS:[M+1]+＝513.55
实施例68
化合物68(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-甲基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将原料羊毛甾醇(3.00g,7.03mmol,1.0eq)溶于THF(四氢呋喃)(273mL)，加入水(68mL)，在室温加入NBS(0.73g,4.08mmol,0.58eq)，25℃搅拌2hrs。TLC(n-hexane:EtOAc＝5:1,磷钼酸)显示反应已经完成。加入二氯甲烷萃取三次，硫酸钠干燥，旋干，后经柱层析(PE:EtOAc＝50:1to5:1),浓缩得到(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-溴-6-羟基-6-甲基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(68-1)(1.3g，纯度90％，收率35.3％)。1H NMR(400MHz,CDCl3)δ3.98(dd,J＝21.0,12.3Hz,1H),3.27–3.19(m,1H),2.14(d,J＝6.0Hz,1H),2.00(d,J＝11.7Hz,5H),1.84–1.61(m,6H),1.58(s,9H),1.33(t,J＝10.8Hz,9H),1.27–1.12(m,3H),1.04(d,J＝12.2Hz,1H),0.99(d,J＝7.9Hz,7H),0.94–0.84(m,7H),0.80(s,3H),0.69(d,J＝2.2Hz,3H).
第二步 将(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-溴-6-羟基-6-甲基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(68-1)(900mg,1.72mmol,1.0eq)，溶于THF(四氢呋喃)(90mL)，加入LAH(433mg,12.40mmol,,7.2eq)。加完完毕后升温至70℃回流，搅拌2hrs，TLC(n-hexane:EtOAc＝5:1,磷钼酸)检测反应完成后，反应体系倒入冰水(10mL)淬灭，用DCM(二氯甲烷)(30mL x 3)萃取，用无水硫酸钠干燥，旋干得到(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-甲基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(68)(0.4g,纯度90％，收率48.7％).1H NMR(400MHz,CDCl3)δ3.23(d,J＝8.8Hz,1H),2.02(s,4H),1.92(d,J＝8.4Hz,1H),1.69(d,J＝24.3Hz,7H),1.58(d,J＝11.1Hz,2H),1.52–1.33(m,8H),1.30(s,2H),1.18(d,J＝25.9Hz,8H),1.01(dd,J＝22.8,9.8Hz,8H),0.93–0.84(m,6H),0.80(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ134.38,78.97,77.33,77.01,76.69,71.13,50.49,50.38,49.79,44.46,44.39,38.87,37.00,36.72,36.45,35.57,30.97,30.82,29.31,29.18,28.23,27.95,27.82,26.48,24.26,21.10,20.99,19.13,18.67,18.24,15.74,15.41
实施例72
化合物72(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-羟基-5-甲基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将原料(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VII)(250mg,0.55mmol,1eq)溶于甲醇(0.22mL)和二氯甲烷(10mL)，然后加入4-二甲氨基吡啶(67mg,0.55mmol,1eq)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(209mg,1.09mmol,2eq)。将反应液室温搅拌2hrs，TLC(PE/DCM＝2:1)检测反应完成。反应液倒入水中，用二氯甲烷(50mL x 3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(PE/DCM＝5:1)得到白色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸甲基酯(72-1)(180mg,收率62％)。1H NMR(400MHz,CD3Cl):δ4.48(dd,J＝11.4,4.7Hz,1H),3.65(s,3H),2.36(ddd,J＝15.3,10.2,5.2Hz,1H),2.22(ddd,J＝15.7,9.6,6.4Hz,1H),1.98(m,8H),1.64(m,11H),1.26(m,6H),0.99(s,3H),0.87(t,J＝7.4Hz,11H),0.67(s,3H).13C NMR(100MHz,CD3Cl):δ174.76,171.01,134.29,80.89,77.32,77.00,76.69,51.48,50.45,50.17,49.78,49.19,44.47,37.77,36.86,36.03,35.83,35.23,31.33,30.83,27.97,26.34,25.48,24.17,22.77,21.33,20.95,19.17,18.18,16.92,16.52,15.68.
第二步 将原料(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸甲基酯(72-1)(100mg,0.21mmol,1eq)溶于无水四氢呋喃(10mL)，冰浴下滴加1.0摩尔/升的甲基溴化镁(2.1mL,2.1mmol,10eq)。反应液冰浴下搅拌2hrs，室温搅拌1hr。TLC(PE/EtOAc＝4:1)检测反应完成。反应液倒入饱和氯化铵水中，用二氯甲烷(50mL x 3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(PE/EtOAc＝5:1)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-羟基-5-甲基己-2-基]-3a,6,6,9a,11a-五甲基- 2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(72-2)(60mg,收率53％)。1H NMR(400MHz,CD3Cl):δ4.46(dd,J＝11.4,4.6Hz,1H),2.05(d,J＝4.9Hz,1H),2.02(s,3H),1.96(m,3H),1.58(m,14H),1.30(m,5H),1.17(d,J＝1.8Hz,6H),0.97(s,3H),0.85(d,J＝6.9Hz,12H),0.66(s,3H).13C NMR(100MHz,CD3Cl):δ171.03,134.40,134.19,80.91,71.17,50.44,50.13,49.76,44.41,40.31,37.76,36.85,36.58,35.22,30.84,30.43,29.35,28.98,27.99,27.78,26.34,24.19,21.33,20.96,19.16,18.74,18.09,16.52,15.74.
第三步 将原料乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-羟基-5-甲基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(72-2)(60mg,0.13mmol,1eq)溶于甲醇(20mL)，加入氢氧化钾(712mg,13mmol,100eq)和水(2mL)。反应液加热至80℃搅拌18hrs。TLC(PE/EtOAc＝3:1)检测反应完成。反应液倒入冰水中，用二氯甲烷(50mL x 3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(PE/EtOAc＝3:1)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-羟基-5-甲基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(72-3)(60mg,纯度99％，收率34％)。1H NMR(400MHz,CD3Cl):δ3.22(s,1H),2.02(s,3H),1.92(m,1H),1.66(s,5H),1.56(s,10H),1.32(s,3H),1.19(s,6H),1.04(d,J＝11.2Hz,2H),0.98(d,J＝5.4Hz,6H),0.89(m,6H),0.80(s,3H),0.68(s,3H).13C NMR(100MHz,CD3Cl):δ134.36,78.97,71.20,50.37,50.14,44.44,40.31,38.87,36.99,36.57,35.56,30.87,30.45,29.35,29.01,27.95,26.48,24.25,20.98,19.12,18.74,18.23,15.74,15.41
实施例73
化合物73(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-羟基乙基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将原料乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基- 2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(III)(300mg,0.70mmol,1.0eq)，乙醇胺(214mg,3.5mmol,5eq)溶于二氯甲烷(50mL)中，在室温搅拌30分钟。加入三乙酰氧基硼氢化钠(132mg,3.5mmol,5eq)，搅拌18hrs，TLC(PE:EtOAc＝3:1)检测反应完成后，反应体系加水(50mL)淬灭，用DCM(二氯甲烷)(50mL x 2)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后用无水硫酸钠干燥，过滤并且浓缩。浓缩物用快速色谱法分离纯化(PE:EtOAc＝3:1)分离纯化得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-羟基乙基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(73-1)(120mg,收率32％)。1H NMR(400MHz,CDCl3):δ4.47(dd,J＝11.5,4.3Hz,1H),3.92(d,J＝21.0Hz,2H),2.92(s,2H),2.02(d,J＝10.5Hz,7H),1.65(m,8H),1.46(s,4H),1.27(dd,J＝21.3,8.4Hz,4H),1.14(s,2H),0.97(s,3H),0.90(s,3H),0.85(d,J＝6.7Hz,9H),0.65(s,3H).13C NMR(100MHz,CDCl3):δ171.05,134.25,80.87,50.43,49.89,49.65,46.52,45.86,44.51,37.76,36.86,35.20,34.57,31.96,30.90,30.69,27.84,26.31,24.13,21.32,20.92,19.16,18.42,18.07,16.50,15.60.
第二步 将原料乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-羟基乙基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(73-1)(120mg,0.25mmol,1eq)溶于甲醇(20mL)和水(5mL)，然后加入氢氧化钾(1.42g,25.3mmol,100eq)。将反应液油浴加热至80℃，并在此温度搅拌6hrs，LCMS检测反应完成。反应液导入冰水中，用二氯甲烷(50mL x 3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用Prep-HPLC分离纯化(0.01％FAin water,MeCN)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-羟基乙基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(73)(70mg,纯度100％，收率64％)。1H NMR(400MHz,CD3OD-d4):δ3.74(m,2H),3.13(m,1H),3.03(m,2H),2.89(m,1H),2.05(m,4H),1.96(s,1H),1.74(m,6H),1.57(m,6H),1.41(m,2H),1.23(dd,J＝19.1,8.9Hz,2H),1.03(d,J＝10.7Hz,1H),1.00(s,3H),0.97(m,6H),0.91(m,3H),0.78(m,3H),0.75(m,3H).13C NMR(100MHz,CD3OD-d4):δ134.68,134.09,78.20,56.90,50.52,50.26,49.65,49.42,45.62,44.37,38.52,36.78,35.52,34.55,32.54,30.84,30.43,27.72,27.10,27.04,26.21,23.16,20.60,18.07,17.97,17.65,14.84,14.68.LC-MS:[M+H]+＝432.50.
实施例74
化合物74(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-羟基乙基)(甲基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备

将原料(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-羟基乙基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(73)(50mg,0.12mmol,1eq)溶于二氯甲烷(10mL)，然后加入37％甲醛溶液(1mL)和三乙酰氧基硼氢化钠(43.8mg,1.16mmol,10eq),室温温度搅拌18hrs，LCMS检测反应完成。反应液导入饱和碳酸氢钠水溶液中，用二氯甲烷(50mL x 2)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用制备HPLC分离纯化(0.01％FAin water,MeCN)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-羟基乙基)(甲基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(74)(40mg,纯度98％，收率75％)。1H NMR(400MHz,CD3OD-d4):δ3.72(t,J＝5.8Hz,2H),3.13(m,1H),2.76(m,4H),2.51(s,3H),2.05(s,4H),1.98(m,1H),1.72(m,6H),1.56(m,6H),1.35(dd,J＝21.8,9.5Hz,2H),1.20(dd,J＝19.6,10.1Hz,2H),1.03(m,1H),0.99(s,3H),0.95(d,J＝8.0Hz,6H),0.90(s,3H),0.79(s,3H),0.74(s,3H).13C NMR(100MHz,CD3OD-d4):δ134.60,134.05,78.19,58.03,57.11,54.97,50.51,50.31,49.64,44.33,40.56,38.53,36.78,35.52,34.93,31.38,30.84,30.45,27.78,27.18,27.04,26.22,23.19,20.62,18.19,17.99,17.88,14.85,14.72.LC-MS:[M+H]+＝446.50
实施例75
化合物75(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7-羟基-7-甲基辛-2-基]3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备

第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(II)(500mg,1.1mmol)溶解在四氢呋喃(30mL)中，N2换气三次，降温至0℃，加入叔丁醇钾(253mg,2.3mmol)固体，并在0℃搅拌30min，将化合物R1(500mg,1.1mmol)溶解在THF(5ml)中，滴加入上述反应体系中，自然升至室温，搅拌2h。TLC(PE：EtOAc＝10:1)无原料剩余，降温至零度加入1M/HCl(2mL)，分液，用乙酸乙酯萃取两次，无水硫酸钠干燥，旋干，过柱子，得到，白色固体(2E,6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]庚-2-烯酸甲基酯(75-1)((430mg,0.86mmol,76.65％).1H NMR(399MHz,CDCl3)δ7.03–6.85(m,1H),5.80(d,J＝15.6Hz,1H),4.48(dd,J＝11.7,4.5Hz,1H),3.77–3.62(m,3H),2.25(s,1H),2.12–1.92(m,8H),1.89(d,J＝21.3Hz,1H),1.57–1.39(m,4H)1.57–1.39(m,5H),1.36–1.21(m,3H),1.15(dd,J＝19.7,10.5Hz,3H),0.98(s,3H),0.87(dd,J＝14.6,4.9Hz,12H),0.66(s,3H)
第二步 将(2E,6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]庚-2-烯酸甲基酯(75-1)(380mg,0.762mmol)溶解在乙酸乙酯(380mL)中，加入Pd/C(钯碳)(38mg,0.762mmol)，氢气换气三次，室温搅拌30min.TLC(PE：EtOAc＝10:1)无原料剩余，TLC检测反应完全，硅藻土过滤，乙酸乙酯漂洗，旋干，浓缩物用快速色谱法分离纯化(PE:EtOAc＝(100％-20％)得到白色固体(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]庚酸甲基酯(75-2)(350mg,0.629mmol,82.56％).1H NMR(400MHz,CDCl3)δ4.49(dd,J＝11.5,4.6Hz,1H),3.66(d,J＝1.1Hz,3H),2.30(t,J＝8.0Hz,2H),2.11–1.94(m,7H),1.94–1.82(m,1H),1.82–1.46(m,8H),1.46–1.09(m,8H),0.99(s,3H),0.87(q,J＝2.7,2.2Hz,12H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ134.42,134.20,51.46，50.38,49.77,44.43，37.78,36.86,36.25, 35.77,35.24,34.18,30.92,30.78,28.18,27.90,26.35,25.90,25.39,24.23，24.15,21.35,20.97,19.17,18.62,18.10,16.52,15.73,1.02.
第三步 将(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]庚酸甲基酯(75-2)(100mg,0.170mmol)溶解在四氢呋喃(5mL)中，N2换气，降温至零度)滴加甲基溴化镁(1M，2mL),TLC,无原料剩余，加入氯化铵淬灭，无水硫酸钠干燥，旋干，加入四氢呋喃(5mL)，用30％氢氧化钾(5mL)和甲醇(5mL)，加热100度过夜，TLC(PE:EtOAc＝5:1)，用EtOAc萃洗三次，硫酸钠干燥。过柱子PE:EtOAc＝(100:1to 20:1)。得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7-羟基-7-甲基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇类(75-3)(10mg,0.017mmol,8.72％).1H NMR(400MHz,Chloroform-d)δ3.22(dd,J＝11.6,4.4Hz,1H),2.01(s,5H),1.78–1.64(m,4H),1.59–1.41(m,9H),1.41–1.30(m,4H),1.30–1.13(m,10H),1.01(dd,J＝24.3,10.1Hz,7H),0.91–0.83(m,6H),0.80(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)134.36,78.97,71.07,50.41,50.38,49.78,44.43,44.05,38.87,36.99,36.39,36.22,35.56,30.96,30.82,29.25,29.19,28.21,27.94,27.82,26.87,26.48,24.83,24.25,20.98,19.12,18.71,18.24,15.73,15.40
实施例76和77
化合物76(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-乙基-6-羟基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
化合物77(1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6-乙基-6-羟基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备

第一步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(II)(5.00g,11.3mmol,1.0eq)溶解在THF(100mL)和H2O(20mL)的混合溶剂中，NaBH4(0.64g,16.9mmol,1.5eq)加入到反应体系中。TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应完全后，体系中加入水(～100mL)稀释，用乙酸乙酯萃取(100mL)两次，合并有机相，盐水洗，无水硫酸钠干燥，硅胶柱层析(PE:EtOAc＝90:10)纯化，得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-羟基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(76-1)(3.4g,6.9mmol，纯度90.5％，收率60.9％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.6,4.5Hz,1H),3.66–3.59(m,2H),2.09–1.97(m,6H),1.96–1.87(m,1H),1.77–1.52(m,8H),1.51–1.38(m,8H),1.37-1.25(m,3H),1.21–1.12(m,2H),1.10-1.02(m,1H),1.00(s,3H),0.94–0.84(m,10H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ171.02,134.46,134.28,80.94,77.33,77.22,77.02,76.70,63.63,50.51,50.37,49.82,44.49,37.81,36.91,36.24,35.28,32.11,30.97,30.80,29.62,28.20,27.92,26.39,24.24,24.18,21.34,21.00,19.19,18.68,18.13,16.54,15.77。
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-羟基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(76-1)(3.00g,6.7mmol，1.0eq)溶解在DCM(二氯甲烷)(50mL)中，依次加入咪唑(0.83g,12.1mmol，1.8eq)，三苯基膦(2.30g,8.8mmol，1.3eq)和碘(2.23g,8.8mmol，1.3eq)，室温下搅拌2小时。TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应完全，体系直接旋干，硅胶柱层析(PE:EtOAc＝95:5)纯化，得白色固体乙酸 (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-碘戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(76-2)(3.5g,5.7mmol,纯度95.1％，收率84.2％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.6,4.5Hz,1H),3.19-3.13(m,2H),2.05-1.90(m,9H),1.70-1.59(m,8H),1.59-1.39(m,4H),1.35-1.30(m,2H),1.20-1.13(m,3H),1.00(s,3H),0.95-0.75(m,12H),0.69(s,3H)。13C NMR(101MHz,CDCl3)δ170.98,134.38,134.24,80.88,77.32,77.00,76.68,50.47,50.26,49.79,44.48,37.78,37.12,36.87,35.75,35.24,30.92,30.78,30.58,28.19,27.90,26.36,24.23,24.15,21.33,20.96,19.17,18.73,18.10,16.52,15.74,7.94。
第三步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-碘戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(76-2)(3.50g,6.31mmol,1.0eq)溶解于DMF(50mL)中，加入氰化钾(4.78g,73.4mmol,11.6eq)，体系加热到100℃。TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应完全，反应液降到室温，倒入水中，用乙酸乙酯(100mL)萃取两次，合并有机相，盐水洗涤两次，无水硫酸钠干燥，硅胶柱层析(PE:EtOAc＝90:10),得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-氰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(76-3)(2.50g,5.0mmol,纯度91.5％，收率78.6％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.5,4.5Hz,1H),2.35-2.29(m,2H),2.08-1.85(m,10H),1.69-1.30(m,14H),1.29-1.15(m,6H),0.99(s,3H),0.95-0.85(m,12H),0.69(s,3H)。13C NMR(101MHz,CDCl3)δ171.01,162.56,134.37,134.29,119.89,80.90,77.38,77.26,77.06,76.74,50.48,50.30,50.22,49.80,44.51,37.79,36.89,36.50,35.89,35.29,35.25,31.44,30.95,30.75,28.16,27.90,26.36,24.74,24.21,24.15,22.41,21.31,20.96,19.18,18.74,18.51,18.09,17.54,16.62,16.52,15.74。
第四步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-氰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(76-3)(1.00g,2.2mmol，1.0eq)溶于氯化氢甲醇溶液(30mL,4mol/L)中，反应加热到回流。TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测原料点消失，浓缩反应液，用乙酸乙酯溶解残留物，有机相依次用饱和碳酸氢钠(50mL x 3)，饱和盐水(50mL x 3)洗涤，有机相用无水硫酸钠干燥，浓缩，硅胶柱层析(PE:EtOAc＝90:10to 80:20)纯化得到白色固体步(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸甲基酯(76-4)(650mg，1.2mmol，纯度95.5％，收率54.5％)。1H NMR(400MHz,CDCl3)δ3.67(s,3H),3.26-3.21(m,1H),2.30-2.25(m,2H),2.15-1.85(m,5H),1.80-1.65(m,8H),1.50-1.36(m,6H),1.35-1.01(m,7H),1.00-0.95(m,6H),0.94-0.85(m,7H),0.81(s,3H),0.66(s,3H)。
第五步 (5R)-5-[(1R,3aR,5aR,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸甲基酯(76-4)(80mg,0.16mmol)溶于干燥的四氢呋喃(5mL)中，在-10℃和氮气保护下，缓慢滴加乙基氯化镁(1MOL/L)(1.64mL,1.64mmol,10.0eq)，滴加完毕，体系自动升至室温反应1小时。TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应完全后，在冰水浴下，向反应体系中加入饱和氯化铵溶液，直至无气泡产生，乙酸乙酯萃取(～10mL x 3)，合并有机相，饱和 盐水洗涤一次，无水硫酸钠干燥，过滤，浓缩得粗品，粗品用硅胶柱层析(PE:EtOAc＝80:20)纯化得到白色固体，该固体，再用SFC拆分(Column:Daicel CHIRALCEL IA-H,250mm×30mm I.D.，10μm；Mobile phase：CO2/MeOH[0.2％NH3(7M Solution in MeOH)]＝75/25；Flow rate:80g/min；Wave length:UV 214nm；Temperature:35℃)得到(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-乙基-6-羟基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(76，first peak)(12.05mg,0.025mmol,纯度95.8％，收率22.0％)和化合物(1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6-乙基-6-羟基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(77,second peak)(5.09mg,0.011mmol,纯度96.19％，收率9.3％)。
化合物76：1H NMR(400MHz,CDCl3)δ3.24(dd,J＝11.6,4.5Hz,1H),2.02(m,5H),1.91(dd,J＝13.4,7.5Hz,1H),1.69(m,6H),1.56(m,13H),1.45(d,J＝7.4Hz,4H),1.33(m,11H),1.18(m,3H),1.05(m,1H),0.99(d,J＝7.7Hz,6H),0.87(m,12H),0.81(s,3H),0.69(s,3H)。13C NMR(101MHz,CDCl3)δ134.41,79.00,77.33,77.22,77.02,76.70,74.71,50.51,50.42,49.82,44.50,38.90,38.72,37.03,36.89,36.45,35.60,31.12,31.03,31.00,30.85,28.23,27.97,27.86,26.51,24.27,21.01,20.12,19.15,18.72,18.26,15.77,15.42,7.83,7.79
化合物77：1H NMR(400MHz,CDCl3):δ5.21(m,1H),3.25(dd,J＝10.9,4.8Hz,1H),1.95(m,4H),1.80(dt,J＝13.3,3.4Hz,1H),1.61(m,7H),1.46(m,7H),1.30(m,13H),0.98(d,J＝8.2Hz,6H),0.87(m,12H),0.64(s,3H)。
实施例78和79
化合物78(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-丙基壬-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
化合物79(1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6-羟基-6-丙基壬-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参照实施例76，将第五步的格式试剂换为丙基氯化镁，最后由SFC制备(Column:Daicel CHIRALCEL IA-H,250mm×30mm I.D.，10μm；Mobile phase：CO2/MeOH[0.2％NH3(7M Solution in MeOH)]＝80/20；Flow rate:70g/min；Wave length:UV 214nm；Temperature:35℃)得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-丙基壬-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(78，first peak)和化合物(1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6-羟基-6-丙基壬-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(79，second peak)
化合物78：1H NMR(400MHz,CDCl3):δ3.24(dd,J＝11.5,4.5Hz,1H),2.10–1.96(M,4H),1.95–1.85(m,1H),1.75–1.65(m,5H),1.64–1.53(m,3H),1.50–1.40(m,8H),1.35–1.25(m,8H),1.24–1.13(m,3H),1.08-1.02(dd,J＝12.7,2.0Hz,1H),0.99(d,J＝7.6Hz,6H),0.94–0.86(m,12H),0.81(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ134.43,134.41,79.00,77.33,77.22,77.02,76.70,74.56,50.55,50.42,49.82,44.50,41.81,41.68,39.81,38.90,37.03,36.87,36.46,35.60,31.01,30.85,28.25,27.97,27.87,26.51,24.26,21.01,20.23,19.15,18.71,18.27,16.80,16.76,15.77,15.42,14.76
化合物79：1H NMR(400MHz,CDCl3)δ5.24–5.18(m,1H),3.25(dd,J＝10.9,4.8Hz,1H),2.04–1.87(m,4H),1.84-1.76(m,1H),1.70–1.54(m,5H),1.48-1.45(m,2H),1.44–1.10(m,21H),0.99(s,3H),0.97(s,3H),0.95–0.85(m,14H),0.64(s,3H).
实施例80和81
化合物80(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(丙-2-烯基)壬-8-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
化合物81(1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6-羟基-6-(丙-2-烯基)壬-8-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参照实施例76，将第五步的格式试剂换为烯丙基氯化镁，最后由SFC(Column:Daicel CHIRALCEL IA-H,250mm×30mm I.D.，10μm；Mobile phase：CO2/MeOH[0.2％NH3(7M Solution in MeOH)]＝80/20；Flow rate:70g/min；Wave length:UV 214nm；Temperature:35℃)制备得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(丙-2-烯基)壬-8-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(80，first peak)和化合物(1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6-羟基-6-(丙-2-烯基)壬-8-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(81，second peak)。
化合物80：1H NMR(400MHz,CDCl3)δ5.91-5.80(m,2H),5.17–5.08(m,4H),3.24(dd,J＝11.6,4.5Hz,1H),2.30–2.16(m,4H),2.10–1.98(m,4H),1.96–1.84(m,1H),1.78–1.55(m,7H),1.52–1.14(m,13H),1.08-1.02(m,2H),0.99(d,J＝7.7Hz,6H),0.90(d,J＝6.3Hz,3H),0.88(s,3H),0.81(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3):δ133.61,78.19,76.52,76.40,76.20,75.88,70.09,49.85,49.61,49.01,43.70,42.23,38.09,36.22,36.16,35.72,34.79,30.21,30.05,27.45,27.16,27.05,25.70,23.46,20.20,19.86,18.34,17.88,17.70,17.45,14.97,14.61,3.63
化合物81：1H NMR(400MHz,CDCl3)δ5.91–5.79(m,2H),5.21(m,1H),5.23–5.19(m,4H),3.25(dd,J＝10.9,4.7Hz,1H),2.30–2.15(m,4H),2.05–1.90(m,4H),1.84–1.76(m,1H),1.67–1.60(m,3H),1.50–1.35(m,8H),1.30–1.10(m,8H),1.00–0.96(m,6H),0.92–0.84(m,9H),0.64(s,3H).
实施例82和83
化合物82(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6,6-二环丙基-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
化合物83(1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6,6-二环丙基-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参照实施例76，将第五步的格式试剂换为环丙基氯化镁，最后由SFC(Column:Daicel CHIRALCEL IA-H,250mm×30mm I.D.，10μm；Mobile phase：CO2/MeOH[0.2％NH3(7M Solution in MeOH)]＝80/20；Flow rate:70g/min；Wave length:UV 214nm；Temperature:35℃)制备得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6,6-二环丙基-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(82，first peak)和化合物(1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6,6-二环丙基-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(83，second peak)。
化合物82：1H NMR(400MHz,CDCl3)δ3.24(dd,J＝11.5,4.5Hz,1H),2.08–1.97(m,4H),1.96–1.87(m,1H),1.77–1.64(m,5H),1.63–1.30(m,13H),1.29-1.14(m,3H),1.08–1.03(m,1H),0.99(d,J＝7.3Hz,6H),0.94–0.90(m,3H),0.88(s,3H),0.84–0.80(m,4H),0.69(s,3H),0.50-0.20(m,8H).13C NMR(101MHz,CDCl3)δ133.61,78.19,76.52,76.40,76.20,75.88,70.09,49.85,49.61,49.01,43.70,42.23,38.09,36.22,36.16,35.72,34.79,30.21,30.05,27.45,27.16,27.05,25.70,23.46,20.20,19.86,18.34,17.88,17.70,17.45,14.97,14.61,3.63
化合物83：1H NMR(400MHz,CDCl3)δ5.23–5.19(m,1H),5.12-5.09(s,1H),3.25(dd,J＝10.9,4.8Hz,1H),2.26–2.12(m,1H),2.08–1.88(m,5H),1.84–1.54(m,8H),1.52-1.04(m,13H),1.04–0.95(m,6H),0.94–0.85(m,9H),0.76–0.68(m,2H),0.67–0.56(m,5H),0.52-0.34(m,2H),0.32–0.26(m,1H).
实施例84
化合物84(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(3-羟基环丁基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将原料乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(III)(200mg,0.47mmol,1.0eq)溶于二氯甲烷(10mL)，加入3-氨基环丁-1-醇(81mg,0.93mmol,2.0eq)，反应液室温搅拌30分钟，加入三乙酰氧基硼氢化钠(177mg,4.7mmol,10eq)后继续搅拌过夜。TLC(PE:DCM＝3:1)显示反应已经完成。反应体系加水(50mL)淬灭，用DCM(二氯甲烷)(50mL x 2)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后用无水硫酸钠干燥，过滤并且浓缩得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(3-羟基环丁基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(84-1)(200mg,收率68％)。LC-MS:[M+H]+＝500.55.
第二步 将原料乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(3-羟基环丁基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(84-1)(200mg,0.40mmol,1eq)溶于甲醇(50mL)和水(5mL)，然后加入氢氧化钾(673mg,12.0mmol,300eq)。将反应液油浴加热至80℃，并在此温度搅拌16hrs，LCMS检测反应完成。反应液导入冰水中，用二氯甲烷(50mL x 3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用Prep-HPLC分离纯化(0.01％FAin water,MeCN)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(3-羟基环丁基)氨基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(84)(20mg,纯度100％，收率10％)。1H NMR(400MHz,CD3OD-d4):δ4.45(s,0.5H),4.05(m,0.5H),3.82(s,0.5H),3.23(m,0.5H),3.13(m,1H),2.91(d,J＝9.1Hz,1H),2.82(s,1H),2.68(d,J＝6.8Hz,1H),2.43(dd,J＝13.3,6.7Hz,1H),2.31(d,J＝8.4Hz,1H),2.05(s,4H),1.98(s,1H),1.66(m,12H),1.38(s,2H),1.21(d,J＝11.2Hz,1H),1.03(d,J＝12.7Hz,1H),0.99(s,3H),0.96(s,6H),0.90(s,3H),0.78(s,3H),0.75(s,3H).13C NMR(100MHz,CD3OD-d4):δ134.66,134.06, 78.17,62.68,59.12,50.49,50.25,49.65,49.09,44.37,43.63,43.43,38.53,36.87,36.85,36.78,35.51,35.22,35.16,34.48,34.46,32.38,32.33,30.81,30.43,29.26,27.73,27.18,27.03,26.21,23.18,20.60,18.20,17.98,17.56,14.87,14.73.LC-MS:[M+H]+＝458.55。
实施例85
化合物85(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[3-(羟基甲基)氮杂环丁-1-基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参照实施例84，将第一步的胺换为氮杂环丁-3-基甲醇，最终得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[3-(羟基甲基)氮杂环丁-1-基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(85)。1H NMR(400MHz,CD3OD-d4):δ4.05(t,J＝9.5Hz,2H),3.87(m,2H),3.62(d,J＝4.3Hz,2H),3.15(dt,J＝16.5,8.4Hz,2H),3.02(td,J＝11.7,5.5Hz,1H),2.93(s,1H),2.05(s,4H),1.97(d,J＝13.9Hz,1H),1.64(m,12H),1.22(m,3H),1.03(d,J＝12.5Hz,1H),0.99(s,3H),0.96(s,6H),0.90(s,3H),0.78(s,3H),0.74(s,3H).13C NMR(100MHz,CD3OD-d4):δ134.66,134.07,78.18,59.83(s,2H),55.33,55.24,53.07,50.50,50.09,49.63,44.36,38.52,36.77,35.51,34.29,31.15,30.80,30.51,30.43,27.67,27.17,27.03,26.20,23.16,20.60,18.18,17.9,17.70,14.83,14.71.LC-MS:[M+H]+＝458.55。
实施例86
化合物86(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-羟基乙基)氨基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-醇的制备

第一步 将(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VII)(3g,6.541mmol，1.0eq)溶于苯(40mL)，加入吡啶(20mL),Cu(OAc)2(醋酸铜,0.473g,2.616mmol,0.4eq),置换氩气3次；升温至90℃,分批加入Pb(OAc)4(四醋酸高铅,8.98g,20.276mmol,3.1eq)，回流12h后自然降至室温,TLC监测(PE:EtOAc＝2:1,磷钼酸显色,Rf1＝0.42,Rf2＝0.89)。反应完,将反应液浓缩除去苯,用200ml二氯甲烷溶解后，依次用100ml 5％HCl(乳化严重，垫硅藻土过滤),饱和100ml NaHCO3,100ml饱和食盐水洗，干燥浓缩柱层析(PE-PE：EtOAc＝30:1)，得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-丁-3-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(86-1)(1.5g,2.908mmol,44.46％).1H NMR(399MHz,CDCl3)δ5.71–5.59(m,1H),4.95–4.76(m,2H),4.48(dd,J＝11.5,4.7Hz,1H),2.08–1.98(m,7H),1.79–1.59(m,7H),1.59–1.42(m,4H),1.28(dtd,J＝19.3,8.8,5.2Hz,3H),1.18–1.09(m,2H),0.99(d,J＝5.9Hz,5H),0.86(d,J＝1.5Hz,9H),0.70(s,3H).13C NMR(100MHz,Chloroform-d)δ170.99,145.50,134.44,134.17,111.52,80.89,50.46,49.83,49.74,44.45,41.82,37.77,36.88,35.23,30.90,30.81,28.22,27.88,26.35,24.23,24.14,21.31,20.96,20.05,19.16,18.08,16.51,15.97.
第二步.将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-丁-3-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(86-1)(1.5g,3.635mmol,1.0eq)溶于二氯甲烷(30mL)中,置换氮气三次,降温至0℃。缓慢通臭氧,10分钟后TLC监测(PE:EtOAc＝10:1,磷钼酸显色,Rf1＝0.84,Rf2＝0.51)；反应完全后，通N2赶走臭氧，加入PPh3(2.86g,10.905mmol,3.0eq),升至室温反应30分钟,TLC监测(PE:EtOAc＝10:1,磷钼酸显色,Rf1＝0.85,Rf2＝0.49),浓缩反应液，柱层析(PE-PE:EtOAc＝20:1),浓缩得到乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-甲酰基乙基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(86-2)(800mg,1.544mmol,42.46％).1H NMR(399MHz,CDCl3)δ9.55(d,J＝3.3Hz,1H),4.47(dd,J＝11.6,4.5Hz,1H),2.35(dqd,J＝10.1,6.8,3.2Hz,1H),2.08–1.99(m,7H),1.93–1.81(m,2H),1.71–1.60(m,6H),1.53–1.33(m,3H),1.32–1.17(m,3H),1.12–1.05(m,3H),0.98(s,3H),0.87(d,J＝9.5Hz,9H),0.72(s,3H).13C NMR(101MHz,CDCl3)δ205.34,170.99,134.28(d,J＝34.8Hz),80.80,77.17,50.40,50.15,49.27,45.54,45.14,37.77,36.90,35.21,31.13,30.77,27.88,26.95,26.38,24.17,24.13,24.11,21.32,20.90,19.18,19.16, 18.04,16.51,16.25,13.46.
第三步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-甲酰基乙基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(86-2)(200mg,0.482mmol,1.0eq)溶于二氯甲烷(20mL)中，加入乙醇胺(58.92mg,0.965mmol,2.0eq)和三乙酰氧基硼氢化钠(1022.31mg,4.824mmol.10.0eq)，室温反应过夜,TLC监测(PE:EtOAc＝10:1,磷钼酸显色,Rf1＝0.51,Rf2＝0.33)。反应完，加入20ml水和20ml二氯甲烷，分液，水相用二氯甲烷(20ml x2)萃取，干燥浓缩后柱层析(PE-DCM：MeOH＝10:1 0.1％三乙胺)。得到粗品淡黄色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-羟基乙基)氨基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(86-3)(300mg,0.457mmol,94.71％)。LC-MS：[M+H]+＝460.30
第四步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-羟基乙基)氨基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(86-3)(300mg,0.653mmol)溶于甲醇(10mL)中，加入30％KOH(10mL)，升温至100℃，反应过夜LCMS监测(CL210736-022-1)。反应完，浓缩反应液除甲醇，加入20ml二氯甲烷，分液水相用20ml二氯甲烷萃取，浓缩送制备得淡黄色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-羟基乙基)氨基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-醇(86)(8mg,0.018mmol,2.79％).1H NMR(400MHz,Methanol-d4)δ8.45(s,1H),5.40(s,1H),3.71(t,J＝5.3Hz,2H),3.14–2.90(m,4H),1.99(s,5H),1.74(d,J＝11.1Hz,2H),1.64(dt,J＝15.9,6.4Hz,4H),1.57–1.40(m,4H),1.25(s,2H),1.21–1.06(m,3H),0.99(dd,J＝11.2,4.3Hz,4H),0.92(s,4H),0.89(s,3H),0.83(s,3H),0.71(d,J＝1.5Hz,3H).13C NMR(101MHz,Methanol-d4)δ134.80,133.96,78.19,56.22,53.09,50.51,49.58,44.67,38.57,36.82,35.52,34.83,30.78,30.50,29.30,27.36,27.21,27.06,26.24,23.17,20.62,18.24,18.00,16.01,14.92,14.76.LC-MS：[M+H]+＝418.30
实施例87
化合物87 1-[(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丙基]氮杂环丁-3-醇的制备
参照实施例86，将第三步的胺换为氮杂环丁烷-3-醇，最终得到化合物1-[(2S)-2- [(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丙基]氮杂环丁-3-醇(87)。1H NMR(400MHz,Methanol-d4)δ8.43(s,1H),4.49(p,J＝6.2Hz,1H),4.20(q,J＝10.0Hz,2H),3.71(dd,J＝9.9,6.3Hz,2H),3.05(dd,J＝10.6,5.5Hz,2H),2.80(dd,J＝12.6,10.2Hz,1H),2.03–1.93(m,4H),1.76–1.59(m,6H),1.57–1.41(m,4H),1.32(dddd,J＝13.4,10.9,8.1,2.1Hz,1H),1.25–1.05(m,3H),0.96–0.87(m,9H),0.82(s,3H),0.70(d,J＝6.2Hz,6H).13C NMR(101MHz,Methanol-d4)δ134.81,133.94，78.19,63.82,62.47,59.77,50.50,49.59,44.68,38.56,36.81,35.51,34.32,34.32,30.79,30.51,27.59,27.39,27.20,27.05,27.05,26.24,26.24,23.15,20.61,18.23,18.11,18.00,15.99,15.99,14.81.LCMS:[M+H]+＝430.35
实施例88
化合物88(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(3-羟基环丁基)氨基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参照实施例86，将第三步的胺换为3-氨基环丁醇，最终得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(3-羟基环丁基)氨基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(88).1H NMR(400MHz,Methanol-d4)δ8.44(s,1H),3.06(dd,J＝9.9,6.6Hz,1H),2.79(d,J＝12.4Hz,1H),2.65–2.48(m,2H),2.36(q,J＝6.7Hz,1H),2.22(t,J＝10.3Hz,1H),1.98(d,J＝7.3Hz,4H),1.91(d,J＝10.2Hz,1H),1.75–1.58(m,6H),1.50(dd,J＝21.0,10.8Hz,4H),1.29(q,J＝11.2Hz,1H),1.15(ddd,J＝23.4,14.8,10.7Hz,2H),1.05–0.96(m,4H),0.91(dd,J＝13.8,1.7Hz,6H),0.83(s,3H),0.70(dd,J＝4.3,1.7Hz,6H).13C NMR(101MHz,Methanol-d4)δ136.81,133.94,78.19,49.58，48.23,48.02,47.81,46.95,44.64，38.56,36.81,35.52,35.22,30.49,27.42,27.20,27.05,23.14,20.61,18.22,17.99.LC-MS:[M+H]+＝444.35
实施例89
化合物89(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[3-(羟基甲基)氮杂环丁-1-基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参照实施例86，将第三步的胺换为氮杂环丁烷-3-基甲醇，最终得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[3-(羟基甲基)氮杂环丁-1-基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(89).1H NMR(400MHz,Methanol-d4)δ8.56(s,1H),4.23–4.16(m,1H),3.99(t,J＝8.8Hz,2H),3.27(dd,J＝12.7,3.0Hz,4H),3.03(ddp,J＝12.6,8.6,4.2Hz,1H),2.89(dd,J＝12.6,10.4Hz,1H),2.22–2.04(m,4H),2.03–1.92(m,1H),1.91–1.70(m,6H),1.65(tt,J＝7.4,4.1Hz,2H),1.58(q,J＝9.0Hz,2H),1.45(dddd,J＝13.2,10.7,8.1,2.0Hz,1H),1.34–1.17(m,2H),1.12–0.99(m,9H),0.95(s,3H),0.82(d,J＝5.2Hz,6H).13C NMR(101MHz,Methanol-d4)δ134.82,133.92,78.19,61.10,59.51,50.05,44.69,38.56,36.81,35.51,33.84,30.79,30.50,27.57,27.20,27.05,26.24,23.15,20.61,18.23,18.00,15.89,14.87,14.76.LCMS:[M+H]+＝444.35
实施例90
化合物90(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(羟基环丙基)戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸甲基酯(V)(100mg,0.170mmol)溶解在THF(5mL)，室温加入钛酸四异丙酯(150mg,0.103mmol)，氮气换气三次，在室温滴加乙基 溴化镁(1mL)。搅拌过夜，TLC(PE:EtOAc＝10:1)，有很多原料，用饱和食盐水低温淬灭，乙酸乙酯稀释，无水硫酸钠干燥，过滤，旋干，过柱子(PE:EtOAc＝100％to 50％)，浓缩得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(羟基环丙基)戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(90-1)(3mg,0.005mmol,4.82％).1H NMR(399MHz,CDCl3)δ4.48(dd,J＝11.5,4.6Hz,1H),2.03(d,J＝2.0Hz,8H),1.94–1.83(m,1H),1.76–1.57(m,10H),1.46(s,3H),1.15(s,9H),0.98(s,3H),0.90(d,J＝6.4Hz,3H),0.86(d,J＝2.6Hz,9H),0.71(d,J＝1.8Hz,2H),0.67(s,3H),0.42(d,J＝2.0Hz,2H).13C NMR(100MHz,CDCl3)δ170.99,134.43,134.21,80.91,77.30,76.99,76.67,55.86,50.46,50.38,49.77,44.44,38.80,37.76,36.86,36.45,36.20,36.15,35.23,30.93,30.77,28.17,27.93,27.87,27.80,26.34,24.23,24.13,22.62,21.29,20.96,19.14,19.10,18.65,18.09,16.49,15.73,13.55,13.44.
第二步 化合物乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(羟基环丙基)戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(90-1)(60mg,0.062mmol)溶解在THF(3mL)和MeOH(3mL)，室温加入1M LiOH(3mL)，室温搅拌5h。TLC(PE：EtOAc＝10:1)原料反应完毕后，旋干溶剂，用乙酸乙酯萃取，无水硫酸钠干燥,过柱子(PE：EtOAc＝100％to 50％)浓缩得到(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(羟基环丙基)戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(90)(10mg,0.021mmol,17.34％)和1H NMR(399MHz,CDCl3)δ3.21(dd,J＝11.4,4.5Hz,1H),2.02(d,J＝7.0Hz,4H),1.88(d,J＝7.5Hz,1H),1.73–1.64(m,4H),1.50–1.35(m,6H),1.32(d,J＝7.5Hz,2H),1.25(d,J＝11.8Hz,4H),1.17(dd,J＝22.2,11.6Hz,2H),1.03(d,J＝11.2Hz,2H),0.98(s,3H),0.96(s,3H),0.90(d,J＝6.3Hz,3H),0.86(s,3H),0.79(s,3H),0.71(t,J＝5.4Hz,2H),0.67(s,3H),0.47–0.38(m,2H).13C NMR(100MHz,CDCl3)δ134.36,134.34,78.96,77.30,76.98,76.66,55.94,50.36,49.77,44.44,38.85,38.80,36.98,36.44,36.20,35.55,31.40,30.95,30.80,30.15,29.67,28.18,27.93,27.81,26.46,24.25,22.59,20.97,19.11,18.66,18.22,15.72,15.39,13.59,13.46。
实施例91
化合物91(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-7-甲基-6-(丙-2-基)辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参照实施例76，将第五步的格式试剂换为异丙基氯化镁，最后由SFC制备得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-7-甲基-6-(丙-2-基)辛-2-基]-3a,6,6,9a,11a-五甲基- 2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(91)。1H NMR(400MHz,CDCl3)δ3.24(dd,J＝11.5,4.5Hz,1H),2.03(m,4H),1.91(m,3H),1.64(m,9H),1.29(m,12H),1.05(dd,J＝12.6,2.0Hz,1H),1.00(s,3H),0.98(s,3H),0.92(m,17H),0.81(s,3H),0.69(s,3H).
LC-MS[M-17]+＝483
实施例92
化合物92(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-羟基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸乙基酯(V)(50mg,0.10mmol)溶解在无水四氢呋喃(5mL)中，氮气保护，冰浴下加入四氢铝锂(5.69mg,0.150mmol)，自然升至室温，搅拌1小时，TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应，反应结束，用十水合硫酸钠淬灭，过滤，滤液浓缩，硅胶柱层析(PE:EtOAc＝80:20)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-羟基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(92)(25mg,0.056mmol,56.59％)。1H NMR(400MHz,CDCl3)δ3.65(t,J＝6.5Hz,2H),3.23(dd,J＝11.6,4.5Hz,1H),2.01(m,2.10-1.95,4H),1.91(m,1.95-1.85,1H),1.70(m,1.77-1.64 5H),1.53(m,1.63-1.42,7H),1.26(m,1.40-1.14,6H),1.06(dd,J＝10.1,7.9Hz,2H),0.99(d,J＝7.7Hz,6H),0.91(d,J＝6.6Hz,3H),0.88(s,3H),0.81(s,3H),0.70(s,3H).13C NMR(101MHz,CDCl3)δ134.43,134.40,79.00,77.33,77.21,77.01,76.69,63.17,50.42,50.40,49.82,44.49,38.90,37.03,36.39,36.00,35.60,33.31,31.00,30.84,28.22,27.97,27.87,26.51,24.27,22.47,21.01,19.15,18.67,18.26,15.75,15.42.LC-MS[M-17]+＝399
实施例93
化合物93(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-羟基-2-甲基丙基)氨基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参照实施例86，将第三步的胺换为1-氨基-2-甲基丙醇，最终得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-羟基-2-甲基丙基)氨基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(93).1H NMR(399MHz,Methanol-d4)δ8.52(s,1H),3.13(t,J＝8.2Hz,1H),2.94(d,J＝12.2Hz,1H),2.85(d,J＝12.8Hz,1H),2.66(t,J＝11.6Hz,1H),2.07(s,4H),1.74(d,J＝13.2Hz,4H),1.63–1.47(m,4H),1.27(s,8H),1.06(d,J＝6.6Hz,3H),0.98(d,J＝14.2Hz,6H),0.91(s,3H),0.79(s,6H).13C NMR(100MHz,Methanol-d4)δ134.77,133.92,78.15,67.42,57.72,54.48,50.47,49.52,48.46,48.20,47.98,47.77,47.56,47.34,47.13,46.92,44.67,38.53,36.78,35.49,34.24,30.77,30.48,27.37,27.17,27.02,26.22,23.13,20.59,18.20,17.97,15.87,14.94,14.72.LCMS:[M+H]+＝446.50
实施例94
化合物94(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7-羟基-6,6-二甲基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将异丁酸乙酯(63mg,0.361mmol)溶解在四氢呋喃(1ml)中，降温至-70℃，滴加二异丙基氨基锂(0.902mL,1.803mmol)，并且保持温度在-70℃搅拌10min，将化合物乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-碘戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(76-2)(100mg,0.180mmol)溶解在四氢呋喃(1ml)中，在-70℃滴加上述体系中，保持该温度搅拌30min，然后升至室温反应两小时。TLC(PE:EtOAc＝10:1)监测反应。降温至零度，加入两滴饱和氯化铵水溶液淬灭待，过柱子(PE:EtOAc＝100％to 10％)得到化合物(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2,2-二甲基庚酸甲酯(94-1)(10mg,0.015mmol,8.39％)。1H NMR(400MHz,CDCl3)δ3.31(s,1H),3.23(d,J＝6.8Hz,2H),1.99(s,9H),1.88(m,1H),1.69(dd,J＝19.2,14.4Hz,4H),1.47(m,3H),1.32(s,3H),1.24(s,8H),1.13(m,3H),1.04(d,J＝11.2Hz,1H),0.98(d,J＝7.1Hz,6H),0.87(d,J＝12.2Hz,12H),0.80(s,3H),0.67(s,3H).
第二步 将四氢铝锂(26mg,0.183mmol)加入四氢呋喃中，氮气保护，降温至零度，将化合物(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2,2-二甲基庚酸甲酯(94-1)(20mg,0.038mmol)溶解在四氢呋喃中，滴加上述体系中，升至室温，搅拌两个小时。TLC(PE:EtOAc＝10:1)监测反应，低温用饱和氯化铵水溶液淬灭，过柱子(PE:EtOAc＝80:20)，浓缩得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7-羟基-6,6-二甲基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇94(10mg，95％)。
1H NMR(400MHz,CDCl3)δ3.30(s,2H),3.22(dd,J＝11.3,3.8Hz,1H),1.92(m,5H),1.69(dd,J＝17.3,13.0Hz,6H),1.52(m,2H),1.33(s,4H),1.24(t,J＝10.1Hz,5H),1.13(m,2H),1.03(d,J＝12.9Hz,1H),0.98(d,J＝7.2Hz,6H),0.87(d,J＝11.9Hz,12H),0.80(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ134.36,78.97,77.31,76.99,76.67,72.11,50.58,50.37,49.78,44.45,39.10,38.86,37.14,36.99,36.47,35.56,35.09,30.97,30.81,28.22,27.94,27.82,26.47,24.25,23.83,20.98,20.60,19.12,18.69,18.23,15.74,15.41.LC-MS:[M+H]+＝441.55
实施例95
化合物95(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-羟基环丁基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备

第一步 化合物甲基三苯基碘化物(189mg,0.47mmol，1.0eq)溶在无水甲苯(3mL)中，0℃下加入正丁基锂(0.37mL,0.93mmol，2.0eq)，搅拌30分钟后得到浅黄色溶液，再加入环氧氯丙烷(43.17mg,0.47mmol，1.0eq)，搅拌30分钟后加入正丁基锂(0.37mL,0.93mmol，2.0eq)，再搅拌30分钟，随后体系降温到-40℃。乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(III)(200mg,0.47mmol，1.0eq)溶在无水甲苯(3mL)中缓慢加入到反应液中，搅拌1小时后，自然升至室温。TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应，反应完毕。反应液用饱和氯化铵溶液(～10mL)淬灭，二氯甲烷萃取，无水硫酸钠干燥，硅胶柱层析(PE:EtOAc＝90:10)浓缩得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-羟基环丁亚基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(95-1)(20mg,0.03mmol,7.1％)。
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-羟基环丁亚基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(95-1)(40mg,0.08mmol)溶解在甲醇(5mL)中，加入钯碳(10mg,10％)，加氢气球置换气体三次后搅拌5小时，硅藻土过滤除去钯碳，滤液浓缩干，硅胶柱层析纯化(PE:EtOAc＝80:20，磷钼酸烤板)得到棕色固体(乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-羟基环丁基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(95-2)(30mg,0.056mmol,67.22％)。粗品直接投入下一步。
第三步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-羟基环丁基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(95-2)(30mg,0.06mmol)溶解在乙醇(1mL)中，加入4N氢氧化钠溶液(0.5mL)，加热到50℃，搅拌5小时，TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应，反应完全后，反应液加水稀释，稀盐酸调pH＝4～5，乙酸乙酯萃取，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝80:20)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-羟基环丁基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(95)(6mg,0.012mmol,20.15％).1H NMR(400MHz,CDCl3)δ4.43–4.34(m,0H),4.09(s,1H), 3.24(dd,J＝11.5,4.5Hz,1H),2.45(dd,J＝7.2,3.9Hz,1H),2.02(dd,J＝6.4,2.6Hz,6H),1.89(dd,J＝22.3,8.8Hz,1H),1.76–1.59(m,7H),1.49–1.40(m,4H),1.36–1.24(m,9H),1.21(dd,J＝17.8,7.8Hz,2H),1.05(dd,J＝12.6,1.9Hz,1H),0.99(d,J＝8.0Hz,6H),0.91–0.85(m,6H),0.81(s,3H),0.68(s,3H).
实施例96
化合物96(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-羟基乙基)氧基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯III(300.0mg,0.724mmol)溶解在二氯甲烷(10mL)和异丙醇(10mL)中，室温加硼氢化钠(30.0mg 0.80mmol)，室温搅拌1h，点板检测(PE:EtOAc＝10:1)，原料反应完全，低温加入饱和氯化铵水溶液，用二氯甲烷萃取三次，无水硫酸钠干燥，旋干，过柱子。(PE:EtOAc＝50:1to 5:1)得到乙酸(1R,3a R,5aR,7S,9aS,1 1a R)-1-[(2R)-4-羟基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(96-1)(200mg,0.405mmol,59.73％)白色固体1HNMR.(399MHz,CDCl3)δ4.47(1H,dd,J 11.5,4.5),3.66(2H,ddt,J 17.7,10.4,5.5),1.96(9H,m),1.68(6H,m),1.52(6H,m),1.25(4H,m),0.98(3H,s),0.91(3H,t,J 5.9),0.85(9H,s),0.68(3H,d,J 6.4).
第二步 将化合物乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-羟基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(96-1)(50.0mg,0.023mmol)溶解在二氯甲烷(2mL)中，室温加入四丁基溴化铵(43.52mg,0.135mmol)，溴乙酸-2-甲基丙-2-基酯(262.42mg,1.345mmol)，室温加入40％氢氧化钠水溶液(2mL,0.022mmol)，室温反应过夜，TLC(PE:EA＝10:1)，点板无原料有剩余，分液，加入二氯甲烷萃取两次，水洗有机相，无水硫酸钠干燥，旋干过柱子PE:EA(100％-20％),得到类白色固体[(3R)-3-[(1R,3a R,5aR,7S,9a S,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]氧基}乙酸-2-甲基丙-2-基酯(96-2)(40mg，0.068mmol，78.12％)1HNMR.(399MHz,CDCl3)δ4.48(1H,dd,J＝11.5,4.6),3.92(2H,d,J＝1.5),3.52(2H,t,J＝7.2),2.02(8H,d,J＝9.6),1.67(7H,m),1.47(16H,d,J＝9.7),1.32(4H,m),1.15(2H,dd,J＝17.7,9.8),0.98(4H,s),0.91(1H,d,J＝6.0),0.86(10H,d,J＝2.2),0.67(3H,s).
第三步 将四氢铝锂(32.0mg,0.184mmol)溶解在四氢呋喃(1.0mL)中，氮气保护，降温至零度，将[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]氧基}乙酸-2-甲基丙-2-基酯4-yl]butoxy]acetate(40mg,0.073mmol)溶解在四氢呋喃(1.0mL)中，滴加在上述体系中。滴加完后自然升至室温反应3hr。TLC(PE:EA＝3:1)，原料反应完，降温至0℃加入几滴氯化铵淬灭，硅藻土过滤，旋干，过柱子PE:EA(100％-20％)得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-羟基乙基)氧基]丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(96)(15.27mg,0.026mmol,35.89％)。1HNMR.(400MHz,CDCl3)δ3.71(2H,t,J＝4.6),3.51(4H,m),3.22(1H,dd,J＝1 1.5,4.5),1.95(5H,m),1.75(4H,m),1.51(5H,m),1.23(6H,m),1.05(1H,d,J＝2.0),0.98(6H,d,J＝7.5),0.91(3H,d,J＝5.7),0.87(3H,s),0.80(3H,s),0.68(3H,s)。13CNMR(101MHz,CDCl3)δ134.39,134.29,78.95,77.31,76.99,76.67,71.69,69.54,61.86,50.68,50.36,49.80,44.50,38.86,36.99,35.88,35.55,33.85,30.97,30.78,28.26,27.94,27.81,26.46,24.22,20.96,19.12,18.93,18.22,15.69,15.40。LC-MS:[M-17]+＝415.55
实施例97
化合物97(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-羟基乙基)氧基]戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备

第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(II)(5g,11.29mmol)溶解在二氯甲烷(100mL)和异丙醇(100mL)中，室温加硼氢化钠(27mg 0.76mmol)，室温搅拌1h，点板检测(PE:EtOAc＝10:1)，原料反应完全，低温加入饱和氯化铵水溶液，用二氯甲烷萃取三次，无水硫酸钠干燥，旋干，过柱子(PE:EtOAc＝50:1to 5:1)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-羟基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(97-1)(3.6g,7.286mmol,64.50％)。1H NMR(400MHz,Chloroform-d)δ4.49(dd,J＝11.6,4.5Hz,1H),3.73–3.51(m,2H),2.02(s,7H),1.68(dddd,J＝19.7,15.9,7.8,2.7Hz,7H),1.52–1.35(m,6H),1.30(td,J＝13.0,4.0Hz,2H),1.25–1.11(m,2H),1.09–1.02(m,1H),0.99(s,3H),0.93–0.82(m,12H),0.68(s,3H).
第二步 将化合物乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-羟基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(97-1)(3.6g,8.095mmol)溶解二氯甲烷(100mL)中，加入三苯基磷(3.18g,1 2.143mmol)，咪唑(0.83g,12.143mmol)，氮气保护，降温至零度入碘(7.18g,1 6.19mmol)。在室温搅拌3h，TLC(PE:EtOAc＝10:1)。原料反应完全，降温至零度，加入饱和的亚硫酸氢钠溶液淬灭，用二氯甲烷萃取三次，无水硫酸钠干燥，旋干用乙腈，打浆，过滤，旋干得到白色固体化合物乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-碘戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(97-2)(3.8g,6.167mmol,76.17％)。1H NMR(399MHz,CDCl3)δ4.48(dd,J＝11.6,4.5Hz,1H),3.25–3.0 5(m,2H),2.03(s,7H),1.90(s,2H),1.76–1.65(m,5H),1.57(d,J＝9.9Hz,4H),1.52–1.39(m,4H),1.31(dd,J＝12.8,3.8Hz,2H),1.20–1.08(m,3H),0.98(s,3H),0.91–0.83(m,12H),0.67(s,3H)
第三步 将化合物乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-碘戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(97-2)(50.0mg,0.046mmol)溶解四氢呋喃(2mL)中，加入钠氢(3 6.1mg,0.90mmol)。升温至回流搅拌3h，TLC(PE:EtOAc＝10:1)。原料反应完全，降温至室温，倒入冰水中，用二氯甲烷萃取三次，无水酸钠干燥，旋干，过柱子，PE:EtOAc(100％-20％)，得到白色固体化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-羟基乙基)氧基]戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(97)(9.01mg,0.018mmol,20.16％)。1H(399MHz,CDCl3)δ3.75–3.69(2H,m),3.55–3.49(2H,m),3.43(2H,t,J＝6.2Hz),3.21(1H,dd,J＝11.4,4.5Hz),2.01(4H,s),1.93–1.87(1H,m),1.67(9H,dd,J＝21.1,13.2Hz),1.49–1.39(4H,m),1.32–1.14(4H,m),1.05(1H,s),0.97(6H,d,J＝7.3Hz),0.89(3H,d,J＝6.2Hz),0.85(3H,s),0.79(3H,s),0.67(3H,s).13C NMR(100MHz,CDCl3)δ134.33,78.95,77.28,76.97,76.65,71.89,71.62,61.85,50.37,50.30,49.78,44.45,38.85,36.99,36.20,35.55,32.36,30.95,30.79,28.15,27.92,27.81,26.46,26.37,24.21,20.96,19.10,18.63,18.22,15.72,15.38.LC-MS:[M-17]+＝429.55
实施例98
化合物98(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,4E)-5-甲氧基戊-4-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-1)(700mg,1.49mmol,1.0eq)溶解在稀盐酸中(5mol/L,20mL)和THF(20mL)的混合溶剂中，反应液加热到50℃，搅拌2小时，TLC(PE:EtOAc＝10:1，磷钼酸烤板)监测反应。反应完全后，反应液用乙酸乙酯萃取，饱和盐水洗涤，无水硫酸干燥，硅胶柱层析纯化(PE:EtOAc＝95:5to 85:15)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(500mg,1.09mmol,纯度80％，收率58.5％)。1H NMR(400MHz,CDCl3)δ9.77(t,J＝1.7Hz,1H),4.50(dd,J＝11.6,4.5Hz,1H),2.40(td,J＝7.9,1.7Hz,2H),2.12–1.97(m,7H),1.96–1.85(m,1H),1.78–1.63(m,7H),1.59–1.24(m,9H),1.21–1.06(m,3H),1.00(s,3H),0.90(dd,J＝17.5,5.5Hz,12H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ202.99,171.02,134.43,134.30,129.64,115.29,80.93,77.33,77.02,76.70,50.51,50.24,49.82,44.50,44.35,37.81,36.90,36.31,35.74,35.27,30.96,30.79,28.19,27.92,26.38,24.24,24.18,21.33,20.99,19.19,18.96,18.57,18.12,16.53,15.75.
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(500mg,1.10mmol，1.0eq)和氟化铯(83mg,0.55mmol，0.5eq)溶解在无水四氢呋喃(10mL)中，加入(三氟甲基)三甲基硅烷(1.56g,10.95mmol.5.0eq)，室温搅拌1H，TBAF(5.0mL,5.0mmol)加入到反应液中，搅拌1H。TLC监测反应TLC(PE:EtOAc＝5:1,磷钼酸烤板)反应完全后，反应液用乙酸乙酯稀释，饱和NaHCO3溶液洗涤，无水硫酸钠干燥，硅胶柱层(PE:EtOAc＝80:20)纯化得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(98-2)(190mg,0.33mmol,29.65％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.6,4.5Hz,1H),3.97–3.87(m,1H),2.08–1.86(m,8H),1.77–1.34(m,16H),1.33–1.25(m,2H),1.22–1.12(m,2H),1.09(d,J＝12.8Hz,1H),1.00(s,3H),0.98–0.82(m,12H),0.69(s,3H).19F(376MHz,CDCl3)δ-80.02.
第三步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(98-2)(190mg,0.36mmol)溶解在乙醇(1mL)和氢氧化钠溶液(1mL,4mol/L)混合溶液中，反应液加热到50℃，搅拌2小时，TLC(PE:EtOAc＝5:1磷钼酸烤板),反应完毕后，反应液浓缩掉乙醇，加入乙酸乙酯，分别用饱和氯化铵，饱和盐水洗涤，有机相无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝90:10to 70:30)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(98)(100mg,0.19mmol,53.8％)。1H NMR(400MHz,CDCl3)δ3.96-3.86(m,1H),3.24(dd,J＝11.5,4.5Hz,1H),2.11–1.98(m,4H),1.97-1.85(m,1H),1.76–1.43(m,15H),1.35–1.15(m,5H),1.08-1.03(m,1H),0.99(d,J＝7.4Hz,6H),0.91(d,J＝6.2Hz,3H),0.88(s,3H),0.83–0.78(m,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ134.39,134.30, 78.96,77.29,76.97,76.65,50.36,50.31,49.78,44.45,38.85,36.98,36.33,36.23,35.86,35.65,35.54,30.95,30.78,28.19,27.92,27.80,26.46,24.22,21.79,21.62,20.96,19.11,18.59,18.21,15.71,15.38.
实施例99
化合物99(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-环丙基-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备的制备
第一步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(100mg,0.22mmol，1.0eq)溶解在无水四氢呋喃(5mL)中，0°氮气保护下加入环丙基氯化镁(2.2mL,2.19mmol，10eq)，TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应，反应完全后，氯化铵淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝90:10)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-环丙基-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(99-1)(80mg,0.16mmol,收率73.0％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.5,4.5Hz,1H),3.82(ddt,J＝28.3,21.7,7.3Hz,1H),2.86(d,J＝5.2Hz,1H),2.08–1.97(m,7H),1.96–1.86(m,2H),1.77–1.62(m,7H),1.61–1.46(m,8H),1.40–1.24(m,5H),1.21–1.12(m,2H),1.08–1.02(m,1H),1.00(s,3H),0.90(d,J＝6.4Hz,3H),0.88(d,J＝4.2Hz,9H),0.69(s,3H),0.58–0.45(m,2H),0.31–0.18(m,2H).
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-环丙基-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯99-1(80mg,0.16mmol)溶解在乙醇(2mL)中，加入氢氧化钠溶液(2mL,4mol/L)，反应液加热到50℃，搅拌4小时。TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应。反应完全后，反应液降温到室温，用1N的盐酸调pH＝5，乙酸乙酯萃取3次，合并有机相，饱和盐水洗涤,无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝90:10to 50:50)得 到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-环丙基-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(99)(50mg,0.11mmol,纯度96％,收率68.8％)。1H NMR(400MHz,CDCl3)δ3.17(dd,J＝11.6,4.5Hz,1H),2.79(dd,J＝12.9,7.6Hz,1H),1.97(d,J＝8.0Hz,4H),1.89–1.79(m,1H),1.73–1.45(m,10H),1.41–1.05(m,9H),0.98(dd,J＝12.6,1.7Hz,2H),0.92(d,J＝7.8Hz,6H),0.83(d,J＝6.3Hz,3H),0.81(s,3H),0.74(s,3H),0.62(s,3H),0.51-0.38(m,2H),0.23–0.11(m,2H).13C NMR(101MHz,CDCl3)δ134.42,78.99,50.50,50.46,50.42,49.82,44.49,38.82,37.80,37.57,37.03,36.50,36.40,36.25,35.60,30.99,30.85,28.25,28.18,27.96,27.86,26.51,24.27,22.58,22.47,21.01,19.14,18.69,18.26,18.08,18.05,15.75,15.41
实施例100
化合物100(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-羟基乙基)氧基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-甲酰基乙基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(86-2)(800mg,1.81m mol,1.0eq.)溶解在二氯甲烷(20mL)和异丙醇(20mL)中，室温加硼氢化钠(30.0mg 0.80mmol)，室温搅拌1h， 点板检测(PE:EtOAc＝10:1)，原料反应完全，低温加入饱和氯化铵水溶液，用二氯甲烷萃取三次，无水硫酸钠干燥，旋干，过柱子(PE:EtOAc＝50:1to 5:1)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-羟基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(100-1)(600mg,1.08mmol,74.72％)。1H NMR(399MHz,CDCl3)δ4.48(dd,J＝11.7,4.6Hz,1H),3.64(d,J＝10.6Hz,1H),3.33(d,J＝10.2Hz,1H),2.03(s,7H),1.88(m,1H),1.67(m,8H),1.31(d,J＝13.4Hz,3H),1.18(m,4H),1.00(m,6H),0.86(s,9H),0.70(s,3H)
第二步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-羟基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(100-1)(100mg,0.24mmol,1.0eq.)溶解在二氯甲烷(2.0mL)。室温加入四丁基溴化铵(80mg,0.48mmol,2.0eq.),溴乙酸-2-甲基丙-2-基酯(468mg,2.40mmol,10.0eq.)，室温加入40％氢氧化钠水溶液。室温下搅拌16h，TLC(PE:EtOAc＝10:1)监测反应。反应液用二氯甲烷(10.0mL*3)萃取，有机相合并，干燥，浓缩过柱子(PE:EtOAc＝50:1to 5:1)得[(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丙基]氧基}乙酸-2-甲基丙-2-基酯(100-2)(80mg,0.15mmol,68.37％)。1H NMR(399MHz,CDCl3)δ4.48(dd,J＝11.4,4.8Hz,1H),3.92(s,2H),3.47(d,J＝8.4Hz,1H),3.19(d,J＝8.3Hz,1H),2.03(s,7H),1.87(s,1H),1.69(m,7H),1.44(m,12H),1.19(m,5H),1.03(d,J＝6.5Hz,3H),0.98(s,3H),0.86(d,J＝3.8Hz,9H),0.69(s,3H).
第三步 将四氢铝锂(70.5mg,1.51mmol 10.0eq.)溶解在四氢呋喃(5.0mL)中，氮气保护，降温至零度，将[(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丙基]氧基}乙酸-2-甲基丙-2-基酯(80mg,0.15mmol1.0eq.)溶解在四氢呋喃(1.0mL)中，滴加在上述体系中。滴加完后自然升至室温反应2hr。TLC(PE:EtOAc＝3:1)监测原料反应完，降温至0℃加入几滴氯化铵淬灭，硅藻土过滤，旋干，过柱子(PE:EtOAc＝100％to 20)得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-羟基乙基)氧基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(100)(19.13mg,0.043mmol,27.93％)。1H NMR(399MHz,CDCl3δ3.71(t,J＝4.6Hz,2H),3.52(t,J＝4.6Hz,1H),3.45(m,2H),3.21(dd,J＝11.5,4.5Hz,1H),3.14(m,1H),2.01(d,J＝2.5Hz,4H),1.85(ddd,J＝14.7,12.3,8.2Hz,1H),1.69(m,6H),1.53(m,4H),1.36(s,1H),1.21(dd,J＝14.0,10.3Hz,2H),1.04(d,J＝1.9Hz,1H),0.98(dd,J＝9.7,6.8Hz,9H),0.85(s,3H),0.79(s,3H),0.69(s,3H).13CNMR(101MHz,CDCl3)δ134.49,134.20,78.94,77.30,76.99,76.71,76.67,71.87,61.85,50.35,49.52,47.22,44.69,38.86,37.39,37.00,35.55,30.95,30.81,27.93,27.80,27.74,26.49,24.26,20.95,19.12,18.21,17.42,15.83,15.39.LC-MS:[M-17]+＝401.50
实施例101
化合物101(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(80mg,0.18mmol，1.0eq)溶解在无水四氢呋喃(5mL)中，0°氮气保护下加入甲基氯化镁(0.72mL,1.80mmol，2.5mol/L,10eq)，TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应，反应完全后，氯化铵淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝90:10)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(101)(37mg,0.08mmol,纯度95％，收率42.2％)。1H NMR(400MHz,CDCl3)δ3.73(dd,J＝12.2,6.1Hz,1H),3.17(dd,J＝11.5,4.5Hz,1H),1.90(dddd,J＝30.2,16.8,8.9,5.9Hz,5H),1.69–1.57(m,5H),1.49(ddd,J＝18.1,12.1,8.6Hz,3H),1.26(dddd,J＝24.2,13.0,10.4,5.1Hz,9H),1.12(t,J＝5.1Hz,4H),1.00–0.90(m,8H),0.85–0.79(m,7H),0.74(s,3H),0.62(s,3H).13C NMR(101MHz,CDCl3)δ134.40,79.00,77.34,77.02,76.70,68.33,68.24,50.41,49.82,44.48,39.89,39.82,38.90,37.03,36.43,36.40,36.23,35.59,30.99,30.84,28.23,27.97,27.86,26.51,24.28,23.59,23.48,22.56,22.48,21.01,19.15,18.67,18.26,15.75,15.43.LC-MS:[M-17]+＝413.15
实施例102
化合物102(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参照实施例101，将格式试剂换为乙基氯化镁，最终得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(102)。1H NMR(400MHz,CDCl3)δ3.52-3.40(m,1H),3.17(dd,J＝11.5,4.5Hz,1H),2.00–1.91(m,4H),1.88–1.81(m,1H),1.68–1.58(m,5H),1.54–1.42(m,6H),1.35–1.22(m,7H),1.20-1.05(m,4H),0.98(dd,J＝12.6,2.1Hz,2H),0.92(d,J＝7.8Hz,6H),0.88(t,J＝7.5Hz,3H),0.83(d,J＝6.4Hz,3H),0.81(s,3H),0.74(s,3H),0.62(s,3H).13C NMR(101MHz,CDCl3)δ128.14,128.11,56.83,55.93,50.50,47.42,44.73,38.67,38.62,37.78,36.88,30.83,30.66,27.82,27.78,26.49,26.42,24.17,24.05,21.23,21.17,19.20,19.16,16.50,13.75,13.56.LC-MS:[M-17]+＝427.35
实施例103和104
化合物103或104：
(1R,5aR,7S,9aS,11aR)-6,6,9a,11a-四甲基-1-[(2R,6R)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇或(1R,5aR,7S,9aS,11aR)-6,6,9a,11a-四甲基-1-[(2R,6S)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
其中，化合物103和化合物104均为单一构型的异构体，分别为以下异构体中的一个：
参照实施例98得到化合物98，经过SFC手性拆分(柱子型号:Daicel(大赛璐)CHIRALCEL IA-H,250mm×30mm A.S.，10μm,流动相：CO2/MeOH[0.2％NH3(浓度：7M MeOH溶液)]＝65/35,流速:80g/min,波长:UV 214nm,温度:35℃)拆分得到化合物(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R,6R)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇 (103,保留时间：18.42min)和化合物(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R,6S)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(104,保留时间：20.59min)。
化合物103(保留时间：18.42min)1H NMR(400MHz,CDCl3)δ33.96-3.86(m,1H)，3.17(dd,J＝11.6,4.5Hz,1H),2.01-1.91(m,4H),1.88-1.80(m 1H),1.70–1.57(m,8H),1.54–1.38(m,8H),1.29–1.22(m,2H),1.15–1.10(m,1H),0.98(d,J＝10.5Hz,1H),0.92(d,J＝7.7Hz,6H),0.84(d,J＝6.3Hz,3H),0.81(s,3H),0.74(s,3H),0.62(s,3H).13C NMR(101MHz,CDCl3)δ134.45,134.35,79.01,77.34,77.02,76.71,50.40,49.82,44.50,38.90,36.38,35.90,35.59,30.99,28.23,27.97,27.84,26.50,24.27,21.00,19.15,18.66,18.25,15.75,15.43.
化合物104(保留时间：20.59min)1H NMR(400MHz,CDCl3)δ33.96-3.86(m,1H)，3.17(dd,J＝11.6,4.5Hz,1H),2.01-1.91(m,4H),1.88-1.80(m 1H),1.70–1.57(m,8H),1.54–1.38(m,8H),1.29–1.22(m,2H),1.15–1.10(m,1H),0.98(d,J＝10.5Hz,1H),0.92(d,J＝7.7Hz,6H),0.84(d,J＝6.3Hz,3H),0.81(s,3H),0.74(s,3H),0.62(s,3H).13C NMR(101MHz,CDCl3)δ134.44,134.35,79.02,77.34,77.02,76.71,50.40,50.36,49.83,44.50,38.90,37.03,36.28,35.69,35.59,30.99,30.83,28.24,27.97,27.84,26.50,24.27,21.67,21.00,19.16,18.63,18.26,15.75,15.43.
实施例105
化合物105(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-羟基-2-甲基丙基)氧基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
将[(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丙基]氧基}乙酸-2-甲基丙-2-基酯(100-2)(70mg,0.13mmol,1.0eq.)溶解在四氢呋喃(5mL)中，室温至零度，滴加甲基氯化镁(0.26mL,3mol/L,6.0eq.)，自然升至室温搅拌1h，点板检测(PE:EtOAc＝10:1)，原料反应完全，低温加入饱和氯化铵水溶液， 用乙酸乙酯萃取三次，无水硫酸钠干燥，旋干，过柱子。(PE:EtOAc＝50:1to 5:1)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-羟基-2-甲基丙基)氧基]丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(105)(14.69mg,0.033mmol,22.95％)。1H NMR(399MHz,CDCl3)δ3.43(dd,J＝9.0,3.3Hz,1H),3.18(ddd,J＝15.2,13.1,7.2Hz,4H),2.32(s,1H),2.01(d,J＝5.4Hz,4H),1.84(m,1H),1.68(ddd,J＝12.2,11.5,5.6Hz,7H),1.37(m,5H),1.19(d,J＝2.4Hz,6H),1.03(m,1H),0.99(dd,J＝8.4,6.5Hz,9H),0.86(s,3H),0.79(s,3H),0.70(s,3H).13CNMR(100MHz,CDCl3)δ134.49,134.21,79.22,78.93,77.29,76.97,76.65,70.30,50.35,49.52,47.23,44.65,38.86,37.33,37.00,35.55,30.94,30.84,27.93,27.81,27.70,26.49,26.10,24.24,20.95,19.12,18.21,17.44,15.83,15.38
LC-MS:[M-17]+＝429.55
实施例106
化合物106(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-甲基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(250mg,0.55mmol，1.0eq)溶解在无水四氢呋喃(5mL)中，0°氮气保护下加入甲基氯化镁(0.41mL,0.82mmol，1.5eq)，TLC(PE: EtOAc＝5:1,磷钼酸烤板)监测反应，反应完全后，氯化铵淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝90:10)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(106-1)(200mg,0.38mmol,纯度80％，收率55.3％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.5,4.5Hz,1H),3.85–3.75(m,1H),2.09–1.96(m,7H),1.92(dd,J＝13.4,7.7Hz,1H),1.78–1.59(m,7H),1.52–1.24(m,12H),1.19(d,J＝6.1Hz,3H),1.14(dd,J＝9.8,4.7Hz,2H),1.00(s,3H),0.89(dd,J＝9.4,5.2Hz,13H),0.69(s,3H).
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(106-1)(100mg,0.21mmol,1.0eq)溶解在无水二氯甲烷(5mL)中，氮气保护下，0℃加入戴斯马丁氧化剂(135mg,0.32mmol)，反应1小时后，TLC(PE:EtOAc＝5:1,磷钼酸烤板),监测反应，反应完毕后，反应用十水合硫酸钠淬灭，硅藻土过滤，滤液浓缩干，硅胶柱层析纯化(PE:EtOAc＝85:15)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-6-氧亚基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(106-2)(80mg,0.15mmol,72.3％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.6,4.5Hz,1H),2.39(dd,J＝14.6,8.0Hz,2H),2.14(d,J＝5.0Hz,3H),2.06–1.85(m,9H),1.75–1.25(m,21H),1.21–1.12(m,3H),1.00(s,3H),0.89(dd,J＝13.7,6.3Hz,12H),0.68(s,3H).
第三步 参照实施例101，将格式试剂换为乙基溴化镁，最终得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-甲基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(106)。1H NMR(399MHz,CDCl3)δ3.22(d,J＝11.3Hz,1H),2.01(s,4H),1.88(dd,J＝21.6,8.9Hz,1H),1.68(m,6H),1.47(dd,J＝14.7,7.2Hz,4H),1.38(m,4H),1.26(m,6H),1.13(s,4H),1.03(d,J＝14.4Hz,2H),0.98(s,3H),0.96(s,3H),0.88(m,9H),0.79(s,3H),0.67(s,3H).13C NMR(101MHz,Chloroform-d)δ134.37,78.96,77.23,72.97,50.47,50.38,49.78,41.78,38.86,36.99,36.79,36.43,35.56,34.17,30.96,30.81,28.21,27.93,27.82,26.47,24.24,20.97,20.57,19.11,18.67,18.23,15.73,15.39,8.19.LC-MS：[M-17]+＝441.50
实施例107
化合物107(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,3E)-6-羟基-6-甲基庚-3-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备

第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(III)(100mg,0.23mmol,1.0eq.)溶解在二甲亚砜(5mL)中，室温加哌啶(0.07mg,0.362mmol,0.05eq.)和醋酸(14.69mg,0.033mmol,0.05eq.)，加热至60℃。在60℃，滴加丙二酸单乙酯(14.69mg,0.033mmol,22.95％)，滴加时间大概在0.5h，并且保持该温度搅拌2h，TLC(PE:EtOAc＝10:1)监测原料反应完全，降至室温加入水淬灭，用乙酸乙酯萃取两次，无水硫酸钠干燥，旋干，过柱子PE:EtOAc＝50:1to 5:1)得到白色固体(2E,4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-2-烯酸乙酯(IV)和(2E,5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己-2-烯酸乙酯(107-1)的混合物(70.00mg,0.14mmol,60.15％)
第二步 称取(2E,4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-2-烯酸乙酯(IV)和(2E,5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己-2-烯酸乙酯的混合物(107-1)(70.00mg,0.14mmol,1.0eq.)溶解在四氢呋喃(5.0mL)中,氮气保护，降温至零度，滴加甲基氯化镁(0.28mL,0.84mmol,6.0eq.)，自然升至室温，并且室温搅拌1H。TLC(PE:EtOAc＝10:1)监测，原料消失，用饱和氯化铵淬灭。用乙酸乙酯(2 x 5mL)萃取，无水硫酸钠干燥，旋干送制备得到(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,3E)-6-羟基-6-甲基庚-3-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(107)(2.28mg,0.005mmol,3.15％)。1H NMR(399MHz,CDCl3)δ5.37(t,J＝8.3Hz,2H),3.22(dd,J＝11.5,4.5Hz,1H),2.11(t,J＝5.6Hz,2H),2.00(s,4H),1.70(dd,J＝23.6,10.5Hz,5H),1.50(dd,J＝11.7Hz,4H)1.25(d,J＝11.7Hz,5H),1.18(s,6H),1.03(d,J＝12.0Hz,1H),0.98(t,J＝7.2Hz,9H),0.86(s,3H),0.79(s,3H),0.69(s,3H).13CNMR(100MHz,CDCl3)δ142.23,134.34,122.45, 78.95,77.29,76.97,76.65,70.48,50.36,49.97,46.81,44.43,40.96,38.86,37.00,35.55,30.91,30.86,29.66,29.00,28.65,27.93,27.80,26.46,24.21,20.95,20.65,19.11,18.20,15.98,15.39.LC-MS:[M+1]+＝425.55
实施例108
化合物108(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-(2-羟基环丙基)丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(II)(200mg,0.45mmol,1.0eq)溶解在二氯甲烷(20mL)中，氮气保护0°下加入三乙胺(0.19mL,1.36mmol，3.0eq)和叔丁基二甲硅基三氟甲磺酸酯(179mg,0.69mmol，1.5eq),TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应，反应完全后，反应液浓缩至干，加入正已烷50mL，搅拌10分钟，过滤除去固体，滤液浓缩干得到中间体粗品。氮气保护下，二碘甲烷(968mg,3.61mmol，8.0eq)加入到二乙基锌(1.0M in hexanes)(3.61mL，3.61mmol，8.0eq)中，中间体溶解在甲苯(15mL)中滴加到反应体系中，搅拌4小时，反应液用饱和氯化铵淬灭，乙酸乙酯萃取，无水硫酸钠干燥，硅胶最层析纯化(PE:EtOAc＝95:5)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(2-{[二甲基(2-甲基丙-2-基)甲硅基]氧基}环丙基)丁-2-基]- 3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(108-1)(80mg,0.11mmol,收率31.2％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.6,4.6Hz,1H),3.36(dtd,J＝24.9,6.5,3.2Hz,1H),2.07–1.96(m,7H),1.96–1.86(m,1H),1.76–1.58(m,7H),1.44(ddd,J＝19.0,16.5,8.6Hz,4H),1.38–1.23(m,3H),1.21–1.12(m,3H),1.00(s,3H),0.99–0.94(m,3H),0.92(s,3H),0.90–0.85(m,17H),0.73–0.67(m,3H),0.65-0.55(m,3H),0.11–0.06(m,6H).
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(2-{[二甲基(2-甲基丙-2-基)甲硅基]氧基}环丙基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(108-1)(80mg,0.14mmol,1.0eq)直接溶解在四丁基氟化铵(1mol/L in THF)(1mL,1.00mmol)中，反应液加热到50度，搅拌1小时，TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应，反应结束后，反应液加入乙酸乙酯稀释，用饱和盐水洗涤2次，无水硫酸钠干燥，Flash柱纯化(PE:EtOAc＝95:5to 90：10)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-(2-羟基环丙基)丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(108-2)(60mg,0.11mmol,收率75.1％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.6,4.6Hz,1H),3.50(dtd,J＝20.4,6.6,3.1Hz,1H),2.04(d,J＝8.1Hz,8H),1.72(s,8H),1.52(s,3H),1.42–1.12(m,6H),1.05–0.98(m,5H),0.88(d,J＝3.6Hz,10H),0.71(d,J＝1.6Hz,5H)。
第三步 白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-(2-羟基环丙基)丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(108-2)(50mg,0.11mmol,1.0eq)溶解在无水四氢呋喃(1mL)中，氮气保护，冰水浴下加入四氢铝锂(6.23mg,0.16mmol,1.5eq)，搅拌30分钟，TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应，反应完全后，用十水合硫酸钠淬灭，硅藻土过滤，滤液浓缩干得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-(2-羟基环丙基)丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(108)(15.85mg,0.033mmol,收率30.2％)。1H NMR(400MHz,CDCl3)δ3.50(dd,J＝20.5,3.1Hz,1H),3.24(dd,J＝11.5,4.5Hz,1H),2.02(dd,J＝7.7,4.7Hz,4H),1.97–1.90(m,1H),1.78–1.59(m,7H),1.53–1.44(m,3H),1.40–1.13(m,6H),1.09–1.05(m,1H),1.03(d,J＝6.4Hz,2H),0.99(d,J＝6.3Hz,6H),0.93–0.89(m,1H),0.88(s,3H),0.81(s,3H),0.72(t,J＝4.0Hz,3H),0.70–0.65(m,2H).13C NMR(101MHz,CDCl3)δ134.50,78.99,77.34,77.23,77.03,76.71,50.40,38.90,37.03,35.58,30.97,27.97,27.84,26.49,24.21,20.98,19.16,18.24,15.75,15.43.LC-MS:[M-17]+＝397
实施例109
化合物109(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,4E)-6-羟基己-4-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
(2E,5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己-2-烯酸乙酯(IV)(50mg,0.10mmol)溶解在无水四氢呋喃(1mL)中，反应液氮气保护下，降温到-78℃，加入DIBAL-H(0.301mL,0.30mmol)，保温反应30分钟，TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应完全，反应完全后，用30％氢氧化钠溶液淬灭，乙酸乙酯萃取，有机相饱和盐水洗涤，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝90:10to 80:20)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,4E)-6-羟基己-4-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(109)(16mg,0.03mmol,收率32.7％)。1H NMR(400MHz,CDCl3)δ5.72-5.58(m,2H),4.12-4.09(m,2H),3.24(dd,J＝11.5,4.5Hz,1H),2.22–2.15(m,1H),2.07–1.87(m,6H),1.82–1.49(m,10H),1.40-1.28(m,1H),1.26-1.15(m,2H),1.05(dd,J＝12.6,2.0Hz,1H),0.99(d,J＝8.3Hz,6H),0.90(d,J＝5.7Hz,3H),0.87(s,3H),0.81(s,3H),0.70(s,3H).13C NMR(101MHz,CDCl3)δ134.46,134.34,131.95,130.29,78.99,77.34,77.03,76.71,63.92,50.40,50.12,49.83,44.52,39.14,38.90,37.03,36.62,35.59,30.88,28.17,27.97,27.85,26.50,24.28,20.99,19.16,18.70,18.25,15.80,15.43.LC-MS:[M-17]+＝397
实施例110
化合物110(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7,7-二氟-6-羟基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(100mg,0.22mmol，1.0eq)和氟化铯(17mg,0.11mmol，0.5eq)溶解在无水甲苯(4mL)和无水四氢呋喃(0.5mL)的混合溶剂中，加入(三氟甲基)三甲基-硅烷(136mg,1.10mmol.5.0eq)，室温搅拌1H，TBAF solution(10mL,10mmol)加入到反应液中，搅拌1H，TLC监测反应TLC(PE:EtOAc＝5:1,磷钼酸烤板)，反应完全后，反应液用乙酸乙酯稀释，饱和NaHCO3溶液洗涤，无水硫酸钠干燥，硅胶柱层(PE:EtOAc＝90:10to 80:20)纯化得到乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7,7-二氟-6-羟基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(110-1)(60mg,0.09mmol,43.09％)。1H NMR(400MHz,CDCl3)δ4.43(dd,J＝11.6,4.5Hz,1H),3.76–3.60(m,1H),2.02–1.80(m,9H),1.68–1.50(m,11H),1.45–1.32(m,5H),1.26–1.20(m,2H),1.09(dt,J＝18.5,9.1Hz,3H),0.93(s,4H),0.87–0.75(m,14H),0.62(s,3H).
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7,7-二氟-6-羟基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(110-1)((60mg,0.09mmol)。溶在乙醇(2mL,0.098mmol)中，加入氢氧化钠溶液(0.5mL,4mol/L)，反应加热到50度，搅拌3hrs左右，TLC(PE:EtOAc＝5:1)监测反应，反应完全后，反应液用乙酸乙酯萃取，无水硫酸钠干燥，过柱机纯化(PE:EtOAc＝85:15)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7,7-二氟-6-羟基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(110)((18.9mg,0.04mmol,纯度97％,收率39.8％)。1H NMR(400MHz,CDCl3)δ5.76-5.48(m,1H),3.81–3.68(m,1H),3.24(dd,J＝11.6,4.5Hz,1H),2.07–1.87(m,5H),1.68(dddd,J＝20.9,16.3,5.4,2.6Hz,8H),1.55–1.37(m,7H),1.31–1.14(m,4H),1.05(dd,J＝12.6,2.2Hz,1H),0.99(d,J＝7.8Hz,6H),0.93–0.87(m,6H),0.81(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ134.36,79.00,77.34,77.02,76.71,50.40,50.38,49.82,44.49,38.90,37.03,35.59,30.99,30.83,28.24,27.97,27.85,26.50,24.27,21.00,19.16,18.26,15.75, 15.43.LC-MS[M-17]+＝449.
实施例111
化合物111(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,4E)-6-羟基-6-甲基庚-4-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例107，最后一步纯化得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,4E)-6-羟基-6-甲基庚-4-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(111)。1H NMR(399MHz,CDCl3)δ5.57(s,2H),3.22(dd,J＝11.6,4.7Hz,1H),2.14(d,J＝9.6Hz,1H),1.97(d,J＝34.6Hz,5H),1.68(dd,J＝19.4,11.0Hz,7H),1.46(s,3H),1.30(s,6H),1.19(dd,J＝25.4,13.7Hz,4H),1.03(d,J＝12.5Hz,1H),0.97(d,J＝7.5Hz,6H),0.86(m,6H),0.79(s,3H),0.68(s,3H).13CNMR(100MHz,CDCl3)δ139.29,134.39,134.28,125.53,78.95,77.31,76.99,76.67,70.74,50.34,50.08,49.77,44.45,39.03,38.85,36.98,36.68,35.54,30.93,30.84,29.93,29.83,28.10,27.93,27.80,26.46,24.20,20.95,19.12,18.62,18.21,15.77,15.39.LC-MS:[M-17]+＝425.55
实施例112
化合物112(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基-6-甲基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备

第一步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-6-氧亚基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(106-2)(80mg,0.15mmol，1.0eq)和氟化铯(12mg,0.08mmol，0.5eq)溶解在无水甲苯(1mL)和无水四氢呋喃(0.2mL)的混合溶剂中，加入(三氟甲基)三甲基硅烷(107mg,0.75mmol.5.0eq)，室温搅拌1H，TBAF solution(1.0mL,1.0mmol)加入到反应液中，搅拌1Hr，TLC监测反应TLC(PE:EtOAc＝5:1,磷钼酸烤板)，反应完全后，反应液用乙酸乙酯稀释，饱和NaHCO3溶液洗涤，无水硫酸钠干燥，硅胶柱层(PE:EtOAc＝80:20)乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基-6-甲基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(112-1)(60mg,0.09mmol,纯度80％收率53.4％)。
1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.5,4.5Hz,1H),2.08–1.96(m,7H),1.91(dd,J＝12.4,8.4Hz,1H),1.78–1.38(m,18H),1.35(s,3H),1.29(dd,J＝17.1,7.3Hz,3H),1.22–1.12(m,2H),1.00(s,3H),0.91(d,J＝6.2Hz,3H),0.88(d,J＝3.0Hz,9H),0.69(s,3H).
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基-6-甲基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(112-3)(60mg,0.09mmol)溶在乙醇(1mL)中，加入氢氧化钠溶液(0.5mL,5mol/L)，反应加热到50℃，搅拌3hrs左右，TLC(PE:EtOAc＝5:1,磷钼酸烤板)，监测反应，反应完全后，反应液用稀盐酸(1N)调pH＝5，乙酸乙酯萃取，无水硫酸钠干燥，过柱机纯化(PE:EtOAc＝85:15)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基-6-甲基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(112)(46mg,0.08mmol,纯度85％,收率70.7％)。1H NMR(400MHz,CDCl3)δ3.24(dd,J＝11.5,4.5Hz,1H),2.08–1.98(m,4H),1.96-1.86(m,1H),1.78–1.64(m,6H),1.62-1.58(m,2H),1.55–1.38(m,6H),1.35(s,3H),1.32–1.15(m,4H),1.05(dd,J＝12.6,1.9Hz,2H),0.99(d,J＝7.3Hz,6H),0.91(d,J＝6.2Hz,3H),0.88(s,3H),0.81(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ134.44,134.36,79.00,77.33,77.22,77.02,76.70,50.47,50.45,50.41,49.82,44.51,38.89,37.03,36.49,36.43,35.59,35.49,30.99,30.82,28.25,27.96,27.84,26.50,24.27,21.00,19.37,19.15,18.69,18.61,18.25,15.76,15.42.LC-MS:[M-17]+＝481.45
实施例113
化合物113 3-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊基]氧杂环丁-3-醇的制备
第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(III)(500mg,1.17mmol,1.0eq.)溶于甲醇(20.0mL)中，加入碳酸钾(483.27mg,3.52mmol),3eq.)，室温下加入(1-重氮基-2-氧代丙基)膦酸二甲酯(336.45mg,1.75mmol),1.5eq.)，室温下反应3h，TLC监测(PE:EtOAc＝10:1,磷钼酸显色,Rf1＝0.61,Rf2＝0.87)反应完后，低温浓缩反应液，用二氯甲烷与水稀释，分液，用二氯甲烷萃洗两次，无水硫酸钠干燥，过柱子(PE：EtOAc＝100％-20％),浓缩得白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-戊-4-炔-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(113-1)(204.4mg,0.482mmol,41.21％)。1H NMR(400MHz,Chloroform-d)δ4.51–4.43(m,1H),2.23(s,1H),2.03(s,8H),1.93(s,2H),1.76–1.58(m,8H),1.48–1.40(m,1H),1.35–1.11(m,6H),1.06(d,J＝5.7Hz,3H),0.99(s,3H),0.86(s,9H),0.68(s,3H)
第二步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-戊-4-炔-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(113-1)(50.00mg,0.12mmol,1.0eq)溶解在四氢呋喃(3.0mL)中,氮气保护，降温至-70℃，滴加正丁基锂(0.23mL,0.36mmol，3.0eq)，升温至-40℃，反应30min。在降温至-70℃。滴加杂氧环丁酮(170mg,0.60mmol，5eq.)，自然升温至室 温搅拌2h，TLC(PE:EtOAc＝10:1)监测，反应完后，低温浓缩反应液，用二氯甲烷与水稀释，分液，用二氯甲烷萃洗两次，无水硫酸钠干燥，过柱子PE：EtOAc＝(100％-20％)，浓缩得到白色固体3-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-炔基]氧杂环丁-3-醇(113-2)(17.84mg,0.040mmol,33.49％)。1H NMR(400MHz,Chloroform-d)δ4.78(d,J＝6.3Hz,2H),4.67(d,J＝6.4Hz,2H),3.21(d,J＝9.0Hz,1H),2.85(s,1H),2.35–2.25(m,1H),2.06–1.90(m,6H),1.62(ddd,J＝26.8,22.4,10.2Hz,11H),1.25(ddd,J＝29.3,19.6,10.1Hz,4H),1.03(d,J＝5.8Hz,3H),0.97(d,J＝6.9Hz,6H),0.86(s,3H),0.79(s,3H),0.68(s,3H).
13C NMR(100MHz,CDCl3)δ134.47,134.15,86.46,84.95,80.56,78.94,77.31,76.99,76.68,67.32,50.33,49.77,44.50,38.85,36.99,36.22,35.53,30.79,2 7.93,27.77,26.46,26.07,24.25,20.92,19.13,18.20,15.87,15.40.
第三步 将3-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-炔基]氧杂环丁-3-醇(113-2)(15mg,0.033mmol,1.0eq)溶解在乙酸乙酯(3.0mL)中,加入Pd/C 10％(1.5mg,10％)，氢气换气，室温搅拌20min.TLC(PE:EtOAc＝10:1)，监测，反应完后，低温浓缩反应液，用二氯甲烷与水稀释，分液，用二氯甲烷萃洗两次，无水硫酸钠干燥，过柱子PE：EtOAc＝(100％-20％)，浓缩得到白色固体3-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊基]氧杂环丁-3-醇(113)(6.03mg,0.013mmol,40.21％).1H NMR(400MHz,CDCl3)δ4.55(d,J＝6.6Hz,2H),4.49(d,J＝6.8Hz,2H),3.22(dd,J＝11.6,4.5Hz,1H),2.02(d,J＝7.3Hz,4H),1.90(d,1H)1.63(m,10H),1.24(m,9H),0.98(d,1H)0.97(d,J＝7.4Hz,6H),0.89(d,J＝6.2Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(100MHz,CDCl3)δ134.30,83.92,83.87,78.97,77.31,76.99,76.67,74.81,50.35,49.78,44.46,3 8.86,38.21,36.99,36.36,36.27,35.55,30.95,30.80,28.22,27.94,27.80,26.47,24.25,20.97,19.98,19.12,18.62,18.22,15.73,15.40.LC-MS:[M-17]+＝441.55
实施例115
化合物115 3-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-炔基]氧杂环丁-3-醇的制备

将乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-戊-4-炔-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(113-1)(50.00mg,0.12mmol,1.0eq)溶解在四氢呋喃(3.0mL)中,氮气保护，降温至-70℃，滴加正丁基锂(0.23mL,0.36mmol，3.0eq)，升温至-40℃，反应30min。在降温至-70℃。滴加杂氧环丁酮(170mg,5.227mmol，5eq.)，自然升温至室温搅拌2h，TLC(PE:EtOAc＝10:1)监测，反应完后，低温浓缩反应液，用二氯甲烷与水稀释，分液，用二氯甲烷萃洗两次，无水硫酸钠干燥，过柱子(PE：EtOAc＝100％-20％)，浓缩得得到白色固体3-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-炔基]氧杂环丁-3-醇(115)(17.84mg,0.040mmol,33.49％).1H NMR(400MHz,CDCl3)δ4.78(d,J＝6.3Hz,2H),4.67(d,J＝6.4Hz,2H),3.21(d,J＝9.0Hz,1H),2.85(s,1H),2.35–2.25(m,1H),2.06–1.90(m,6H),1.62(ddd,J＝26.8,22.4,10.2Hz,11H),1.25(ddd,J＝29.3,19.6,10.1Hz,4H),1.03(d,J＝5.8Hz,3H),0.97(d,J＝6.9Hz,6H),0.86(s,3H),0.79(s,3H),0.68(s,3H).13C NMR(100MHz,CDCl3)δ134.47,134.15,86.46,84.95,80.56,78.94,77.31,76.99,76.68,67.32,50.33,49.77,44.50,38.85,36.99,36.22,35.53,30.79,2 7.93,27.77,26.46,26.07,24.25,20.92,19.13,18.20,15.87,15.40.LC-MS:[M-17]+＝437.45
实施例116
化合物116(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基-6-(三氟甲基)庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备的制备

第一步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(98)(100mg,0.19mmol,1.0eq)溶在无水二氯甲烷(3mL)中，氮气保护0℃下加入戴斯马丁氧化剂(121mg,0.29mmol,1.5eq)，反应液转至室温搅拌，TLC监测反应(PE:EtOAc＝5:1,磷钼酸烤板)。反应结束后用亚硫酸氢钠萃灭，碳酸氢钠洗涤，二氯甲烷萃取，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝80:50)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(116-1)(80mg,0.12mmol,64.3％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.6,4.5Hz,1H),2.69(h,J＝11.5Hz,2H),2.04(d,J＝10.2Hz,7H),1.95–1.86(m,1H),1.69(dd,J＝10.3,6.4Hz,9H),1.50–1.37(m,4H),1.36–1.24(m,3H),1.16(s,3H),1.00(s,3H),0.92(d,J＝6.3Hz,3H),0.88(s,6H),0.87(s,3H),0.69(s,3H).
第二步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(116-1)(80mg,0.15mmol,1.0eq)溶在无水甲苯(4mL)和无水四氢呋喃(0.5mL)的混合溶剂中，氮气保护下依次加入氟化铯CSF(10mg,0.07mmol,0.5eq)和TMSCF3(407mg,1.50mmol,10eq)，反应1小时后,加入TBAF的四氢呋喃溶液(1.50mL,1.50mmol)中，室温搅拌1小时，TLC监测反应(PE:EtOAc＝5:1,磷钼酸烤板))监测反应，点板显示反应结束。反应液直接浓缩干，硅胶柱层析纯化(PE:EtOAc＝80:25)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基-6-(三氟甲基)庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(116-2)(60mg,0.07mmol,44.06％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.5,4.5Hz,1H),2.07–1.97(m,7H),1.96–1.82(m,2H),1.77–1.58(m,8H),1.51–1.12(m,11H),1.00(s,3H),0.91(d,J＝6.1Hz,3H),0.88(d,J＝3.1Hz,9H),0.69(s,3H).
第三步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基-6-(三氟甲基)庚 -2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(116-2)(50mg,0.08mmol,1.0eq)溶解在无水四氢呋喃(5mL)中，氮气保护下，加入四氢铝锂(6.38mg,0.17mmol,2.1eq)，室温搅拌1小时，TLC监测反应(PE:EtOAc＝3:1,磷钼酸烤板))监测反应，反应结束后，反应液用十水合硫酸钠淬灭，硅藻土过滤，滤液浓缩干，硅胶柱层析纯化(PE:EtOAc＝90:10to 75:25)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-7,7,7-三氟-6-羟基-6-(三氟甲基)庚-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(116)(23.9mg,0.04mmol,49.5％)。1H NMR(400MHz,CDCl3)δ3.24(dd,J＝11.6,4.5Hz,1H),2.03(dt,J＝11.8,6.1Hz,4H),1.95-1.83(m,3H),1.75-1.55(m,9H),1.47–1.15(m,9H),1.05(dd,J＝12.5,2.0Hz,2H),0.99(d,J＝7.7Hz,6H),0.91(d,J＝6.2Hz,3H),0.88(s,3H),0.81(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ134.46,134.32,78.99,50.43,50.38,49.81,44.51,38.89,37.12,36.54,36.30,35.57,30.97,30.80,28.23,27.96,27.83(s,3H),26.48,24.24,20.98,19.14,18.81,18.56,18.24,15.75,15.41.LC-MS:[M-17]+＝535.25
实施例117
化合物117(7R)-3-羟基-7-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]辛腈的制备
第一步 三甲基碘化亚砜(508mg,2.30mmol,3.5eq)于室温下溶于干燥的无水四氢呋喃(5mL)中，加入60％的钠氢(55mg,2.30mmol,3.5eq)，反应30分钟后，滴加乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(300mg,0.66mmol,1.0eq)的THF(1mL)溶液，室温下搅拌16小时。TLC(PE:EtOAc＝10:1，磷钼酸烤板)，监测反应，反应完毕后，反应液用水淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥浓缩后经硅胶柱层析纯化(PE:EtOAc＝90:10)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(氧杂环丙-2-基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲- 7-醇(117-1)(110mg,0.21mmol,32.3％)。1H NMR(400MHz,CDCl3)δ3.17(dd,J＝11.5,4.5Hz,1H),2.84(s,1H),2.69(dd,J＝6.2,2.8Hz,1H),2.40(dt,J＝5.4,2.8Hz,1H),1.97(m,5H),1.89–1.80(m,1H),1.70–1.56(m,6H),1.51(d,J＝14.9Hz,2H),1.43–1.32(m,5H),1.16(m,5H),1.01–0.96(m,2H),0.92(d,J＝7.9Hz,6H),0.84(d,J＝6.3Hz,3H),0.81(s,4H),0.74(s,3H),0.62(s,3H)。
第二步 (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-(氧杂环丙-2-基)戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(117-1)(100mg,0.23mmol，1.0eq)溶解在甲醇(4mL)和水(0.5mL)的混合溶剂中，依次加入氰化钠(130mg,2.65mmol,11eq)和氯化铵(25mg,0.47mmol,2eq)，反应加热到100℃回流40小时，TLC(PE:EtOAc＝1:1,磷钼酸烤板)监测反应.反应结束后，加水稀释，乙酸乙酯萃取，饱和盐水洗涤，无水硫硫酸钠干燥，硅胶柱层析纯化得到白色固体(7R)-3-羟基-7-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]辛腈(117)(4mg,0.01mmol,3.2％)。1H NMR(400MHz,CDCl3)δ3.70–3.56(m,2H),3.44–3.34(m,1H),3.17(dd,J＝11.5,4.4Hz,1H),1.96(s,4H),1.88–1.79(m,1H),1.70–1.64(m,2H),1.52(d,J＝11.7Hz,2H),1.20(s,15H),0.98(d,J＝12.4Hz,2H),0.92(d,J＝8.2Hz,6H),0.83(d,J＝6.2Hz,3H),0.80(s,3H),0.74(s,3H),0.62(s,3H).13C NMR(101MHz,CDCl3)δ134.78,124.53,77.99,76.25,75.99,75.67,49.37,48.85,43.50,37.94,36.07,35.40,34.62,30.02,29.85,27.29,26.98,26.82,26.22,25.49,23.31,21.27,19.99,18.14,17.69,17.25,14.74,14.66,14.44
实施例118
化合物118(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(羟基环丁基)戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-戊-4-炔-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(113-1)(50.00mg,0.12mmol,1.0eq)溶解在四氢呋喃(3.0mL)中,氮气保护，降温至-70℃，滴加正丁基锂(0.23mL,0.36mmol，3.0eq)，升温至-40℃，反应30min。在降温至-70℃。滴加环丁酮(170mg,5.227mmol，5eq.)，自然升温至室温搅拌2h，TLC(PE:EtOAc＝10:1)监测反应.反应结束后，加水稀释，乙酸乙酯萃取，饱和盐水洗涤，无水硫硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝100％-20％),浓缩得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(羟基环丁基)戊-4-炔-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(118-2)(17.84mg,0.040mmol,33.49％).LC-MS:[M+H]+＝435.55
第二步 将(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(羟基环丁基)戊-4-炔-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(118-2)(15mg,0.033mmol,1.0eq)溶解在乙酸乙酯(3.0mL)中,加入Pd/C 10％(1.5mg,10％)，氢气换气，室温搅拌20min.TLC(PE:EtOAc＝10:1)，监测，过滤。滤液浓缩并用硅胶柱层析纯化(PE:EtOAc＝100％-20％)，得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(羟基环丁基)戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(118)(6.03mg,0.013mmol,40.21％).1H NMR(400MHz,Chloroform-d)δ3.21(dd,J＝11.6,4.2Hz,1H),2.04–1.95(m,7H),1.74–1.63(m,4H),1.55(d,J＝25.4Hz,8H),1.41(dd,J＝22.7,16.2Hz,6H),1.24–1.14(m,5H),1.03(d,J＝13.5Hz,1H),0.97(d,J＝7.4Hz,6H),0.89(d,J＝6.0Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(100MHz,CDCl3)δ134.35,78.96,77.30,76.98,76.66,75.43,50.38,49.78,44.46,40.03,38.86,36.99,36.58,36.48,35.97,35.92,35.56,30.91,30.82,28.21,27.93,27.83,26.47,24.25,20.98,20.07,19.11,18.67,18.23,15.73,15.39,12.11.LC-MS[M-17]+＝439.55
实施例119
化合物119(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-甲基庚-4-炔-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备

将乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-戊-4-炔-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(113-1)(50.00mg,0.12mmol,1.0eq)溶解在四氢呋喃(3.0mL)中,氮气保护，降温至-70℃，滴加正丁基锂(0.23mL,0.36mmol，3.0eq)，升温至-40℃，反应30min。再降温至-70℃。滴加丙酮(34.8mg,0.60mmol，5eq.)，自然升温至室温搅拌2h，TLC(PE:EtOAc＝10:1)监测反应.反应结束后，加水稀释，乙酸乙酯萃取，饱和盐水洗涤，无水硫硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝(100％-20％),得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-甲基庚-4-炔-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(119)(3.29mg,0.007mmol,5.67％).1H NMR(400MHz,CDCl3)δδ3.22(dd,J＝11.5,4.4Hz,1H),2.23(d,J＝16.9Hz,1H),2.06–1.85(m,6H),1.68(dd,J＝18.2,12.0Hz,5H),1.63–1.53(m,5H),1.48(s,6H),1.33–1.12(m,4H),1.03(d,J＝13.5Hz,3H),0.97(d,J＝7.6Hz,6H),0.86(s,3H),0.79(s,3H),0.68(s,3H).13C NMR(100MHz,CDCl3)δ134.44,134.21,86.10,81.52,78.93,77.29,76.98,76.66,65.33,50.35,49.80,49.69,44.44,38.85,36.99,36.27,35.54,31.79,30.80,30.79,27.93,27.87,27.80,26.46,25.92,24.20,20.92,19.12,19.04,18.21,15.87,15.39.LC-MS[M-17]+＝423.55
实施例120
化合物120 2-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊基]丙-1,3-二醇的制备

第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(II)(1.0g,2.33mmol,1.0eq.)溶解在二甲甲烷(20mL)中，室温加哌啶(15.80mg,0.19mmol,0.08eq.)，醋酸(12.30mg,0.19mmol,0.08eq.)和丙二酸二乙酯(410.00mg,2.56mmol,1.1eq.)，室温搅拌16h，点板检测(PE:EtOAc＝10:1)，原料反应完全，降至室温加入水淬灭，用乙酸乙酯萃取两次，无水硫酸钠干燥，旋干，过柱子(PE:EtOAc＝50:1to 5:1)得到白色固体(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-(乙氧基羰基)庚-2-烯酸乙酯(120-1)(600mg,1.03mmol,45.45％)。1H NMR(399MHz,CDCl3)δ6.97(t,J＝7.9Hz,1H),4.47(dd,J＝11.5,4.4Hz,1H),4.28(q,J＝7.1Hz,2H),4.19(dd,J＝15.5,7.3Hz,2H),2.33(d,J＝8.5Hz,1H),2.23–2.14(m,1H),2.06–1.85(m,8H),1.74–1.59(m,6H),1.46(dd,J＝16.6,8.3Hz,3H),1.29(dt,J＝16.2,7.1Hz,10H),1.15(dd,J＝20.6,10.7Hz,3H),0.98(s,3H),0.89(d,J＝6.0Hz,3H),0.85(d,J＝6.6Hz,9H),0.66(s,3H)
第二步 将(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-(乙氧基羰基)庚-2-烯酸乙酯(120-1)(0.40mg,0.70mmol)溶解在EtOAc(50mL)中，加入Pd/C 10％(40mg,10％)，氢气换气，25℃搅拌1h.点板检测反应完全后，硅藻土过滤，EtOAc漂洗，旋干，过柱子(PE:EtOAc＝100％-20％)浓缩得到R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-(乙氧基羰基)庚酸乙酯(120-2)(300mg,0.51mmol,74.81％)
第三步 将铝锂氢(133.00mg,3.50mmol 10.0eq.)加入四氢呋喃中，氮气保护，降温至零度，将化合物R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10, 11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-(乙氧基羰基)庚酸乙酯(120-2)(200.00mg,0.35mmol 1eq.)溶解在四氢呋喃(5mL)中，滴加上述体系中，升至室温，搅拌两个小时。TLC(PE:EtOAc＝1:1)，原料反应完毕，低温用饱和氯化铵水溶液淬灭，过柱子(PE:EtOAc＝100％-20％),浓缩得到白色固体(2-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊基]丙-1,3-二醇120(100mg，0.217mmol 62.11％)。1H NMR(400MHz,CDCl3)δ3.81(d,J＝10.6Hz,2H),3.68–3.61(m,2H),3.21(d,J＝11.7Hz,1H),2.00(s,4H),1.86(s,1H),1.66(d,J＝16.6Hz,7H),1.50–1.32(m,6H),1.21(d,J＝22.0Hz,6H),1.17–1.10(m,1H),1.01(s,1H),0.97(d,J＝7.8Hz,6H),0.86(d,J＝8.8Hz,6H),0.79(s,3H),0.66(s,3H).13C NMR(101MHz,CDCl3)δ134.36,78.96,77.30,76.98,76.66,66.93,66.69,50.42,50.35,49.77,44.43,42.01,38.85,36.98,36.40,36.34,35.54,30.95,30.79,28.22,28.10,27.93,2 7.80,26.46,24.23,23.95,20.96,19.11,18.66,18.22,15.72,15.39.LC-MS:[M-17]+＝443.50
实施例121
化合物121(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-7-(吡唑-1-基)庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参照实施例117，将第二步的氰化钠换成吡唑，得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-7-(吡唑-1-基)庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(121).1H NMR(400MHz,CDCl3)δ7.56(d,J＝1.1Hz,1H),7.43(d,J＝1.9Hz,1H),6.29(s,1H),4.24(d,J＝13.5Hz,1H),4.25-4.20(m,2H),4.08-3.95(m,1H),2.06–1.98(m,4H),1.90(dd,J＝13.3,9.1Hz,1H),1.78-1.51(m,8H),1.51–1.32(m,7H),1.31–1.16(m,4H),1.05(dd,J＝12.6,1.8Hz,2H),0.99(d,J＝8.2Hz,6H),0.90(d,J＝6.3Hz,3H),0.87(s,3H),0.81(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ139.54,134.42,134.37,130.42,105.45,79.00,77.34,77.03,76.71,50.40,49.81,44.48,38.90,37.02,36.36,35.59,30.98,30.84,28.24,27.97,27.85,26.50,24.27,21.00,19.15,18.68,18.26,15.75,15.43.LC-MS:[M+1]+＝497.30
实施例122
化合物122 3-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]氧杂环丁-3-醇的制备
第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-甲酰基乙基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(86-2)(300mg,0.72mmol,1.0eq.)溶于甲醇(20.0mL)中，加入碳酸钾(332.45mg,2.16mmol,3eq.)，室温下加入(1-重氮基-2-氧代丙基)膦酸二甲酯(221.22mg,1.15mmol,1.6eq.)，室温下反应3h，TLC监测(PE:EtOAc＝10:1,磷钼酸显色,Rf1＝0.61,Rf2＝0.87)反应完后，低温浓缩反应液，用二氯甲烷与水稀释，分液，用二氯甲烷萃洗两次，无水硫酸钠干燥，过柱子(PE:EtOAc＝100％-20％)浓缩得白色固体乙酸(122-1)(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-丁-3-炔-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯的(120.00mg,0.33mmol,45.11％)。1H NMR(400MHz,Chloroform-d)δ13.21(d,J＝7.1Hz,1H),2.43(m,1H),2.24(d,J＝3.9Hz,0H),2.01(m,9H),1.62(m,17H),1.25(d,J＝9.0Hz,1H),1.19(d,J＝6.9Hz,2H),1.16(d,J＝6.7Hz,1H),1.03(d,J＝12.7Hz,1H),0.97(m,3H),0.87(m,2H),0.79(s,4H),0.69(s,3H)
第二步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-丁-3-炔-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(122-1)(100.00mg,0.27mmol,1.0eq)溶解在四氢呋喃(5.0mL)中,氮气保护，降温至-70℃，滴加正丁基锂(0.51mL,0.81mmol，3.0eq)， 升温至-40℃，反应30min。在降温至-70℃。滴加杂氧环丁酮(97.2mg,1.35mmol，5eq.)，自然升温至室温搅拌2h，TLC(PE:EtOAc＝10:1)监测，低温浓缩反应液，用二氯甲烷与水稀释，分液，用二氯甲烷萃洗两次，无水硫酸钠干燥，过柱子(PE:EtOAc＝100％-20％)浓缩得到白色固体3-[(3S)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁-1-炔基]氧杂环丁-3-醇(122-2)(20.00mg,0.045mmol,16.67％)LC-MS:423.55
第三步 将白色固体3-[(3S)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁-1-炔基]氧杂环丁-3-醇(122-2)(15mg,0.033mmol,1.0eq)溶解在乙酸乙酯(3.0mL)中,加入Pd/C 10％(1.5mg,10％)，氢气换气，室温搅拌20min.TLC(PE:EtOAc＝10:1)监测，过滤，滤液浓缩后过柱(PE:EtOAc＝(100％-20％)，得到白色固体3-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]氧杂环丁-3-醇(122)(6.38mg,0.013mmol,41.50％)1H NMR(400MHz,Chloroform-d)δ(m,2H),4.51–4.44(m,2H),3.22(dd,J＝11.6,4.5Hz,1H),2.05–1.87(m,7H),1.73–1.58(m,8H),1.53–1.43(m,4H),1.31(d,J＝7.5Hz,2H),1.22–1.09(m,3H),1.03(d,J＝12.6Hz,1H),0.97(d,J＝7.2Hz,6H),0.93(d,J＝6.1Hz,3H),0.86(s,3H),0.79(s,3H),0.68(s,3H).13C NMR(100MHz,CDCl3)δ134.41,134.26,83.86,83.76,78.94,77.30,76.98,76.66,74.89,50.35,50.09,49.78,44.47,38.85,36.99,36.27,35.54,34.29,30.93,30.77,29.27,28.12,27.93,27.80,26.46,24.22,20.95,19.12,18.70,18.21,15.74,15.39.LC-MS:[M+1]+＝427.55
实施例123
化合物123(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-7-甲氧基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(氧杂环丙-2-基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(117-1)(40mg,0.09mmol,1.0eq)溶解在甲醇(5mL)和水(2.5mL)的混合溶剂中，加入氢氧化钾(15mg，0.27mmol，3.0eq)，反应加热到85℃，搅拌过夜，TLC(PE:EtOAc＝10:1，磷钼酸烤板),监测反应。反应液用乙酸乙酯萃取，饱和盐水洗涤，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝80:20)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-7-甲氧基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(123)(4mg,0.01mmol,7.8％)。1H NMR(400MHz,CDCl3)δ3.77(s,1H),3.39(s,3H),3.23(dd,J＝7.6,4.2Hz,1H),2.02-1.97(s,4H),1.95–1.86(m,1H),1.74-1.63(m,6H),1.50–1.57(m,2H),1.45-1.13(m,12H),1.08-1.03(s,2H),0.99(d,J＝8.3Hz,6H),0.91–0.86(m,9H),0.81(s,3H),0.68(s,3H).LC-MS[M+H]+＝443
实施例124
化合物124(7R)-7-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]辛-1,3-二醇的制备
第一步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a, 4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(100mg,0.22mmol,1.0eq.)溶于无水四氢呋喃(8.0mL)中，氮气置换后，冰浴冷却，滴加乙烯基溴化镁(28.74g,0.22mmol,1.0eq.),滴加完毕后，升至室温，TLC监测(PE:EtOAc＝10:1)，反应结束后，加入10mL饱和氯化铵水溶液淬灭，以乙酸乙酯15mL*3萃取，有机相干燥，浓缩，柱层析(PE:EtOAc＝50：1～20：1)得白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基辛-7-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(124-1)(50mg，0.085mmol)。
第二步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基辛-7-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(124-1)(50mg,0.11mmol，1.0eq.)溶于四氢呋喃(8.0mL)中,室温下9-BBN(2mL,0.11mmol,1.0eq.),升温至60℃，搅拌16小时后，原料TLC监测消失，随后降至0℃，加入双氧水(31％，2mL,0.11mmol,1.0eq.),继续在0℃下搅拌，TLC监测(PE:EtOAc＝1：1)，反应结束后，加入水5mL稀释，接着以乙酸乙酯5mL*3萃取，有机相合并干燥，浓缩经制备柱层析(PE:EtOAc＝100：1～10：1)纯化得乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6,8-二羟基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(124-2)(20mg,0.034mmol,30.98％)。1H NMR(399MHz,CDCl3)δ(m,1H),3.87(s,3H),2.04–1.96(m,7H),1.86(s,2H),1.75–1.60(m,10H),1.60–1.24(m,16H),1.14(t,J＝13.4Hz,3H),0.98(s,3H),0.87(d,J＝10.2Hz,12H),0.66(s,3H).
第三步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6,8-二羟基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(124-2)(20mg,0.04mmol，1.0eq.)溶于四氢呋喃(3.0mL)中,再加入甲醇(3.0mL),加入1M氢氧化锂(2.0mL,0.044mmol),继续在室温下搅拌，TLC监测(PE:EtOAc＝1：1)，反应结束后，加入水5mL稀释，接着以乙酸乙酯5mL*3萃取，有机相合并干燥，浓缩经制备HPLC(PE:EtOAc＝100：1～10：1)纯化得(7R)-7-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]辛-1,3-二醇124(15mg,0.027mmol,61.31％)。1H NMR(399MHz,CDCl3)δ3.86(s,3H),3.21(d,J＝10.7Hz,1H),1.94(d,J＝46.6Hz,9H),1.68(s,7H),1.46(s,3H),1.38(s,3H),1.19(dd,J＝22.5,10.6Hz,3H),1.04(s,2H),0.97(d,J＝7.4Hz,6H),0.87(d,J＝12.3Hz,6H),0.79(s,3H),0.66(s,3H).13C NMR(100MHz,CDCl3)δ134.37,134.32,78.96,77.30,76.98,76.66,72.52,61.99,50.36,49.77,44.44,38.85,38.36,36.98,36.38,36.35,36.17,36.12,35.55,30.95,30.80,28.20,27.93,27.81,26.46,24.24,22.20,20.96,19.11,18.66,18.22,15.72,15.39.LC-MS[M+1]+＝443.55
实施例125
化合物125(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]庚-1,2-二醇的制备的制备
第一步 三甲基碘化亚砜(508mg,2.30mmol,3.5eq)于室温下溶于干燥的无水四氢呋喃(5mL)中，加入60％的钠氢(55mg,2.30mmol,3.5eq)，反应30分钟后，滴加乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(300mg,0.66mmol,1.0eq)的THF(1mL)溶液，室温下搅拌16小时。TLC(PE:EtOAc＝10:1，磷钼酸烤板)，监测反应，反应完毕后，反应液用水淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥浓缩后经硅胶柱层析纯化(PE:EtOAc＝90:10)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(氧杂环丙-2-基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(125-1)(110mg,0.21mmol,32.3％)。1H NMR(400MHz,CDCl3)δ3.17(dd,J＝11.5,4.5Hz,1H),2.84(s,1H),2.69(dd,J＝6.2,2.8Hz,1H),2.40(dt,J＝5.4,2.8Hz,1H),1.97(m,5H),1.89–1.80(m,1H),1.70–1.56(m,6H),1.51(d,J＝14.9Hz,2H),1.43–1.32(m,5H),1.16(m,5H),1.01–0.96(m,2H),0.92(d,J＝7.9Hz,6H),0.84(d,J＝6.3Hz,3H),0.81(s,4H),0.74(s,3H),0.62(s,3H)。
第二步 (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(氧杂环丙-2-基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(125-1)(60mg,0.14mmol,1.0eq)溶解在水(2mL)和二氧六环(2mL)的混合溶剂中，加入催化量的四丁基硫酸氢氨(9mg,0.03mmol,0.2eq)，加热到回流搅拌48hr.TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应进展，反应结束后，反应液用乙酸乙酯稀释，饱和盐水洗涤，无水硫酸钠干燥，浓缩干得到中间体，中间体溶解在甲醇(5mL)中，加入钯碳(10mg)，氢气置换3次后，氢气氛围搅拌过夜，随后硅藻土助滤，滤液浓缩干，剩余物硅胶柱层析(PE:EtOAc＝80:20)纯化得到白色固(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]庚-1,2-二醇(125)(10mg,0.02mmol,14％)。1H NMR(400MHz,CDCl3)δ3.77-3.68(m,1H),3.67-3.63(m,1H),3.47-3.41(m,1H),3.23(dd,J＝11.5,4.6Hz,1H),2.04-1.98(m,4H),1.96–1.86(m,1H),1.76–1.59(m,7H),1.51–1.34(m,8H),1.24(s, 3H),1.05(d,J＝12.8Hz,2H),0.99(d,J＝7.9Hz,6H),0.91–0.87(m,6H),0.81(s,3H),0.69(s,3H).LC-MS[M-17]+＝429.3
实施例126和127
(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7-氟-6-羟基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇和(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-氟-7-羟基辛-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将原料三苯基乙基碘化膦(273.54mg,0.654mmol,6.0eq)溶解在无水四氢呋喃(40mL)中，体系冷却至-78℃，加入正丁基锂(31.42mg,0.491mmol,5.0eq)，并保持温度搅拌30min，然后回到室温搅拌。乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基(37-2)(50mg,0.109mmol，1.0eq)溶解在无水四氢呋喃(5mL)中，加入到反应液中，体系升至室温，搅拌24小时。TLC监测反应TLC(PE:EtOAc＝20:1，磷钼酸烤板)，反应完全后，反应液加入水(20mL)，乙酸乙酯萃取，饱和盐水洗涤，无水硫酸钠干燥，硅胶柱层析(PE:EtOAc＝96:4)得到白色固体乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,5E)-庚-5-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基(126-1)(35mg,0.067mmol,纯度90％，收率61.38％)。1H NMR(400MHz,CDCl3)δ5.48–5.33(m,2H),4.50(dd,J＝11.5,4.5Hz,1H),2.07–1.96(m,8H),1.96–1.84(m,2H),1.77–1.63(m,6H),1.61(s,1H),1.60(s,1H),1.58–1.37(m,6H),1.36–1.21(m,4H),1.20–1.11(m,2H),1.00(s,3H),0.93.–0.83(m,12H),0.68(s,3H).
第二步 将原料乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,5E)-庚-5-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(160mg,0.35mmol,1.0eq)和碳酸氢钠(32.51mg,0.39mmol,1.1eq)溶于DCM(二氯甲烷)(10mL)中，氮气置换，体系冰浴下降温到0℃，加入间氯过氧苯甲酸(97.15mg,0.563mmol,1.3eq)。反应混合物在氮气氛围，室温搅拌2hr。TLC(PE:EtOAc＝20:1，磷钼酸烤板)监测反应，点板产物点明显比原料点浓，停止反应。反应液使用饱和碳酸氢钠溶液(3×10mL)溶液洗涤。合并有机相用饱和食盐水(10mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(PE:EtOAc＝95:5to 92:8)纯化，得到白色固体乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(3-甲基氧杂环丙-2-基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(126-2)(100mg,纯度90％,收率54.34％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.5,4.5Hz,1H),3.09–3.00(m,1H),2.90(dd,J＝10.3,5.9Hz,1H),2.08–1.97(m,7H),1.96–1.86(m,1H),1.78–1.62(m,6H),1.61–1.38(m,10H),1.35–1.24(m,6H),1.21–1.04(m,3H),1.00(s,3H),0.89(dd,J＝13.7,4.8Hz,12H),0.69(s,3H).
第三步 将原料乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(3-甲基氧杂环丙-2-基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(126-2)(90mg,0.191mmol,1.0eq)溶解在CH3CN(乙腈)(20mL)中，加入氟化氢三乙胺(184.93mg,1.147mmol,1.0eq)，反应混合物在氮气氛围120℃反应120h。TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应完全后，停止反应。将水(20mL)加入到反应体系中，用EA(乙酸乙酯)(3×25mL)萃取，合并有机相用饱和食盐水(20mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(PE:EtOAc＝95:5to 93:7)得到乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-氟-5-羟基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯和乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-氟-6-羟基庚-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯。
化合物126-3：first eluent(白色固体，14mg,纯度95％，收率14.18％)；1HNMR(400MHz,CDCl3)δ4.56(dd,J＝10.0,6.0Hz,0.5H),4.50(dd,J＝11.6,4.5Hz,1H),4.44(dd,J＝10.0,6.0Hz,0.5H),3.59–3.47(m,1H),2.05(s,3H),2.04–1.86(m,4H),1.79–1.57(m,9H),1.53–1.35(m,8H),1.34–1.11(m,8H),1.00(s,3H),0.89(dd,J＝12.4,5.1Hz,12H),0.69(s,3H).
化合物127-1:Second eluent(白色固体，20mg,纯度95％，收率20.27％)；1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.6,4.5Hz,1H),4.36–4.16(m,1H),3.84–3.72(m,1H),2.05(s,3H),2.04–1.86(m,5H),1.78–1.39(m,14H),1.31(dd,J＝12.9,9.4Hz,3H),1.26(s,2H),1.20(d,J＝6.2Hz,3H),1.18–1.11(m,2H),1.00(s,3H),0.89(dd,J＝11.5,4.7Hz,12H),0.69(s,3H)
第四步
化合物126
将原料126-3(15mg,0.03mmol,1eq)溶解于THF(四氢呋喃)(1mL)和MeOH(甲醇)(1mL)中，滴加1N氢氧化锂(0.6mL)，反应混合物在室温搅拌3hrs。TLC(PE:EtOAc＝5:1，磷钼酸烤板)监测反应完全，反应液降到室温，反应液使用1N HCl酸化至PH＝3～4后，浓缩掉乙醇后用EtOAc(乙酸乙酯)(20mL×3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(PE：EtOAC＝90:10to 88：12)得到126(3.65mg,纯度99.37％，收率26.38％)。
化合物126：1H NMR(400MHz,CDCl3)δ4.61–4.40(m,1H),3.52(dd,J＝15.3,6.6Hz,1H),3.24(dd,J＝11.5,4.5Hz,1H),2.09–1.97(m,1H),1.95–1.85(m,1H),1.75–1.65(m,5H),1.62–1.53(m,9H),1.48–1.36(m,7H),1.25(s,3H),1.00(s,3H),0.98(s,3H),0.91(d,J＝6.3Hz,3H),0.88(s,3H),0.81(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ134.44,134.38,124.84,107.91,79.00,50.41,49.82,44.49,38.90,37.03,36.47,36.36,36.28,36.10,35.59,30.99,30.84,29.71,28.24,27.97,27.87,26.51,24.28,21.01,19.15,18.68,18.26,17.00,15.76,15.43.LC-MS:[M+H]+＝445.4
化合物127
参照实施例126，把126-3换成127-1得到化合物127。
化合物127：1H NMR(400MHz,CDCl3)δ4.37–4.15(m,1H),3.86–3.72(m,1H),3.24(dd,J＝11.6,4.5Hz,1H),2.09–1.97(m,4H),1.96–1.85(m,1H),1.78–1.63(m,6H),1.58–1.52(m,5H),1.50–1.38(m,5H),1.34–1.23(m,3H),1.20(d,J＝6.3Hz,4H),0.99(d,J＝7.8Hz,6H),0.91(d,J＝6.3Hz,3H),0.88(s,3H),0.81(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ134.44,134.37,124.83,98.82,79.00,50.41,49.82,44.49,38.90,37.03,36.40,36.32,36.12,35.96,35.59,30.99,30.84,28.23,27.97,27.86,26.51,24.27,21.65,21.00,19.15,18.62,18.47,18.26,15.76,15.43.LC-MS:[M+H]+＝445.5
实施例128
化合物128(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己腈的制备
乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-氰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(76-3)(100mg,0.22mmol,1.0eq)加入到EtOH(乙醇)(5mL)中，加入氢氧化钠水溶液(10％,0.5mL)，加热到回流搅拌4小时。TLC(E:EtOAc＝5:1，磷钼酸烤板)监测反应完全，反应液浓缩去除乙醇，加水稀释，用乙酸乙酯(20mL)萃取两次，合并有机相，用饱和氯化铵和盐水分别洗涤一次，无水硫酸钠干燥，硅胶柱层析(PE:EtOAc＝90:10),得到(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己腈(12.84mg,纯度93％，收率14.1％)。1H NMR(400MHz,CDCl3)δ3.24(dd,J＝11.6,4.5Hz,1H),2.32(td,J＝7.0,4.3Hz,2H),2.02(ddd,J＝10.8,8.4,3.6Hz,4H),1.93(dd,J＝13.4,7.4Hz,1H),1.62(m,12H),1.25(m,5H),1.05(dd,J＝12.6,2.2Hz,1H),0.99(m,6H),0.92(d,J＝6.2Hz,3H),0.88(s,3H),0.81(s,3H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ134.48,134.30,119.89,78.96,77.35,77.23,77.03,76.71,50.40,50.24,49.82,44.53,38.89,37.03,35.91,35.59,35.32,30.99,30.79,28.19,27.97,27.84,26.49,24.23,22.43,20.98,19.15,18.53,18.24,17.57,15.75,15.42.
实施例129
化合物129(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3,3-二甲基氧杂环丙-2-基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-6-甲基庚-5-烯-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(I)(4.0g,4.2mmol,1.0eq)溶于DCM(二氯甲烷)(100mL)中，加入碳酸氢钠(0.39g,4.7mmol,1.1eq),间氯过氧苯甲酸(0.88g,5.1mmol,1.2eq)。室温反应1小时TLC(PE：EtOAc＝5:1，磷钼酸)，检测反应完成。反应液用饱和碳酸氢钠溶液清洗两次(100mL x 2)，硫酸钠干燥，浓缩。柱层析纯化(PE:EtOAc＝1:10～1:3)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3,3-二甲基氧杂环丙-2-基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(129-1)(1.6g,纯度85％,收率65.7％)。1H NMR(400MHz,CDCl3):δ4.50(dd,J＝11.5,4.5Hz,1H),2.69(t,J＝6.2Hz,1H),2.05-2.00(m,8H),1.67-1.31(m,17H),1.35-1.08(m,8H),1.01-0.96(m,3H),0.96-0.85(m,11H),0.72-0.57(m,3H).
第三步 将原料乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3,3-二甲基氧杂环丙-2-基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(129-1)(1.0g,2.1mmol,1eq)溶于THF(四氢呋喃)(40mL)中，氮气保护，冰浴下加入氢化铝里(0.16g,4.2mmol,2eq)。室温反应1.5小时。TLC(PE：EtOAc＝5:1，磷钼酸)。反应结束后加入十合水硫酸钠淬灭，过滤，滤液浓缩。柱层析纯化(DCM:MeOH＝1:10～1:5)。得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3,3-二甲基氧杂环丙-2-基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(129)(600mg,纯度90％，收率59.13％)。1H NMR(400MHz,CDCl3)δ3.24(dd,J＝11.5,4.5Hz,1H),2.69(t,J＝6.2Hz,1H),2.11–1.88(m,6H),1.76–1.51(m,12H),1.32–1.22(m,8H),1.07–0.97(m,8H),0.93–0.86(m,7H),0.81(s,3H),0.70(s,3H).13C NMR(101MHz,CDCl3)δ134.45,134.35,78.97,77.34,77.23,77.03,76.71,64.94,64.80,58.43,58.14,50.41,50.38,50.29,49.82,44.51,38.89,37.03,36.34,36.22,35.59,32.81,32.62,31.00,30.98,30.83,28.24,28.20,27.97,27.85,26.50,25.91,25.62, 24.95,24.94,24.25,21.00,19.15,18.75,18.68,18.65,18.58,18.26,15.76,15.42
实施例130
化合物130(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸的制备
(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰基氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸乙酯(V)(200mg,0.40mmol)溶解在乙醇(2mL)中，加入氢氧化钠溶液(2mL,4mol/L)，反应液加热到回流，搅拌过夜。TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应。反应完全后，反应液降温到室温，用1N的盐酸调pH＝1，乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝90:10to 50:50)得到白色固体(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸(130)(150mg,0.331mmol,82.84％)。1H NMR(400MHz,CDCl3)δ3.24(dd,J＝11.6,4.5Hz,1H),2.33(m,2H),2.04(d,J＝8.2Hz,4H),1.91(dd,J＝13.4,7.5Hz,1H),1.70(m,6H),1.50(m,7H),1.19(m,7H),0.99(d,J＝7.8Hz,5H),0.91(t,J＝5.9Hz,3H),0.87(s,3H),0.81(s,3H),0.69(s,3H).
实施例131
化合物131(7R)-7-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]辛-3-酮的制备
参照实施例90，得到另外一个化合物(7R)-7-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]辛-3-酮的制备(131).1H NMR(399MHz,CDCl3)δ3.21(dd,J＝11.6,4.4Hz,1H),2.37(m,4H),2.00(s,4H),1.85(s,1H),1.67(m,7H),1.45(dd,J＝16.8,8.3Hz,4H),1.34(dd,J＝15.7,7.7Hz,2H),1.18(m,4H),1.03(t,J＝7.3Hz,4H),0.97(d,J＝7.8Hz,6H),0.88(d,J＝6.3Hz,3H),0.85(s,3H),0.79(s,3H),0.66(s,3H).13C NMR(100MHz,CDCl3)δ212.08,134.37,134.31,78.95,77.29,76.97,76.66,50.36,50.19,49.76,44.44,42.89,38.85,36.98,36.29,35.82,35.79,35.54,30.92,30.79,28.15,27.93,27.81,26.46,24.22,20.96,20.72,19.11,18.58,18.22,15.70,15.39,7.84,0.99.
实施例132
化合物132(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-氨基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-氰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[2,1-i]菲-7-基酯(76-3)(100mg,0.243mmol)溶解在THF(5mL)中，氮气换气三次，降温零度，加入LAH(170mg,4.860mmol)，低温搅拌2h。TLC(PE：EA＝10:1)，原料反应完毕，后处理加入甲醇淬灭，用硅藻土过滤旋干，送制备HPLC分离得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-氨基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(132)(30mg,0.069mmol,28.22％)。1H NMR(400MHz,MeOD)δ3.17–3.09(m,1H),2.90(t,J＝7.6Hz,2H),2.05(s,4H),1.96(dd,J＝13.1,7.6Hz,1H),1.79–1.67(m,5H),1.67–1.56(m,6H),1.53–1.44(m,4H),1.32(dd,J＝19.9,8.9Hz,2H),1.20(t,J＝11.5Hz,2H),1.09(d,J＝9.9Hz,1H),1.00(s,3H),0.97(s,3H),0.94(d,J＝6.3Hz,3H),0.90(s,3H),0.79(s,3H),0.74(s,3H).13C NMR(101MHz,MeOD)δ134.64,134.23,78.23,50.55,50.36,49.64,48.24,48.02,47.81,47.60,47.38,47.17,46.96,44.31,39.43,38.56,36.81,36.23,35.56,35.52,30.90,30.51,27.87,27.74,27.21,27.07,26.26,23.23,22.92,20.66,18.22,18.02,17.73,14.92,14.76.
实施例133
化合物133(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-甲氧基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,4E)-5-甲氧基戊-4-烯-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(98-1)(100mg,0.21mmol，1.0eq)溶解在四氢呋喃(2mL)和甲醇(2mL)的混合溶剂中，加入钯碳(20mg,20％)，用氢气球加氢反应2 小时，硅藻土助滤除去钯碳，滤液浓缩干，硅胶柱层析纯化(PE:EtOAc＝90:10)得到白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-甲氧基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(133-1)(60mg,0.13mmol,纯度80％，收率49.5％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.5,4.5Hz,1H),3.37(t,J＝6.6Hz,2H),3.33(s,3H),2.08–1.96(m,7H),1.95-1.85(m,1H),1.78-1.56(m,8H),1.53–1.12(m,12H),1.07–0.98(m,4H),0.92-0.86(m,12H),0.68(s,3H).
第二步 白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-甲氧基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(133-1)(60mg,0.13mmol，1.0eq)溶解在乙醇(2mL)中，加入氢氧化钠溶液(2mL,4mol/L)，反应液加热到50℃，搅拌过夜。TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应。反应完全后，反应液降温到室温，用1N的盐酸调pH＝5，乙酸乙酯萃取3次，合并有机相，饱和盐水洗涤，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝90:10to 50:50)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-甲氧基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(133)(30mg,0.07mmol,纯度97％,收率52.0％)。
1H NMR(400MHz,CDCl3)δ3.37(t,J＝6.6Hz,2H),3.33(s,3H),3.23(dd,J＝11.5,4.5Hz,1H),2.07-1.97(m,4H),1.95–1.86(m,1H),1.78–1.47(m,11H),1.44-1.22(m,8H),1.08–1.02(m,2H),0.99(d,J＝8.1Hz,6H),0.91–0.88(m,3H),0.87(s,3H),0.81(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ134.37,78.97,77.31,76.99,76.67,73.03,58.56,50.36,49.79,44.45,38.88,37.00,36.37,36.05,35.57,30.96,30.82,30.14,28.18,27.95,27.84,26.48,24.25,22.87,20.99,19.13,18.65,18.24,15.72,15.41.
实施例134
化合物134(4R)-1-环己基-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮的制备

第一步 将乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(II)(300.00mg,0.678mmol)溶解在THF(10mL)中，氮气保护，降温至0℃，滴加环己烯溴化镁(0.16mL)，自然升至室温搅拌1hr，TLC监测(PE:EA＝10:1,磷钼酸显色,Rf1＝0.6,Rf2＝0.7)，反应结束后，降温至0℃，加入饱和氯化铵水溶液淬灭，用乙酸乙酯10mL*3萃取，有机相合并，干燥，浓缩，过柱子(PE:EA(100％～50％)，得乙酸(1R,3aR,5aR,7S,9a S,11aR)-1-[(2R)-5-环己基-5-羟基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(134-1)(110mg,0.188mmol,27.73％)。1H NMR(399MHz,CDCl3)δ4.47(s,1H),3.30(s,1H),2.03(s,7H),1.71(d,J＝29.4Hz,13H),1.44(s,3H),1.24(s,8H),1.16(s,6H),0.99(s,3H),0.89(s,3H),0.86(s,9H),0.67(s,3H).
第二步 将乙酸(1R,3aR,5aR,7S,9a S,11aR)-1-[(2R)-5-环己基-5-羟基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(134-1)(30.0mg,0.057mmol1eq)溶于丙酮(5.0mL)中，降温至0℃，缓慢滴加琼斯试剂((0.043mL，2.0eq.)，反应5分钟后,TLC(PE:EA＝5:1,磷钼酸显色,Rf1＝0.72,Rf2＝0.34)监测反应。反应结束后低温滴加15.0mL异丙醇淬灭,搅拌30分钟,浓缩后用20.0ml二氯甲烷溶解,分别用10.0mL 1.5N NaHSO3和10.0mL H2O洗一次干燥浓缩之后，得到粗品白色固体乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-环己基-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(134-2)(20mg,0.030mmol,53.54％)。1H NMR(399MHz,CDCl3)δ4.47(d,J＝7.5Hz,1H),2.38(dd,J＝37.6,8.4Hz,3H),2.02(s,7H),1.71(dd,J＝29.6,14.1Hz,10H),1.48(dd,J＝29.6,14.1Hz,4H),1.27(d,J＝10.4Hz,7H),1.14(m,5H),0.98(s,3H),0.86(s,12H),0.66(s,3H).
第三步 称取乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-环己基-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(134-2)(100mg,0.24mmol,1.0eq.)加入四氢呋喃(3.0mL),甲醇(3.0mL),1M氢氧化锂水溶液(2.0mL),室温下搅拌过夜， TLC监测(PE:EA＝3:1,磷钼酸显色,Rf1＝0.7,Rf2＝0.2)，反应结束后，浓缩出去四氢呋喃和甲醇，随后浓缩液中加入水(10.0mL),再以乙酸乙酯(20mL*3)萃取，有机相合并，干燥，浓缩经制备HPLC纯化得(4R)-1-环己基-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,1 0,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮(134)(42.3mg,0.087mmol,45.75％)。1H NMR(399MHz,CDCl3)δ3.20(1H,dd,J＝11.5,4.5),2.44(1H,ddd,J＝15.5,10.1,5.2),2.32(2H,ddd,J＝11.3,8.9,5.3),2.06–1.86(5H,m),1.83–1.69(5H,m),1.69–1.60(5H,m),1.59–1.40(5H,m),1.24(10H,ddt,J＝29.6,16.3,10.2),1.02(1H,dd,J＝12.7,1.9),0.9 6(6H,d,J＝8.4),0.85(6H,d,J＝5.9),0.78(3H,s),0.65(3H,s).13C NMR(101MHz,CDCl3)δ214.86,134.35,134.32,78.92,77.33,77.01,76.69,50.86,50.6,50.34,49.77,44.46,38.85,37.74,36.98,36.08,35.55,30.95,30.78,29.97,28.59,28.51,2 8.08,27.93,27.80,26.46,25.85,25.72,25.68,24.22,20.95,19.11,18.48,18.21,15.73,15.40,0.99.
实施例135
化合物135(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]庚-2-酮的制备
第一步 将(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己酸(VI)(200mg,0.46mmol)溶于DMF(N,N-二甲基甲酰胺)(5.0mL)中，加入N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(353.15mg,0.93mmol)和二异丙基乙基胺(180.05mg,1.39mmol)，室温搅拌0.5h后加入N,O-二甲基羟胺盐酸盐(42.55mg,0.70mmol)，室温下反应4h，TLC监测(PE:EA＝3:1,磷钼酸显色,Rf1＝0.53,Rf2＝0.64)反应完后，反应液加水和EtOAc洗萃，有机相盐水洗一次合并干燥浓缩，粗品经柱层析(PE:EA＝0to 5:1)得白色固体(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲氧基-N-甲基己酰胺(135-1)(210mg,0.408mmol, 87.82％).1H NMR(399MHz,CDCl3)δ3.67(d,J＝1.6Hz,3H),3.22(s,1H),3.16(s,3H),2.37(s,2H),2.02(d,J＝8.8Hz,5H),1.68(s,8H),1.52–1.45(m,3H),1.41(s,2H),1.27(d,J＝6.1Hz,3H),1.23–1.12(m,3H),1.03(d,J＝12.5Hz,2H),0.98(s,3H),0.96(s,3H),0.90(d,J＝6.2Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H).
第二步 将(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲氧基-N-甲基己酰胺(135-1)(100mg,0.212mmol)溶解在四氢呋喃(5.0mL)中，氮气置换三次将反应降至0℃逐滴加入甲基氯化镁(0.8mL,2.4mmol)，低温搅拌5分钟后将反应升至室温搅拌6h。TLC监测(PE:EA＝3:1,磷钼酸显色,Rf1＝0.61,Rf2＝0.77)反应完后，将反应液加氯化铵水溶液淬灭，加水和EtOAc洗萃，合并有机相盐水洗一次,干燥浓缩制备分离得到白色固体(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]庚-2-酮(135)(66mg,0.14mmol,65.64％)。1H NMR(399MHz,CDCl3)δ3.22(d,J＝11.4Hz,1H),2.37(t,J＝7.6Hz,2H),2.12(s,3H),2.01(s,4H),1.88(q,J＝10.2,9.1Hz,1H),1.70–1.63(m,5H),1.50–1.41(m,4H),1.37(d,J＝10.3Hz,2H),1.26(d,J＝15.6Hz,4H),1.19–1.11(m,2H),1.07–1.01(m,2H),0.99(s,3H),0.97(s,3H),0.89(d,J＝6.3Hz,3H),0.86(s,3H),0.80(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ209.48,134.31,78.96,77.30,76.98,76.67,50.36,50.19,49.77,44.45,44.28,38.86,36.99,36.29,35.68,35.55,30.93,30.79,29.85,28.16,27.93,27.81,26.47,24.23,20.96,20.65,19.12,18.58,18.22,15.71,15.39.
LC-MS[M-17]+＝411.45
实施例136
化合物136(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-(氧杂环丁-3-基)戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将2-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊基]丙-1,3-二醇(120)(50.00mg,0.11mmol 1eq.)溶解在四氢呋喃(5mL)中，氮气保护，降温至零度，加入正丁基锂(0.067mL 0.11mmol 1eq.)滴加上述体系中，零度搅拌一个小时。TLC(PE:EA＝1:1)，原料反应完毕，低温用饱和氯化铵水溶液淬灭，过柱子，得到4-甲基苯磺酸(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-(羟基甲基)庚基酯(136-1)(30mg，0.049mmol 45.45％)白色固体。1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.9Hz,2H),7.33(d,J＝7.9Hz,2H),4.07(dd,J＝20.6,16.6Hz,2H),3.58(dt,J＝36.8,8.8Hz,2H),3.21(dd,J＝11.4,4.3Hz,1H),2.43(s,3H),2.01(d,J＝9.5Hz,4H),1.83(dd,J＝19.6,10.4Hz,2H),1.66(d,J＝15.3Hz,5H),1.50–1.37(m,2H),1.30–1.23(m,7H),1.21–1.10(m,3H),1.02(d,J＝12.2Hz,1H),0.97(d,J＝8.1Hz,6H),0.82(dd,J＝14.6,7.9Hz,6H),0.79(s,3H),0.65(s,3H)
第二步:将4-甲基苯磺酸(6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-(羟基甲基)庚基酯(136-1)(50.00mg,0.08mmol 1eq.)溶解在四氢呋喃(5mL)中，氮气保护，降温至零度，加入钠氢(3.19mg 0.08mmol1eq.)滴加上述体系中，零度搅拌半个小时，自然升至室温反应一个小时。TLC(PE:EA＝1:1)，原料反应完毕，低温用饱和氯化铵水溶液淬灭，过柱子，得到(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-(氧杂环丁-3-基)戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(136)(26.14mg，0.060mmol 72.61％)白色固体。1H NMR(400MHz,CDCl3)δ4.76(ddd,J＝7.8,5.8,2.0Hz,2H),4.35(t,J＝6.1Hz,2H),3.21(dd,J＝11.6,4.5Hz,1H),3.00–2.88(m,1H),2.08–1.92(m,4H),1.88(dd,J＝13.2,7.6Hz,1H),1.76–1.62(m,6H),1.62–1.49(m,5H),1.43(dd,J＝17.3,8.4Hz,2H),1.38–1.28(m,3H),1.19–1.09(m,2H),1.03(dd,J＝12.6,2.0Hz,1H),0.97(d,J＝8.0Hz,6H),0.85(t,J＝3.1Hz,6H),0.79(s,3H),0.66(s,3H).13CNMR(100MHz,CDCl3)δ134.38,134.31,78.94,77.85,77.29,76.98,76.66,50.36,49.77,44.44,38.86,36.98,36.31,35.97,35.55,35.33,34.20,30.95,30.79,28.17,27.93,27.81,26.47,24.23,23.69,20.96,19.11,18.59,18.22,15.71,15.39,0.99.LC-MS:[M-17]+＝425.55
实施例152
化合物152(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(吡啶-2-基)戊酰胺的制备
参考实施例156，将第一步的胺换为吡啶-2-胺，最终得到化合物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(吡啶-2-基)戊酰胺(152).1HNMR(399MHz,CDCl3)δ8.48(d,J＝3.7Hz,1H),7.73(t,J＝7.0Hz,1H),7.27(s,1H),7.18(m,1H),3.35(s,3H),3.21(d,J＝10.0Hz,1H),2.34(d,J＝11.7Hz,1H),2.16(d,J＝10.5Hz,1H),1.97(m,4H),1.82(m,2H),1.69(d,J＝15.0Hz,2H),1.62(s,3H),1.52(dd,J＝25.3,14.1Hz,3H),1.40(m,2H),1.30(d,J＝11.4Hz,4H),1.15(m,2H),0.97(s,3H),0.94(s,3H),0.81(s,3H),0.78(s,3H),0.74(d,J＝4.9Hz,3H),0.62(s,3H).13CNMR(100MHz,CDCl3)δ173.96,173.13,148.94,138.14,134.30,121.77,120.80,78.92,77.32,77.00,76.68,50.32,50.24,49.74,44.40,38.85,36.96,36.18,35.53,32.04,31.78,30.88,30.77,28.05,27.93,27.79,26.43,24.17,20.93,19.11,18.35,18.20,15.70,15.40.LC-MS:[M+H]+＝507.40
实施例153
化合物153(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(1-甲基苯并[d]咪唑-2-基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 将乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-甲酰基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(33.12mg,0.27mmol)溶于叔丁醇(5.0mL)中，再加入碘(74.54mg,0.29mmol),碳酸钾(93.66mg,0.68mmol)，随后升至70℃搅拌18 小时，TLC监测(PE:EA＝2:1,磷钼酸显色,Rf1＝0.9,Rf2＝0.2)，反应结束后，降至室温后，加入15.0mL亚硫酸钠水溶液，再以乙酸乙酯10mL*3萃取，有机相合并，干燥，浓缩后经制备TLC(PE:EA＝1:1)得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(1-甲基苯并[d]咪唑-2-基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(153-1)(69.4mg,0.12mmol,50.75％)。
第二步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(1-甲基苯并[d]咪唑-2-基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(153-1)(69.4mg,0.12mmol,1.0eq.),加入四氢呋喃(5.0mL),甲醇(5.0mL),1M氢氧化锂水溶液(3.5mL),室温下搅拌过夜，LCMS监测，反应结束后，浓缩除去四氢呋喃和甲醇，随后浓缩液中加入水(10.0mL),再以乙酸乙酯(10.0mL*3)萃取，有机相合并，干燥，浓缩经0.5V甲醇打浆纯化得(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(1-甲基苯并[d]咪唑-2-基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(153)(43mg,0.08mmol,60.78％)。1H NMR(399MHz,CDCl3)δ7.69(d,J＝5.1Hz,1H),7.26(s,1H),7.22(s,2H),3.71(s,3H),3.22(s,1H),2.93(d,J＝11.3Hz,1H),2.75(s,1H),2.01(s,6H),1.70(s,7H),1.65(s,1H),1.56(s,2H),1.52–1.44(m,1H),1.37(d,J＝4.9Hz,2H),1.17(s,2H),1.05(s,3H),0.97(d,J＝6.2Hz,6H),0.86(s,3H),0.79(s,3H),0.70(s,3H).13C NMR(100MHz,CDCl3)δ155.83,142.49,135.75,134.40,134.25,121.87,121.70,119.08,108.76,78.92,77.32,77.20,77.00,76.68,50.33,50.11,49.80,44.52,38.86,36.99,36.64,35.54,34.13,30.95,30.79,29.71,28.25,27.94,27.80,26.45,24.71,24.21,20.97,19.13,18.63,18.21,15.76,15.41.LC-MS:[M+H]+＝503.50
实施例154
化合物154(5R)-N-(2-氟苯基)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基己酰胺的制备
参照实施例37，将第四步的胺换为邻氟苯胺，最终得到化合物(5R)-N-(2-氟苯基)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基己酰胺(154)。1H NMR(399MHz,CDCl3)δ7.32(s,1H),7.19(t,J＝7.6Hz,3H),3.21(s,4H),2.02–1.95(m,7H),1.87–1.77(m,1H),1.70(d,J＝16.1Hz,4H),1.55(d,J＝11.7Hz,3H),1.41(d,J＝9.2Hz,3H),1.22(d,J＝13.0Hz,5H),1.13(d,J＝11.7Hz,1H),1.02(d,J＝11.0Hz,1H),0.98(s,3H),0.95(s,3H),0.82(d,J＝4.2Hz,6H),0.79(s,3H),0.62(s,3H).13C NMR(101MHz,CDCl3)δ 232.04,145.15,145.12,134.31,129.70,129.59,124.97,116.80,78.95,77.31,77.19,76.99,76.67,50.35,50.07,49.74,44.39,38.86,36.98,36.17,35.74,35.54,30.89,30.78,28.04,27.93,27.82,26.46,24.22,21.94,20.95,19.11,18.56,18.22,15.67,15.40.LC-MS:[M+H]+＝538.45
实施例155
化合物155(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(吡啶-4-基)戊酰胺的制备
第一步 称取(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VII)(300mg,0.65mmol,1.0eq.)和N,N’-二甲基甲酰胺(0.007mL,0.087mmol)溶于二氯甲烷(10mL)中，冰浴降温后，滴加入草酰氯(0.27mL,3.27mmol)，随后反应体系升至室温搅拌，TLC(PE:EA＝3：1)监测,完全生成酰氯后，将反应液浓缩，随后再以二氯甲烷(10mL)溶解，将得到的溶液加入到三乙胺(0.27mL,1.96mmol)和吡啶-4-胺(73.87mg,0.78mmol)的10mL二氯甲烷溶液中，接着反应液继续在室温下搅拌，TLC(DCM:MeOH＝20：1)监测，反应结束后，加入水(10.0mL),再以乙酸乙酯(15.0mL*3)萃取，有机相合并，干燥，浓缩粗品经制备层析硅胶板(DCM:EA＝50：1)得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-氧亚基-5-(吡啶-4-基氨基)戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(155-1)(220mg,0.39mmol,59.76％)白色固体。1H NMR(399MHz,CDCl3)δ8.46(s,2H),7.74(s,1H),7.56(s,2H),4.48(d,J＝7.5Hz,1H),2.48(s,1H),2.31(s,1H),2.04(s,3H),2.01(s,3H),1.96–1.90(m,2H),1.69(s,2H),1.67(s,3H),1.58(s,2H),1.48(s,2H),1.36(s,3H),1.30–1.21(m,2H),1.19–1.10(m,2H),0.98(s,3H),0.93(s,3H),0.86(s,9H),0.67(s,3H).
第二步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-5-氧亚基-5-(吡啶-4-基 氨基)戊-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(180mg,0.34mmol)溶于N,N’-二甲基甲酰胺(6mL)中，氮气置换三次后，冰浴降至0℃，接着加入氢化钠(21.75mg,0.544mmol),继续在0℃下搅拌30分钟，随后将碘甲烷(50.16mg,0.35mmol)溶于N,N’-二甲基甲酰胺(1mL)后加至上述反应体系中，加完后升至50℃搅拌1小时，TLC(DCM:MeOH＝20:1)检测，反应结束，随后冷却至室温，加入10mL水稀释后，再加入乙酸乙酯10mL*3萃取，干燥，浓缩后粗品经制备TLC(DCM:EA＝20:1)纯化后得(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(吡啶-4-基)戊酰胺(155)(24mg,0.045mmol,13.37％)白色固体。1H NMR(399MHz,CDCl3)δ8.64(d,J＝5.7Hz,2H),7.17(d,J＝5.6Hz,2H),3.29(s,3H),3.21(d,J＝7.4Hz,1H),2.30(s,1H),2.15(s,1H),1.99(s,4H),1.80(s,3H),1.67(s,3H),1.57(s,2H),1.54–1.46(m,2H),1.37(s,2H),1.26(d,J＝18.1Hz,3H),1.21–1.11(m,2H),1.02(d,J＝11.1Hz,1H),0.98(s,3H),0.95(s,3H),0.82(s,3H),0.78(s,3H),0.75(d,J＝5.7Hz,3H),0.63(s,3H).13C NMR(101MHz,CDCl3)δ173.22,151.04,145.12,145.09,145.08,145.07,145.05,134.25,121.17,78.94,77.31,76.99,76.67,50.33,50.27,49.76,44.45,38.86,36.97,36.81,36.15,35.53,31.85,31.66,30.89,30.75,28.09,27.93,27.80,26.44,24.17,20.93,19.12,18.34,18.20,15.71,15.40.LC-MS:[M+H]+＝507.50
实施例156
化合物156(3R)-N-(2-氟苯基)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基丁酰胺的合成

第一步 称取(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁酸(IX)(150mg,0.34mmol,1.0eq.)溶于二氯甲烷(5.0mL)中,氮气置换，冰浴降温冷却，滴加草酰氯(171.26mg,1.35mmol)的二氯甲烷溶液(3.0mL),搅拌半小时后，TLC(PE:EtOAc＝5:1)检测，反应完全后，浓缩除去二氯甲烷，随后加入二氯甲烷(4.0mL)稀释，在冰浴降温下滴加至邻氟苯胺(37.4mg,0.34mmol)和二异丙基乙基胺(130.79mg,1.01mmol)的二氯甲烷(5.0mL)中，滴加完毕后，渐升至室温，搅拌2小时后，TLC监测(PE:EtOAc＝1：1)，反应结束后，加入水10mL淬灭，随后以乙酸乙酯8mL*3萃取，有机相合并干燥，浓缩经柱层析(PE:EA＝30:1～5：1)纯化得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-氟苯基)氨基]-4-氧亚基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(156-1)(60mg,0.1mmol,68.7％)。
1HNMR(399MHz,CDCl3)δ8.33(t,J＝7.9Hz,1H),7.29(s,1H),7.13–7.00(m,3H),6.08–6.07(m,0H),4.48(dd,J＝11.7,4.5Hz,1H),2.59(d,J＝13.8Hz,1H),2.02(d,J＝14.8Hz,13H),1.67(s,8H),1.41(dd,J＝21.8,13.0Hz,2H),1.19(dt,J＝24.1,16.5Hz,5H),1.03(d,J＝6.2Hz,3H),0.99(s,3H),0.87(s,12H),0.74(s,3H).
第二步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-氟苯基)氨基]-4-氧亚基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(156-1)(100mg,0.18mmol，1.0eq.)溶于N,N’-二甲基甲酰胺(3.0mL)中,氮气置换，冰浴降温至0℃，加入氢化钠(32mg,0.06mmol),随后升至室温，搅拌30分钟，接着加入碘甲烷(26.2mg,0.18mmol),接着继续在室温下搅拌2小时，TLC监测(PE:EtOAc＝2：1)，反应结束后，加入饱和氯化铵水溶液10mL稀释，接着以乙酸乙酯10mL*3萃取，有机相合并干燥，浓缩得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-氟苯基)(甲基)氨基]-4-氧亚基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(50.0mg,0.08mmol,43.86％)白色固体粗品。
第三步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-氟苯基)(甲基)氨基]-4-氧亚基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(50mg,0.09mmol,1.0eq.)溶于四氢呋喃(2.0mL)中,加入甲醇(2.0mL),室温下加入氢氧化锂(2.0mL,2.0mmol),室温搅拌16小时，TLC监测(PE:EA＝1：1)，反应结束后，加入水5mL淬灭，随后以乙酸乙酯5mL*3萃取，有机相合并干燥，浓缩经柱层析(PE:EA＝50:1～5：1)纯化得(3R)-N-(2-氟苯基)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基丁酰胺156(10mg,0.019mmol,20.57％)。1H NMR(399MHz,CDCl3)δ7.32(d,J＝7.1Hz,1H),7.22–7.12(m,3H),3.21(s,4H),2.17(d,J＝11.4Hz,2H),1.96(d,J＝3.4Hz,5H),1.72–1.59(m,6H),1.54–1.43(m,3H),1.29–1.14(m,3H),1.08–0.99(m,2H),0.95(d,J＝9.4Hz,6H),0.87(d,J＝5.2Hz,3H),0.77(d,J＝6.9Hz,6H),0.64(s,3H).13C NMR(100MHz,CDCl3)δ173.22,134.35,134.17,129.86,125.01,116.84,78.93,77.31,76.99,76.67,50.34,49.77,44.53,40.99,40.56,38.84,36.95,36.53,35.52,34.49,34.39,30.75,27.92,27.79,26.40,24.15,20.91,19.46,19.33,19.09,18.18,15.72,15.38,1.00.LC-MS[M+H]+＝500.40
实施例157
化合物157 2-氟-N-(2-羟基乙基)-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]苯甲酰胺的制备
第一步 将乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(III)(150mg,0.35mmol,1.0eq.)溶于甲醇(10.0mL)中，加入3A分子筛(300mg,0.35mmol)，搅拌15分钟，加入醋酸(42.5mg,0.7mmol)和2-{[二甲基(2-甲基丙-2-基)甲硅基]氧基}乙-1-胺(75mg,0.420mmol)，搅拌5分钟，加入氰基硼氢化钠(66.62mg,1.05mmol)，室温搅拌3小时，TLC监测(PE:EA＝10:1,磷钼酸显色)，反应结束后，加入饱和碳酸氢钠水溶液(15mL),以乙酸乙酯(10mL*3)萃取，有机相分离干燥，浓缩，柱层析(PE:EA＝100：1～20：1)得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(10R)-2,2,3,3-四甲基-7-氮杂-4-氧杂-3-硅杂十一烷-10-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(157-1)(100mg，0.12mmol，34.9％)白色固体。1HNMR(399MHz,CDCl3)δ4.47(d,J＝7.5Hz,1H),3.91(s,2H),3.12(s,3H),3.02(s,1H),2.03(s,9H),1.76–1.56(m,7H),1.52(d,J＝23.7Hz,4H),1.35–1.10(m,5H),0.96(d,J＝17.5Hz,6H),0.87(d,J＝11.7Hz,18H),0.68(s,3H).
第二步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(10R)-2,2,3,3-四甲基-7-氮杂-4-氧杂-3-硅杂十一烷-10-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(157-1)(100mg,0.17mmol,1.0eq.)溶于二氯甲烷(5.0mL)中,加入三乙胺(0.047mL，0.34mmol),冰浴降温至0℃，加入邻氟苯甲酰氯(41mg,0.20mmol)后，自然升至室温搅拌2小时，TLC监测(PE:EtOAc＝1：1)，反应结束后，加入水15mL稀释，随后以乙酸乙酯10mL*3萃取，有机相合并干燥，浓缩经薄层层析制备板(PE:EtOAc＝1:1)纯化得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(10R)-7-[(2-氟苯基)羰基]-2,2,3,3-四甲基-7-氮杂-4-氧杂-3-硅杂十一烷-10-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(157-2)(80mg,0.08mmol,46.37％)。LC-MS:[M+H]+＝710.50
第三步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(10R)-7-[(2-氟苯基)羰基]-2,2,3,3-四甲基-7-氮杂-4-氧杂-3-硅杂十一烷-10-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(157-2)(20mg,0.03mmol，1.0eq.)溶于四氢呋喃(2.0mL)中,加入甲醇(2.0mL),加入1.0M氢氧化锂水溶液(2.0mL,2.0mmol),室温搅拌16小时，TLC监测(PE:EA＝1：1)，反应结束后，加入水5mL稀释，接着以乙酸乙酯5mL*3萃取，有机相合并干燥，浓缩经柱层析(PE:EA＝100：1～5：1)纯化得2-氟-N-(2-羟基乙基)-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]苯甲酰胺(157)(10.0mg,0.02mmol,48.68％)。1HNMR(399MHz,CDCl3)δ7.35(d,J＝17.0Hz,2H),7.19(t,J＝7.3Hz,1H),7.09(d,J＝8.6Hz,1H),3.89(s,2H),3.73–3.62(m,2H),3.27(s,1H),3.18(s,1H),3.15(s,1H),1.97(d,J＝17.5Hz,5H),1.65(d,J＝12.2Hz,4H),1.51(s,4H),1.37–1.30(m,2H),1.24(s,3H),1.15–1.05(m,2H),1.02(s,1H),0.97(s,3H),0.94(s,3H),0.78(s,6H),0.62–0.54(m,6H).13CNMR(101MHz,CDCl3)δ168.67,134.42,134.10,131.17,131.10,128.56,124.53,115.96,115.75,78.91,77.31,76.99,76.68,62.27,50.32,49.82,49.75,49.35,48.39,44.40,38.85,36.97,35.51,35.01,34.19,30.94,30.80,30.68,27.93,27.78,26.42,24.12,20.88,19.11,18.49,18.18,15.68,15.57,15.40.LC-MS:[M+H]+＝554.35
实施例158
化合物158(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(噻吩-2-基)戊酰胺的制备
(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VIII)(100mg,0.24mmol,1.0eq)溶在DMF(5mL)中，氮气保护下，依次加入HATU(2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)(110mg,0.29mmol,1.2eq)和DIPEA(N,N-二异丙基乙胺)(0.12mL,0.72mmol,3.0eq)，室温搅拌30分钟后，加入甲基(噻吩-2-基)胺(27mg,0.24mmol,-1.0eq)，室温搅拌3小时，TLC(PE:EtOAc＝3:1)监测反应。原料酸反应完毕，反应液乙酸乙酯稀释，饱和盐水洗涤3次，无水硫酸干燥，硅胶柱层析纯化(PE:EtOAc＝90:10)得到棕色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(噻吩-2-基)戊酰胺(158)(6mg,0.01mmol,4.4％)。1H NMR(400MHz,CDCl3)δ7.20(d,J＝5.4Hz,1H),6.93(dd,J＝5.4,3.7Hz,1H),6.82(d,J＝2.7Hz,1H),3.26(s,3H),3.24–3.21(m,1H),2.35–2.27(m,1H),2.18–2.11(m,1H),2.02(dd,J＝11.4,7.6Hz,6H),1.93–1.87(m,1H),1.68(d,J＝10.5Hz,15H),1.60–1.54(m,1H),1.43–1.31(m,3H),1.18(dd,J＝15.6,10.5Hz,4H),1.00(s,8H),0.97(s,1H),0.89(s,4H),0.80(s,7H),0.75(d,J＝5.7Hz,3H),0.64(s,3H).13CNMR(101MHz,CDCl3)δ174.88,146.97,134.37,125.83,124.50,124.37,78.99,77.34,77.23,77.03,76.71,50.39,50.32,49.80,44.47,38.89,37.02,36.22,35.58,31.04,30.94,30.82,28.10,27.97,27.84,26.48,24.20,20.98,19.15,18.32,18.25,15.75,15.42.LC-MS:[M+H]+＝512.3
实施例159
化合物159(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基- 2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(羟基甲基)戊酰胺的制备
第一步 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VII)(100mg,0.22mmol，1.0eq)溶于二氯甲烷(5mL)中，加入氯化亚砜(5滴)，室温搅拌30分钟，随后体系浓缩干，再次用二氯甲烷(5mL)溶解，加入2-氟苯胺(29mg,0.26mmol，1.2eq)，室温搅拌过夜，TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应，反应结束后，将10mL的水加入到反应体系中，水层用二氯甲烷(25mL×3)萃取。合并有机相并且用水(3×10mL)洗涤。有机相用Na2SO4干燥，过滤，浓缩得到粗品。通过柱层析(PE：EtOAc＝94：6)纯化,浓缩得到乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-氟苯基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(159-1)(78mg,0.15mmol,66.7％).1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.15–6.99(m,3H),4.50(dd,J＝11.6,4.5Hz,1H),2.56–2.25(m,2H),2.05(s,3H),2.04–1.89(m,5H),1.79–1.61(m,6H),1.60–1.37(m,8H),1.25–1.13(m,2H),1.00(s,3H),0.96(d,J＝4.9Hz,3H),0.88(s,9H),0.70(s,3H).
第二步 乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-氟苯基)氨基]-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(159-1)(250mg,0.45mmol,1.0eq)溶在四氢呋喃(5mL)中，氮气保护下，降温到0℃，分批加入NaH(32.6mg,1.36mmol,3.0eq)，保温搅拌30分钟，随后加入SEM-Cl(2-(三甲基硅烷基)乙氧甲基氯)(378mg,2.27mmol,5.0eq)，反应转至室温搅拌2小时，TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应，反应结束后，反应液用氯化铵淬灭，乙酸乙酯萃取，无水硫酸钠干燥，有机相浓缩干后硅胶柱层析纯化(PE:EtOAc＝80:20)得到 白色固体乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(11R)-7-(2-氟苯基)-2,2-二甲基-8-氧亚基-7-氮杂-5-氧杂-2-硅杂十二烷-11-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(159-2)(200mg,0.25mmol,55％)。1H NMR(400MHz,CDCl3)δ7.36(dd,J＝13.0,5.9Hz,1H),7.29–7.26(m,1H),7.21(dd,J＝16.1,8.9Hz,2H),5.25(d,J＝2.7Hz,1H),4.89(dd,J＝10.2,4.9Hz,1H),4.48(s,1H),3.69–3.63(m,2H),2.05–1.92(m,8H),1.88–1.75(m,2H),1.73–1.61(m,5H),1.57–1.45(m,2H),1.40–1.09(m,8H),1.01–0.90(m,6H),0.86(d,J＝6.7Hz,7H),0.81(d,J＝2.2Hz,3H),0.69(d,J＝5.3Hz,3H),0.62(s,3H).
第三步 乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(11R)-7-(2-氟苯基)-2,2-二甲基-8-氧亚基-7-氮杂-5-氧杂-2-硅杂十二烷-11-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(159-2)(140mg,0.21mmol,1.0eq)溶在四氢呋喃(3mL)和甲醇(3mL)的混合溶剂中，随后加入氢氧化锂水溶液(0.5mL,0.50mmol)，室温搅拌，TLC(PE:EtOAc＝5:1,磷钼酸烤板)监测反应，反应结束后，反应液用乙酸乙酯稀释，饱和盐水洗涤，有机相用无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝80:20)纯化得到白色固体(4R)-N-(5,5-二甲基-2-氧杂-5-硅杂己-1-基)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(159-3)(100mg,0.13mmol,60.9％)。1H NMR(400MHz,CDCl3)δ7.36(d,J＝6.5Hz,1H),7.26–7.24(m,1H),7.23–7.15(m,2H),5.26(d,J＝7.9Hz,1H),4.89(dd,J＝10.1,5.0Hz,1H),3.70–3.62(m,2H),3.23(dd,J＝11.3,4.2Hz,1H),2.20–2.06(m,1H),2.06–1.92(m,5H),1.62(dd,J＝38.9,13.4Hz,9H),1.23(d,J＝15.6Hz,7H),1.07–0.88(m,10H),0.81(d,J＝5.7Hz,6H),0.75–0.59(m,6H),0.01(d,J＝10.1Hz,9H).
第四步 (4R)-N-(5,5-二甲基-2-氧杂-5-硅杂己-1-基)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酰胺(80mg,0.13mmol,1.0eq)溶在二氯甲烷(2mL)中，氮气保护下，降温到0℃，加入TFA(71.26mg,0.63mmol,5.0eq)，反应转至室温搅拌5小时，TLC(PE:EtOAc＝3:1,磷钼酸烤板)监测反应，反应结束后，反应液用二氯甲烷稀释，饱和盐水洗涤，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝80:20)得到白色固体(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(羟基甲基)戊酰胺(159)(13mg,0.02mmol,16.7％)。1H NMR(400MHz,CDCl3)δ7.43–7.28(m,2H),7.24-7.16(m,2H),5.34–5.24(m,1H),4.78-4.70(m,1H),3.23(dd,J＝11.4,4.5Hz,1H),2.12(d,J＝14.7Hz,2H),2.03–1.94(m,5H),1.83–1.43(m,11H),1.34–1.19(m,5H),1.13(d,J＝11.8Hz,1H),1.01–0.95(m,6H),0.86–0.78(m,6H),0.70(d,J＝5.6Hz,3H),0.60(d,J＝19.4Hz,3H).LC-MS:[M+1]+＝540.4
实施例161
化合物161(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-苯基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(100mg,0.22mmol，1.0eq)溶解在无水四氢呋喃(5mL)中，氮气保护下，冰水浴下加入苯基锂(0.58mL,1.10mmol,1.9mol/L,5eq)，随后转至室温反应3hrs，TLC(PE:EtOAc＝10:1，磷钼酸烤板),监测反应进展，反应结束后，体系用饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相用饱和盐水洗涤，无水硫酸钠干燥，硅胶柱层析纯化(PE:EtOAc＝80:20)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-苯基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇161(12mg,0.023mmol,10.6％)。1H NMR(400MHz,CDCl3)δ7.37-7.33(m,4H),7.30–7.27(m,1H),4.67(d,J＝7.2Hz,1H),3.23(dd,J＝11.6,4.4Hz,1H),2.07–1.86(m,5H),1.71(ddd,J＝19.8,11.4,4.6Hz,7H),1.52–1.25(m,12H),1.21–1.12(m,1H),1.05(d,J＝10.9Hz,2H),1.00(s,3H),0.98(s,3H),0.87(d,J＝6.7Hz,7H),0.81(s,3H),0.67(d,J＝3.3Hz,3H).13CNMR(101MHz,CDCl3)δ134.41,128.46,127.53,127.49,125.94,125.85,77.34,77.22,77.02,76.70,50.50,50.47,50.41,49.81,44.48,39.57,38.90,37.02,36.40,36.35,36.12,36.00,35.59,30.98,30.84,28.24,27.97,27.86,27.76,26.50,24.26,22.67,20.96,19.15,18.68,18.62,15.75,15.42,12.64.LC-MS[M-17]+＝475.4
实施例162
化合物162(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基-2-甲基丙基)丙酰胺的制备
参照实施例8，将第四步的胺换为1-氨基-2-甲基丙-2-醇，最终得到化合物(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基-2-甲基丙基)丙酰胺(162).1HNMR(399MHz,CDCl3)δ5.84(s,1H),3.34–3.13(m,3H),2.59(s,1H),2.14(d,J＝8.4Hz,1H),2.01(s,5H),1.88(dd,J＝21.9,12.5Hz,2H),1.68(s,7H),1.58–1.46(m,2H),1.33(s,2H),1.20(s,6H),1.17(d,J＝6.7Hz,3H),1.03(d,J＝12.3Hz,1H),0.97(d,J＝7.7Hz,6H),0.89(s,3H),0.79(s,3H),0.69(s,3H).13CNMR(100MHz,CDCl3)δ178.09,134.39,134.16,78.87,77.32,77.00,76.68,71.08,50.27,49.63,47.42,45.62,44.50,38.85,36.99,35.49,30.93,30.85,27.93,27.76,27.57,27.37,26.45,24.25,20.89,19.14,18.18,17.83,16.12,15.43,1.02.LC-MS:[M+1]+＝460.55。
实施例163和164
化合物163或164
(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,6S)-6-羟基-6-苯基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇或
(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,6R)-6-羟基-6-苯基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
其中，化合物163和化合物164均为单一构型的异构体，分别为以下异构体中的一个：
参照实施例161，得到化合物161后经过手性拆分(柱子类型:Daicel(大赛璐)CHIRALCEL IG,250mm/30mm I.D.，10μm.流动相：CO2/MeOH[0.2％NH3(浓度：7M甲醇溶液)]＝65/35.流速:2.0g/min.波长:UV 214nm.温度:35℃)得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,6S)-6-羟基-6-苯基己-2- 基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(164，保留时间:11.65min)和(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,6R)-6-羟基-6-苯基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(163，保留时间:13.67min)
化合物163:1H NMR(400MHz,CDCl3)δ7.38-7.31(m,4H),7.30-7.25(m,1H),4.68(dd,J＝7.8,5.4Hz,1H),3.23(dd,J＝11.5,4.5Hz,1H),2.06-1.96(m,4H),1.93–1.77(m,2H),1.76–1.69(m,3H),1.58(ddd,J＝16.5,12.8,3.2Hz,5H),1.50–1.31(m,6H),1.28–1.13(m,3H),1.05(dd,J＝12.8,1.9Hz,2H),0.99(d,J＝8.6Hz,6H),0.87(d,J＝6.7Hz,6H),0.81(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ145.03,134.39,128.45,127.49,125.86,50.47,50.41,49.81,44.48,39.57,38.90,37.02,36.35,36.01,35.59,30.98,30.84,28.24,27.97,27.86,26.50,24.26,22.67,21.00,19.15,18.66,18.26,15.76,15.43.LCMS(ESI)[M+H]+＝475.4.
化合物164:1H NMR(400MHz,CDCl3)δ7.38-7.32(m,4H),7.31–7.27(m,1H),4.66(t,J＝6.7Hz,1H),3.23(dd,J＝11.5,4.5Hz,1H),2.02(dd,J＝15.0,5.9Hz,4H),1.94–1.85(m,1H),1.76–1.59(m,10H),1.54–1.42(m,4H),1.38–1.29(m,2H),1.21–1.11(m,2H),1.07–1.02(m,2H),0.99(d,J＝9.3Hz,6H),0.86(d,J＝5.7Hz,6H),0.81(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ144.93,134.41,128.46,127.53,125.94,50.50,50.41,49.81,44.48,39.58,38.90,37.02,36.40,36.12,35.59,30.98,30.83,28.24,27.97,27.86,26.50,24.27,22.77,21.00,19.15,18.62,18.26,15.75,15.42.LCMS(ESI)[M+H]+＝475.4。
实施例165
化合物165(4R)-N-(2-氯苯基)-4-[(3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基戊酰胺的合成
参照实施例63，第一步将1,3,4-硫杂二氮杂环戊熳-2-胺换为(2-氯苯基)(甲基)胺，得到最终产物(4R)-N-(2-氯苯基)-4-[(3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基戊酰胺(165)。1H NMR(400MHz,CDCl3)δ7.53–7.49(m,1H),7.35–7.31(m,2H),7.28(s,1H),3.26–3.21(m,1H),3.20(s,3H),2.06–1.94(m,5H),1.91–1.81(m,2H),1.74–1.63(m,6H),1.61–1.48(m,4H),1.37–1.21(m,6H),1.17–1.10(m,1H),0.98(d,J＝14.2Hz,6H),0.81(d,J＝5.7Hz,6H),0.68(t,J＝5.3Hz,3H),0.62(s,3H).13C NMR(101MHz,CDCl3)δ173.70,141.50,134.38,133.18,133.11,130.69,129.92,129.41,128.17,78.98,50.41,50.34,50.21,49.78,44.45, 38.89,37.02,36.04,35.78,35.59,31.75,31.65,31.11,30.93,30.79,27.96,27.85,26.48,24.16,20.96,19.12,18.25,15.73,15.39.LCMS[M+H]+＝540.4
实施例166
化合物166(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-丙基戊酰胺的制备
参照实施例59，将第二步的溴乙烷换成溴丙烷，最终得到化合物(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-丙基戊酰胺(166).1H NMR(399MHz,CDCl3)δ7.33(s,1H),7.18(d,J＝5.3Hz,3H),3.60(dd,J＝21.0,12.8Hz,2H),3.19(s,1H),1.97(d,J＝24.5Hz,6H),1.74(s,2H),1.66(m,4H),1.55(d,J＝13.2Hz,3H),1.49(s,3H),1.30(s,4H),1.15(d,J＝32.7Hz,4H),0.97(s,3H),0.93(s,3H),0.86(t,J＝7.4Hz,3H),0.78(d,J＝5.4Hz,6H),0.65(d,J＝5.0Hz,3H),0.59(s,3H).13C NMR(100MHz,CDCl3)δ173.53,134.30,134.26,130.58,130.50,129.65,129.58,124.85,116.91,116.70,78.93,77.32,77.00,76.68,50.31,50.22,50.18,49.72,44.37,38.85,36.95,36.06,36.02,35.52,31.73,31.66,31.23,31.05,30.85,30.75,27.96,27.93,27.79,26.42,24.14,20.96,20.92,19.10,18.20,15.66,15.40,11.21.LC-MS:[M+H]+＝552.40
实施例167
化合物167 N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-N-甲基-1,3-硫杂氮杂环戊熳-2-甲酰胺的制备
第一步 称取1,3-硫杂氮杂环戊熳-2-甲酸(54-1)(20.09mg,0.225mmol)溶于干燥的N,N’-二甲基甲酰胺(5.0mL)中,室温下加入HATU(2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)(102.83mg,0.27mmol),加入二异丙基乙基胺(0.056mL,0.338mmol),搅拌半小时后，加入乙酸(3aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(甲基氨基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(80mg,0.186mmol,1.0eq.)，室温搅拌2小时，TLC(石油醚：乙酸乙酯＝3:1)监测。反应结束后，加入水(10.0mL),再以二氯甲烷(7.0mL*3)萃取，有机相合并，干燥，浓缩经柱层析(石油醚：乙酸乙酯＝50:1～5：1)纯化得乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-[甲基(1,3-硫杂氮杂环戊熳-2-基羰基)氨基]丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(167-1)(60mg,0.096mmol,51.6％)。1H NMR(399MHz,CDCl3)δ7.85(d,J＝7.3Hz,1H),7.49(s,1H),4.47(d,J＝8.0Hz,1H),4.04(d,J＝8.1Hz,1H),3.72(s,1H),3.53(s,2H),3.10(s,1H),2.01(d,J＝11.8Hz,8H),1.83–1.63(m,6H),1.49(s,3H),1.39(d,J＝11.4Hz,2H),1.27(d,J＝11.8Hz,3H),1.14(t,J＝12.7Hz,2H),1.00(s,1H),0.98(s,3H),0.92–0.79(m,12H),0.66(d,J＝8.6Hz,3H).LC-MS[M+H]+＝555.50
第二步 称取乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-[甲基(1,3-硫杂氮杂环戊熳-2-基羰基)氨基]丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(167-1)(20mg,0.036mmol)溶于四氢呋喃(2.0mL)和甲醇(2.0mL)的混合溶剂中，室温搅拌下加入1M氢氧化锂水溶液(2.0mL),随后室温下搅拌，TLC监测(石油醚：乙酸乙酯＝1:1)，反应结束后，浓缩除去反应溶剂，随后加入5.0mL水，再以乙酸乙酯(5.0mL*3)萃取，有机相合并，干燥，浓缩经制备柱层析(石油醚：乙酸乙酯＝50:1～5:1)纯化得N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a, 6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-N-甲基-1,3-硫杂氮杂环戊熳-2-甲酰胺(167)(10.0mg,0.018mmol,48.68％)白色固体。1H NMR(399MHz,CDCl3)δ7.89–7.82(m,1H),7.49(s,1H),4.03(s,1H),3.53(s,2H),3.20(s,1H),3.10(s,2H),2.00(s,2H),1.94–1.84(m,5H),1.67(d,J＝15.9Hz,1H),1.50(d,J＝9.2Hz,4H),1.38(s,3H),1.31–1.14(m,2H),1.00(dd,J＝21.0,12.5Hz,5H),0.89(d,J＝5.5Hz,9H),0.85(d,J＝4.2Hz,3H),0.79(s,3H),0.67(d,J＝8.6Hz,3H).
13C NMR(100MHz,CDCl3)δ160.82,160.35,143.09,134.39,123.61,78.93,77.31,76.99,76.67,50.33,49.79,38.86,36.98,35.53,30.78,28.17,27.93,27.80,26.45,20.94,19.12,18.20,15.64,15.40,1.01.LC-MS:[M+H]+＝513.50
实施例168
化合物168(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1,3-硫杂氮杂环戊熳-4-基)戊酰胺的制备
参考实施例56，将第一步1-甲基-5-氨基吡唑换为1,3-硫杂氮杂环戊熳-4-胺，得到最终产物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1,3-硫杂氮杂环戊熳-4-基)戊酰胺(168).1H NMR(399MHz,CDCl3+10％CD3OD)δ8.74(s,1H),7.07(s,1H),3.45–3.17(m,4H),2.28(s,1H),1.99(s,5H),1.71–1.54(m,8H),1.39–1.12(m,8H),1.14(d,J＝11.1Hz,1H)0.96(d,J＝11.1Hz,6H),0.80(d,J＝16.9Hz,9H),0.63(s,3H).13C NMR(100MHz,CDCl3+10％CD3OD)δ175.28,153.16,139.62,139.42,134.47,134.14,125.59,78.03,77.70,77.38,50.44,49.99,49.60,48.50,48.28,48.07,47.86,47.64,47.43,47.22,44.26,38.59,36.80,35.98,35.54,31.68,30.79,30.51,27.72,27.35,27.07,26.26,23.48,20.69,18.46,18.04,17.65,15.11,14.91.LC-MS:[M+H]+＝513.40
实施例169
化合物169 2-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基](甲基)氨基}苯甲酸 的制备
第一步 称取(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸VIII(50mg,0.12mmol)溶于N,N’-二甲基甲酰胺(3mL)中，室温下加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(54.61mg,0.144mmol),1-羟基苯并三唑(9.73mg,0.072mmol),随后继续在室温下搅拌3小时，TLC(石油醚：乙酸乙酯＝3：1)监测。反应结束，随后冷却至室温，加入10mL水稀释后，再加入乙酸乙酯(10mL*3)萃取，干燥，浓缩后得(4R)-1-(苯并[d][1,2,3]三氮杂环戊熳-1-基氧基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮(169-1)(45mg,0.049mmol,65.56％)白色固体粗品，未纯化直接投至下一步中。
第二步 称取(4R)-1-(苯并[d][1,2,3]三氮杂环戊熳-1-基氧基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊-1-酮(169-1)(60mg,0.11mmol)和2-甲氨基苯甲酸(17mg,0.11mmol)溶于N,N’-二甲基甲酰胺(5mL)中，室温搅拌下加入二异丙基乙基胺(0.03mL，0.17mmol),随后继续在室温下搅拌，TLC(乙酸乙酯)监测。反应结束后，加入10mL水稀释后，再加入乙酸乙酯(10mL*3)萃取，干燥，浓缩后粗品经制备HPLC纯化后得2-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基](甲基)氨基}苯甲酸(169)(5.52mg,0.01mmol,8.85％)白色固体。
1H NMR(399MHz,CDCl3)δ7.98(s,1H),7.50(s,1H),7.38(s,1H),7.18(s,1H),3.33(s,1H),3.12(s,3H),1.94(s,6H),1.57(s,5H),1.52(s,3H),1.19(s,3H),1.13(s,6H),0.91(s,3H),0.88(s,3H),0.72(s,6H),0.57(s,3H),0.53(s,3H).13C NMR(101MHz,CDCl3)δ134.29,134.29,78.77,77.36,77.36,77.05,77.05,76.73,76.73,49.91,49.70,49.70,49.49,49.27,49.27,49.06,48.85,48.85,48.63,38.76,38.76,36.88,35.49,27.81, 27.81,27.44,24.03,20.85,19.03,19.03,18.15,15.34,15.34.LC-MS:[M+H]+＝548.55
实施例170
化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(吡啶-2-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的合成
参考实施例161，将胺溴苯换为2-溴吡啶得到最终产物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(吡啶-2-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(170)(34.7mg,0.061mmol,27.92％)。1H NMR(400MHz,CDCl3)δ8.57(d,J＝4.8Hz,1H),7.80(s,1H),7.36(d,J＝7.9Hz,1H),7.31(s,1H),4.82(s,1H),3.23(d,J＝12.1Hz,1H),2.02(s,3H),1.90–1.83(m,1H),1.77–1.64(m,7H),1.60–1.44(m,6H),1.23(ddd,J＝28.0,18.3,8.0Hz,6H),1.05(d,J＝10.8Hz,2H),0.99(d,J＝9.1Hz,6H),0.88(d,J＝7.8Hz,6H),0.81(s,3H),0.66(s,3H).13C NMR(101MHz,CDCl3)δ147.22,144.45,140.09,137.69,134.41,78.99,77.33,77.21,77.01,76.69,50.43,49.80,44.47,39.06,38.89,37.02,36.45,36.36,36.20,35.58,30.97,30.83,30.78,28.22,27.96,27.86,26.49,24.26,20.99,19.14,18.63,18.25,15.75,15.41.LCMS[M+H]+＝494.4.
实施例171
化合物171(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1-甲基吲唑-6-基)戊酰胺的合成
参考实施例56，将1-甲基-5-氨基吡唑换为1-甲基吲唑-6-胺得到最终产物(4R)-4- [(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1-甲基吲唑-6-基)戊酰胺(171)(71.mg,纯度98.3％，收率89％)。1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.76(d,J＝8.4Hz,1H),7.22(s,1H),6.97(dd,J＝8.4,1.3Hz,1H),4.08(s,3H),3.33(s,3H),3.22(dd,J＝11.4,4.4Hz,1H),2.18(s,1H),1.98(d,J＝22.6Hz,5H),1.82(d,J＝11.2Hz,2H),1.72–1.63(m,4H),1.59–1.45(m,4H),1.35–1.17(m,5H),1.14–1.06(m,1H),1.02(d,J＝12.9Hz,1H),0.99(s,3H),0.95(s,3H),0.79(d,J＝8.4Hz,6H),0.68(s,3H),0.60(s,3H).13C NMR(101MHz,CDCl3)δ173.86,142.81,140.13,134.41,134.32,132.90,122.39,120.46,107.58,78.95,50.40,50.23,49.78,44.43,38.88,37.01,36.16,35.66,35.58,32.14,31.40,30.92,30.76,28.08,27.95,27.84,26.47,24.11,20.93,19.12,18.33,18.23,15.70,15.39.LCMS:[M+H]+＝560.5
实施例173
化合物173(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(2-硝基苯基)戊酰胺的制备
参照实施例63，第一步将1,3,4-硫杂二氮杂环戊熳-2-胺换为甲基(2-硝基苯基)胺，最终得到(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(2-硝基苯基)戊酰胺(173)(3.05mg,纯度93.9％，收率30.8％)。1H NMR(400MHz,CDCl3)δ7.94(t,J＝7.5Hz,1H),7.63(t,J＝7.5Hz,1H),7.49(t,J＝7.8Hz,1H),7.31(d,J＝7.8Hz,1H),3.15(s,4H),2.00–1.88(m,7H),1.84–1.75(m,3H),1.72–1.63(m,16H),1.50(d,J＝12.2Hz,2H),1.27(dd,J＝22.2,13.7Hz,4H),1.11–1.04(m,4H),0.92(s,5H),0.89(s,3H),0.74(d,J＝5.4Hz,7H),0.60(t,J＝4.7Hz,3H),0.55(d,J＝2.7Hz,3H).LCMS[M+H]+＝551.4
实施例174
化合物174(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(嘧啶-4-基)戊酰胺的制备
参考实施例24，第二步将N-(2-氨基苯基)丙-2-烯酰胺(24-1)换成4-(甲基氨基)嘧啶，得到最终产物(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(嘧啶-4-基)戊酰胺(174)。1H NMR(399MHz,CDCl3)δ8.97(s,1H),8.57(s,1H),7.84(s,1H),3.49(s,3H),3.21(s,1H),2.60(d,J＝64.0Hz,2H),2.01(s,5H),1.65(s,6H),1.58–1.54(m,2H),1.48(s,2H),1.36(s,2H),1.18(s,3H),1.03(d,J＝12.3Hz,1H),0.97(d,J＝7.9Hz,6H),0.91(s,3H),0.86(s,3H),0.79(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ175.78,145.14,134.39,78.94,77.32,77.21,77.00,76.69,50.39,49.80,44.52,38.87,36.99,36.18,35.55,33.78,31.29,30.95,27.94,26.46,24.22,20.96,19.14,18.54,18.22,15.76,15.41.LC-MS：[M+H]+＝508.35
实施例175
化合物175 2-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-2,3-二氢-1H-异吲哚-1-酮的制备

第一步 将乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-羟基丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(96-1)(140mg,0.325mmol)溶于二氯甲烷(6.0mL)中，加入三乙胺(0.09mL)，随后在室温搅拌下加入对甲苯磺酰氯(92.96mg,0.49mmol),继续在室温搅拌下18小时，TLC(石油醚:乙酸乙酯＝5:1)监测。反应结束后，加入水15mL和乙酸乙酯(10mL*3)萃取，有机相分离，干燥，浓缩得4-甲基苯磺酸-(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基酯(175-1)(152mg,0.25mmol,75.95％yield)白色固体粗品直接投至下一步反应中。1H NMR(399MHz,CDCl3)δ7.78(d,J＝8.3Hz,2H),7.33(d,J＝8.2Hz,2H),4.47(dd,J＝11.5,4.7Hz,1H),4.04(dd,J＝13.0,7.7Hz,2H),2.43(s,3H),2.03(d,J＝2.6Hz,4H),1.99(s,3H),1.80(s,2H),1.72–1.63(m,4H),1.57(s,2H),1.47(d,J＝12.5Hz,2H),1.41(d,J＝8.5Hz,1H),1.26(d,J＝14.0Hz,3H),1.16(s,1H),1.12(d,J＝12.3Hz,2H),0.97(s,3H),0.86(s,6H),0.81(s,3H),0.79(d,J＝6.1Hz,3H),0.62(s,3H).
第二步 称取2,3-二氢-1H-异吲哚-1-酮(12.5mg,0.094mmol)溶于N,N’-二甲基甲酰胺(3.0mL)中，冰浴降至0℃，加入氢化钠(5.13mg,0.13mmol),随后升至室温，搅拌30分钟后，加入4-甲基苯磺酸-(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基酯(175-1)(50mg,0.085mmol)，接着将体系升至45℃，TLC(石油醚:乙酸乙酯＝5:1)监测。反应结束后，冷却至室温，加入水(10.0mL)淬灭,再以乙酸乙酯(6.0mL*3)萃取，有机相合并，干燥，浓缩经制备HPLC纯化得2-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-2,3-二氢-1H-异吲哚-1-酮(175)(4.44mg,0.008mmol,9.71％)。1H NMR(399MHz,CDCl3)δ8.15(s,1H),7.56(s,2H),7.48(s,1H),6.16(s,1H),3.55(s,1H),3.42(s,1H),3.21(s,1H),2.00(s,5H),1.95–1.89(m,1H),1.71(d,J＝15.7Hz,6H),1.58(s,2H),1.48–1.42(m,1H),1.29(s,3H),1.18(s,2H),1.07(d,J＝15.6Hz,2H),0.97(d,J＝7.6Hz,9H),0.86(s,3H),0.79(s,3H),0.69(s,3H).13C NMR(100MHz,CDCl3)δ134.41,134.18,127.43,78.86,77.32,77.21,77.00,76.68,50.32,50.16,49.95,49.78,49.73,49.52,49.31,49.09,44.51,38.82,36.96,35.52,34.63,30.93,30.76,29.66,29.28,28.24,27.90,27.65,26.43,24.19,20.93,19.10,18.63,18.19,15.69,15.38,0.98.LC-MS:[M+MeOH+H]+＝536.40
实施例176
化合物176 2-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-1,2,3,4-四氢异喹啉-1-酮的制 备
参考实施例175，第二步将2,3-二氢-1H-异吲哚-1-酮换为1,2,3,4-四氢异喹啉-1-酮，得到终产物2-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-1,2,3,4-四氢异喹啉-1-酮(176).1H NMR(399MHz,CDCl3)δ8.05(d,J＝7.5Hz,1H),7.37(d,J＝7.3Hz,1H),7.32(d,J＝7.6Hz,1H),7.15(d,J＝7.3Hz,1H),3.60(s,1H),3.51(d,J＝5.9Hz,3H),3.21(s,1H),2.96(t,J＝6.5Hz,2H),1.99(s,5H),1.78–1.63(m,6H),1.56(s,2H),1.49(d,J＝9.1Hz,3H),1.28(s,3H),1.23(s,3H),1.00(d,J＝5.9Hz,3H),0.97(d,J＝8.8Hz,6H),0.86(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(100MHz,CDCl3)δ164.07,137.87,134.39,134.25,131.34,129.72,128.14,126.97,126.73,78.94,77.31,76.99,76.67,50.34,49.78,45.89,45.18,44.51,38.86,36.98,35.54,34.65,33.84,30.94,30.76,28.28,28.22,27.93,27.81,26.45,24.23,20.95,19.11,18.84,18.21,15.71,15.40,1.00.LCMS:[M+H]+＝518.40
实施例178
化合物178 2-氯-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-N-甲基苯甲酰胺的制备
参考实施例54，将第二步邻氟苯甲酰氯换为邻氯苯甲酰氯，得到终产物2-氯-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-N-甲基苯甲酰胺(178).1H NMR(399MHz,CDCl3)δ7.37(s,1H),7.28(s,3H),3.21(s,1H),3.09(s,1H),3.08(s,1.5H),3.07–2.96(m,1H),2.79(s,1.5H),2.00(s,4H),1.64(s,6H),1.53(s,5H),1.36(s,2H),1.17(dd,J＝27.4,15.8Hz,5H),1.02–0.96(m,6H),0.91(d,J＝25.4Hz,3H),0.80–0.68(m,6H),0.59(s,3H).13C NMR(100MHz,CDCl3)δ134.41,134.12,129.92,129.85,129.50,127.14,126.89, 78.91,77.31,77.19,76.99,76.67,50.35,50.32,49.93,49.80,44.55,44.41,38.86,36.96,35.51,32.94,30.94,30.80,30.69,28.26,27.93,27.81,27.77,26.46,26.42,24.24,24.11,20.96,20.88,19.11,18.54,18.18,15.75,15.60,15.39,1.00.LC-MS:[M+H]+＝540.45,[M+ACN+H]+＝581.45
实施例179
化合物179(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基丁基)丙酰胺的制备
参考实施例8，将第四步2-{[二甲基(2-甲基丙-2-基)甲硅基]氧基}乙-1-胺换为1-(甲基氨基)丁-2-醇，得到最终产物(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(2-羟基丁基)丙酰胺(179).1H NMR(399MHz,CDCl3)δ5.82(s,1H),3.61(s,1H),3.39(s,1H),3.20(s,1H),3.20–3.04(m,1H),2.66(d,J＝24.3Hz,1H),2.12(s,1H),2.00(s,6H),1.86(s,2H),1.68(s,4H),1.47(s,4H),1.23(s,4H),1.15(d,J＝5.7Hz,3H),1.05(s,1H),0.97(d,J＝8.1Hz,9H),0.89(s,3H),0.79(s,3H),0.68(s,3H).13C NMR(100MHz,CDCl3)δ178.16,134.39,134.18,78.88,77.31,76.99,76.67,73.28,73.17,50.27,49.62,47.52,45.46,45.17,44.51,38.85,36.99,35.49,30.89,30.86,27.96,27.93,27.77,27.34,26.45,24.25,20.89,19.13,18.18,17.70,16.14,15.42,9.87,1.01.LC-MS[M+H]+＝460.40
实施例180
化合物180(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(2-氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的合成
参考实施例161，将溴苯换为邻氟溴苯，最终得到(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(2-氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(180)(15mg,0.025mmol,34.48％)。1H NMR(400MHz,CDCl3)δ7.50-7.41(m,1H),7.25-7.20(m,1H),7.15(t,J＝7.3Hz,1H),7.07–6.97(m,1H),5.01(dd,J＝13.0,5.8Hz,1H),3.23(dd,J＝11.6,4.4Hz,1H),2.03(d,J＝10.2Hz,4H),1.93–1.85(m,1H),1.78–1.59(m,8H),1.51–1.11(m,10H),1.05(d,J＝11.0Hz,2H),0.99(d,J＝8.6Hz,6H),0.88(d,J＝7.8Hz,6H),0.81(s,3H),0.68(d,J＝2.0Hz,3H).13C NMR(101MHz,CDCl3)δ155.39,134.41,128.79,127.25,124.25,115.38,78.99,68.65,50.49,50.42,49.81,44.49,38.60,38.45,37.03,36.42,36.31,36.05,35.86,35.59,30.99,30.83,28.21,27.97,27.86,26.50,24.26,22.63,22.50,21.00,19.14,18.62,18.26,15.75,15.42.LC-MS:[M-OH]+＝493.5
实施例181和实施例182
化合物181 2-羟基-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-N-(丙-2-基)苯甲酰胺和化合物182(5R)-1-(2-氟苯基)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-(丙-2-基)己-1-酮的制备
参考实施例175，将第二步2,3-二氢-1H-异吲哚-1-酮换为2-氟-N-(丙-2-基)苯甲酰胺，得到最终化合物2-羟基-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-N-(丙-2-基)苯甲酰胺(181)和 (5R)-1-(2-氟苯基)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-(丙-2-基)己-1-酮(182)
化合物181:1H NMR(399MHz,Chloroform-d)δ8.07(dd,J＝7.8,1.9Hz,1H),7.35(ddd,J＝8.8,7.3,1.9Hz,1H),7.02–6.96(m,1H),6.93–6.89(m,1H),4.18(p,J＝6.4Hz,1H),4.13–4.06(m,2H),3.14(dd,J＝11.4,4.8Hz,1H),2.05–1.90(m,6H),1.66(dt,J＝12.7,3.8Hz,3H),1.62–1.54(m,4H),1.53–1.38(m,4H),1.32–1.25(m,1H),1.19(d,J＝6.4Hz,6H),1.17–1.11(m,2H),0.99(q,J＝4.1,3.0Hz,1H),0.96–0.89(m,9H),0.83(s,3H),0.73(s,3H),0.65(s,3H).13C NMR(100MHz,CDCl3)δ164.72,156.95,134.47,134.05,132.68,131.87,121.20,121.09,112.23,78.70,77.36,77.04,76.72,67.28,50.80,50.31,49.82,49.76,49.60,49.39,49.18,48.96,48.75,48.53,44.55,41.46,38.76,36.91,35.49,35.39,33.94,30.93,30.67,28.30,27.80,27.42,26.39,24.14,22.73,22.71,20.88,19.04,18.65,18.13,15.74,15.32,0.91.LCMS:[M+H]+＝550.60
化合物182:1H NMR(399MHz,Chloroform-d)δ7.33(ddt,J＝7.6,5.3,3.1Hz,1H),7.30–7.25(m,1H),7.18–7.13(m,1H),7.06(t,J＝8.9Hz,1H),3.76(p,J＝6.7Hz,1H),3.42(d,J＝72.1Hz,1H),3.20(td,J＝7.3,3.8Hz,1H),3.16–2.90(m,1H),2.00(d,J＝9.2Hz,5H),1.71–1.64(m,4H),1.49(dt,J＝13.9,6.9Hz,4H),1.35(s,1H),1.26(dd,J＝6.8,2.0Hz,4H),1.17(d,J＝2.9Hz,2H),1.07(s,2H),1.03–1.00(m,3H),0.98–0.92(m,9H),0.87(s,3H),0.79–0.77(m,3H),0.70(s,3H),0.54(d,J＝6.3Hz,3H).13C NMR(100MHz,CDCl3)δ165.94,156.85,134.37,134.32,134.13,130.43,128.26,124.50,124.35,115.83,115.62,78.95,78.90,77.33,77.01,76.69,50.39,50.34,50.30,49.81,49.73,49.61,46.05,44.47,44.31,38.96,38.86,38.85,36.98,36.95,35.55,35.50,34.86,30.93,30.80,30.66,28.26,27.94,27.81,27.77,26.47,24.25,24.12,20.97,20.87,20.68,20.62,19.13,19.10,18.90,18.34,18.22,15.69,15.49,15.42,1.01.19F NMR(376MHz,CDCl3)δ-116.05,-116.18,-116.20,-116.22,-116.24.LC-MS:[M+H]+＝552.55
实施例183
化合物183(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1-甲基咪唑-2-基)戊酰胺的合成

第一步 将原料(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VII)(1g,2.18mmol,1.0eq)溶解EtOH(乙醇)(10mL)中，滴加硫酸(0.03mL,98％)，反应体系在75℃搅拌2hr。TLC(石油醚:乙酸乙酯＝5:1)显示反应已经完成。停止反应，旋干体系中的乙醇，加入水(40mL)稀释，用乙酸乙酯(40mL×3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(石油醚:乙酸乙酯＝96:4to 94:6)得到白色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸乙酯(183-1)(663g,纯度95％，收率59.35％)。1H NMR(400MHz,CDCl3)δ4.50(dd,J＝11.5,4.5Hz,1H),4.12(q,J＝7.1Hz,2H),2.29(dddd,J＝22.0,15.5,9.7,5.9Hz,2H),2.05(s,3H),2.03–1.90(m,4H),1.87–1.63(m,7H),1.60–1.28(m,8H),1.26(t,J＝7.1Hz,3H),1.22–1.11(m,2H),1.00(s,3H),0.89(dd,J＝10.7,5.0Hz,12H),0.68(s,3H).
第二步 将原料将反应物二异丙胺(686mg,6.78mmol,6.0eq)溶解在无水四氢呋喃(5mL)中，体系冰水浴降温到-66℃，缓慢加入正丁基锂(2mL,5.65mmol,5.0eq,2.5M in n-Hexane)，保持-66℃搅拌1小时。然后将(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基](183-1)(550mg,1.130mmol,1.0eq)溶解在无水四氢呋喃(5mL)中，加入到反应液中，保持-66℃搅拌30分钟。加入碘甲烷(801mg,5.65mmol,5.0eq)，反应体系升至室温，搅拌2小时。TLC(石油醚:乙酸乙酯＝10:1)监测反应。反应完全后，用1M HCl淬灭反应。反应液加入水(20mL)，乙酸乙酯萃取，饱和盐水洗涤，无水硫酸钠 干燥，硅胶柱层析(石油醚:乙酸乙酯＝98：2)得到白色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-7-[(2-甲基丙酰基)氧基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-甲基戊酸乙酯(183-2)(280mg,纯度85％，收率39.83％)。1H NMR(400MHz,CDCl3)δ4.49(dd,J＝11.4,4.8Hz,1H),4.14(tt,J＝7.2,3.6Hz,2H),2.61–2.51(m,2H),2.07–1.92(m,5H),1.85(dd,J＝18.4,6.7Hz,1H),1.76–1.50(m,9H),1.47–1.36(m,2H),1.36–1.29(m,3H),1.27–1.22(m,4H),1.21–1.12(m,12H),1.00(s,3H),0.90(dd,J＝7.2,4.5Hz,7H),0.87(s,6H),0.66(s,3H)
第三步 将原料(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-7-[(2-甲基丙酰基)氧基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-甲基戊酸乙酯(183-2)(280mg,0.449mmol,1eq)溶解于THF(四氢呋喃)(2mL)和MeOH(甲醇)(2mL)中，滴加1N氢氧化锂(1.2mL)，反应混合物在50℃搅拌48h。TLC(石油醚:乙酸乙酯＝1:1)监测反应完全。反应液降到室温，反应液使用1N HCl酸化至PH＝3～4后，浓缩掉乙醇后用EA(乙酸乙酯)(20mL×3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(PE：EA＝75：25to 70：30)得到白色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-甲基戊酸(183-3)(80mg,纯度90％，收率30.03％)。1H NMR(400MHz,CDCl3)δ3.24(dd,J＝11.6,4.5Hz,1H),2.66–2.59(m,1H),2.07–1.91(m,5H),1.91–1.83(m,1H),1.76–1.21(m,13H),1.20(d,J＝6.9Hz,3H),1.15(s,1H),1.05(dd,J＝12.7,1.9Hz,1H),0.99(d,J＝8.8Hz,6H),0.93(d,J＝5.8Hz,3H),0.87(s,3H),0.81(s,3H),0.68(d,J＝7.8Hz,3H)
第四步 将原料(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-甲基戊酸(183-3)(60mg,0.14mmol,1eq)溶解于DMF(N,N-二甲基甲酰胺)(10mL)中，加入HATU(106mg,0.28mmol,2eq)后将反应体系置换成氮气氛围。反应混合物在室温搅拌30min后，2-氟苯胺(154mg,1.39mmol,10eq)和N,N-二异丙基乙基胺(0.069mL,0.42mmol,3eq)，反应体系在60℃搅拌18h。TLC(石油醚:乙酸乙酯＝1:1)监测反应。反应完全后，体系中加入水(40mL)稀释，用乙酸乙酯(40mL×3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(石油醚:乙酸乙酯＝86：14to 85:15)得到白色固体(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-甲基戊酰胺(183-4)(50mg,纯度95％，收率65.24％)。1H NMR(400MHz,CDCl3)δ7.30(s,1H),7.08(qd,J＝14.3,7.2Hz,3H),3.23(dd,J＝11.5,4.5Hz,1H),2.58–2.49(m,1H),2.08–1.94(m,7H),1.75–1.63(m,6H),1.60–1.55(m,2H),1.53–1.47(m,2H),1.46–1.37(m,3H),1.26(s,4H),1.19(dd,J＝19.7,9.7Hz,4H),1.01–0.95(m,9H),0.88(s,4H),0.80(s,3H),0.64(s,3H).
第五步 将原料(4R)-N-(2-氟苯基)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-2-甲基戊酰胺(183-4)(50mg,0.09mmol,1.0eq)溶解于DCM(二氯甲烷)(7mL)中，将反应体系置于冰水浴中，冷却至0℃左右，然 后依次加入醋酸酐(0.045mL,0.475mmol,5.0eq)，DMAP(2.33mg,0.02mmol,0.2eq)和三乙胺(0.066mL,0.48mmol,5.0eq),反应体系在室温下搅拌2小时。TLC(石油醚:乙酸乙酯＝5:1)监测反应。用甲醇(10mL)萃灭反应后，饱和碳酸氢钠(10mL×3)和水(10mL×3)洗涤，合并的有机相用饱和食盐水(50mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(石油醚:乙酸乙酯＝88:12to 86:14)得到白色固体乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-氟苯基)氨基]-4-甲基-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(183-5)(40mg,纯度95％，收率70.36％)。1H NMR(400MHz,CDCl3)δ8.32(t,J＝7.4Hz,1H),7.16–7.01(m,3H),4.49(dd,J＝11.6,4.5Hz,1H),2.54(ddd,J＝10.5,7.0,3.4Hz,1H),2.05(s,3H),2.03–1.94(m,5H),1.76–1.61(m,6H),1.56(s,4H),1.48–1.33(m,4H),1.25(d,J＝6.8Hz,3H),1.19–1.10(m,2H),0.99–0.94(m,6H),0.87(s,9H),0.64(s,3H).
第六步 将原料乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-氟苯基)氨基]-4-甲基-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(183-5)(30mg,0.05mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(5mL)中，并将反应体系置换成氮气氛围。将反应体系冷却至0℃后，缓慢加入氢化钠(60％,石蜡)(6mg,0.16mmol,3eq)，接下来将反应室温搅拌30min后，加入碘甲烷(23mg,0.16mmol,3eq)，反应体系在室温搅拌30min。TLC(石油醚:乙酸乙酯＝5:1)监测反应。反应完全后，体系中加入水(20mL)稀释，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和食盐水(20mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(石油醚:乙酸乙酯＝94：6to 92：8)得到白色固体乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-氟苯基)(甲基)氨基]-4-甲基-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(183-6)(20mg,纯度95％，收率61.8％)。1H NMR(400MHz,CDCl3)δ7.39–7.30(m,1H),7.22–7.14(m,3H),4.50(dd,J＝11.5,4.5Hz,1H),3.23(d,J＝5.8Hz,3H),2.45(s,1H),2.05(s,3H),2.03–1.87(m,5H),1.72–1.61(m,5H),1.58(s,5H),1.52(s,1H),1.40–1.24(m,4H),1.14(d,J＝12.4Hz,2H),1.08–1.01(m,3H),1.00(d,J＝2.5Hz,3H),0.88(s,6H),0.83(d,J＝3.3Hz,3H),0.69(d,J＝4.9Hz,3H),0.62(dd,J＝18.9,6.2Hz,3H).
第七步 将原料乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-氟苯基)(甲基)氨基]-4-甲基-5-氧亚基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(20mg,0.03mmol,1eq)溶解于THF(四氢呋喃)(1mL)和MeOH(甲醇)(1mL)中，滴加1N氢氧化锂(0.6mL)，反应混合物在50℃搅拌1hrs。TLC(石油醚:乙酸乙酯＝5:1)监测反应。反应完全后，反应液降到室温，反应液使用1N HCl酸化至PH＝3～4后，浓缩掉乙醇后用EA(乙酸乙酯)(20mL×3)萃取，合并的有机相用饱和食盐水(50mL)洗涤，然后用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗产物用快速色谱法分离纯化(PE:EA＝86：14to 85：15)得到白色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-甲基-N-(1-甲基咪唑-2-基)戊酰胺(183)(15.39mg,纯度97.11％，收率80.57％)。1H NMR(400MHz,CDCl3)δ7.34(d,J＝7.9Hz,1H),7.23–7.14(m,3H),3.27–3.20(m,4H),2.46(s,1H), 2.08–1.89(m,6H),1.69(ddd,J＝22.6,13.7,7.4Hz,5H),1.60–1.53(m,2H),1.44(s,4H),1.37–1.21(m,4H),1.07–1.02(m,3H),1.00(s,3H),0.98(d,J＝2.4Hz,3H),0.84(d,J＝3.3Hz,3H),0.81(s,3H),0.69(d,J＝5.0Hz,3H),0.61(dd,J＝17.9,6.2Hz,3H).13C NMR(101MHz,CDCl3)δ177.27,156.96,134.56,134.25,129.73,129.60,124.92,124.85,116.78,79.01,50.91,50.41,49.84,48.54,44.45,41.95,38.90,37.02,35.61,35.14,34.12,30.94,30.81,28.16,27.97,27.85,26.48,24.17,21.00,19.25,19.13,18.93,18.25,15.62,15.42LCMS：M+H]+＝538.4
实施例186
化合物186N-环丙基-2-氟-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]苯甲酰胺的制备
第一步 将化合物乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-甲酰基丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(III)(50mg,0.117mmol)溶解在MeOH(10mL)，加入AcOH(14.5mg,0.700mmol)和环丙胺(33.40mg,0.585mmol)，搅拌5min。 加入氰基硼氢化钠(22.62mg,1.050mmol)，室温反应3h，TLC(石油醚：乙酸乙酯＝10:1)监测。旋干溶剂，加碳酸氢钠水溶液(10mL)和乙酸乙酯(8mL*3)萃取，有机相用无水硫酸钠干燥，旋干，柱层析(石油醚)得到乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(环丙基氨基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(186-1)(30mg,0.057mmol,49.13％)
第二步 将化合物乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(环丙基氨基)丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(186-1)(100mg,0.170mmol)溶于二氯甲烷(5mL)，加入三乙胺(0.01mL,0.065mmol)，降温至零度，加入邻氟苯甲酰氯(41mg,0.204mmol)自然升至室温搅拌2小时。TLC(石油醚：乙酸乙酯＝1:1)监测，原料消失，加入水(10mL)稀释，用乙酸乙酯(10mL*3)萃取，无水硫酸钠干燥，旋干，柱层析(石油醚：乙酸乙酯＝0％-20％)得到化合物乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{环丙基[(2-氟苯基)羰基]氨基}丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(186-2)(60mg,0.081mmol,47.62％)。
第三步 将化合物乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{环丙基[(2-氟苯基)羰基]氨基}丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(186-2)(50mg,0.085mmol)溶解在四氢呋喃(3mL)中，加入甲醇(3mL)，加入1M氢氧化锂(0.091mL,0.091mmol)，室温搅拌16小时，TLC(石油醚：乙酸乙酯＝1:1)检测原料反应完毕。旋干THF，后加入水(10mL)和乙酸乙酯(5mL*3)萃取，无水硫酸钠干燥后浓缩，经制备纯化得N-环丙基-2-氟-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]苯甲酰胺(186)(17.7mg,0.032mmol,37.9％)。1H NMR(399MHz,CDCl3)δ7.32(dd,J＝15.7,9.6Hz,2H),7.15(t,J＝7.3Hz,1H),7.02(t,J＝8.9Hz,1H),3.69(s,1H),3.42(s,1H),3.21(dd,J＝11.4,4.3Hz,1H),2.72(s,1H),2.01(s,4H),1.95–1.86(m,1H),1.75–1.66(m,4H),1.65–1.57(m,4H),1.56–1.43(m,4H),1.32(s,2H),1.26–1.09(m,3H),1.03–0.93(m,9H),0.83(d,J＝33.7Hz,6H),0.70(s,3H),0.59(s,1H),0.54–0.34(m,3H).13C NMR(100MHz,CDCl3)δ168.44,134.39,134.29,130.75,130.67,128.85,124.21,115.50,115.28,78.95,77.30,77.19,76.99,76.67,50.44,50.35,49.81,44.53,44.35,38.86,36.98,35.54,34.39,33.78,30.95,30.80,28.25,27.93,27.81,26.47,24.23,20.97,19.12,18.72,18.22,15.68,15.40.LC-MS:[M+H]+＝550.45
实施例188
化合物188 2-氟-N-[(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丙基]-N-甲基苯甲酰胺的制备
第一步 将化合物乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-甲酰基乙基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(8-2)(100mg,0.233mmol)溶解在四氢呋喃(5mL)中，加入氯化锌(16.4mg,0.12mmol)和甲氨的甲醇溶液(75mg,0.420mmol)，加入氰基硼氢化钠(22.62mg,1.050mmol)，室温反应15h。TLC(石油醚：乙酸乙酯＝10:1)。旋干溶剂，加碳酸氢钠水溶液(10mL)和乙酸乙酯(8.0mL*3)萃取，有机相分离，用无水硫酸钠干燥，浓缩后经柱层析(石油醚：乙酸乙酯＝0％～5％)得到乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2S)-1-(甲基氨基)丙-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(188-1)(30mg,0.061mmol,26.08％)。1H NMR(399MHz,CDCl3)δ4.47(dd,J＝11.6,4.5Hz,1H),2.80(d,J＝12.0Hz,1H),2.53(s,3H),2.02(d,J＝9.3Hz,6H),1.96(s,3H),1.89(d,J＝13.3Hz,1H),1.75–1.57(m,7H),1.49(dd,J＝17.6,8.4Hz,2H),1.36–1.18(m,4H),1.12(d,J＝11.0Hz,1H),1.05(d,J＝6.4Hz,3H),0.98(s,3H),0.85(d,J＝5.5Hz,9H),0.69(s,3H).
第二步 将化合物乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2S)-1-(甲基氨基)丙-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(188-1)(10mg,0.021mmol)溶解在二氯甲烷(3mL)，加入三乙胺(0.009mL,0.065mmol)，降温至0℃，加入邻氟苯甲酰氯(41mg,0.204mmol)自然升至室温搅拌2小时。TLC(石油醚：乙酸乙酯＝1:1)检测，原料消失， 加入5mL水稀释，用乙酸乙酯5mL*2萃取，无水硫酸钠干燥，浓缩后经制备TLC(石油醚：乙酸乙酯＝1:1)纯化后得到化合物乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-{[(2-氟苯基)羰基](甲基)氨基}丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(188-2)(80mg,0.079mmol,46.37％)。LC-MS:[M+H]+＝510.65
第三步 将化合物乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-{[(2-氟苯基)羰基](甲基)氨基}丙-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(188-2)(60mg,0.109mmol)溶解在四氢呋喃THF(3mL)中，加入甲醇MeOH(3mL)，加入氢氧化锂LiOH(0.109mL,0.109mmol,1M)，室温搅拌16小时，TLC(石油醚：乙酸乙酯＝1:1)。点板检测原料反应完毕，旋干THF，后加入水和乙酸乙酯，用乙酸乙酯萃洗两次，无水硫酸钠干燥，送制备拿到2-氟-N-[(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丙基]-N-甲基苯甲酰胺(188)(12.2mg,0.022mmol,20.13％)。1H NMR(399MHz,CDCl3)δ7.35(t,J＝5.5Hz,2H),7.20–7.13(m,1H),7.06(t,J＝8.8Hz,1H),3.76(s,0.5H),3.28–3.15(m,1.5H),3.11(s,0.5H),3.05(s,1.3H),2.85(s,1.6H),2.78(d,J＝12.3Hz,0.5H),2.00(dd,J＝15.1,7.9Hz,4H),1.84(s,1H),1.72(dd,J＝18.4,5.2Hz,3H),1.65–1.52(m,5H),1.52–1.34(m,2H),1.26–1.09(m,3H),1.07–1.00(m,1H),0.99–0.95(m,6H),0.91(d,J＝24.3Hz,3H),0.82–0.57(m,9H).13C NMR(100MHz,CDCl3)δ167.29,167.13,134.57,134.09,133.92,130.89,128.90,125.15,124.59,115.77,115.55,109.99,78.88,77.32,77.20,77.00,76.68,52.68,50.31,49.57,49.44,49.05,48.48,44.95,44.89,38.84,36.99,36.67,35.53,35.17,30.96,30.81,30.67,28.00,27.93,27.80,26.50,26.43,24.23,24.11,20.94,20.86,19.14,18.21,16.26,15.86,15.72,15.40.19F NMR(376MHz,CDCl3)δ-115.02.LC-MS:[M+H]+＝510.35.
实施例191
化合物191(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(4-氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将溴苯换为对氟溴苯，得到最终产物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(4-氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(191)(18.42mg,0.03mmol,纯度94.40％，收率15.54％)。1H NMR(400MHz,CDCl3)δ7.32(dd,J＝ 8.6,5.5Hz,2H),7.03(t,J＝8.7Hz,2H),4.70–4.63(m,1H),3.23(dd,J＝11.6,4.5Hz,1H),2.06–1.97(m,5H),1.93–1.83(m,1H),1.73–1.65(m,6H),1.56(s,7H),1.45–1.38(m,3H),1.28–1.18(m,3H),1.00(s,7H),0.98(s,3H),0.87(d,J＝5.7Hz,8H),0.81(s,3H),0.67(d,J＝2.8Hz,4H).13C NMR(101MHz,CDCl3)δ163.38,134.43,127.51,115.33,115.12,78.99,74.02,50.41,49.81,44.48,39.66,38.89,37.03,36.36,36.07,35.59,30.99,30.83,28.24,27.96,27.86,26.50,24.25,22.67,22.58,20.99,19.14,18.61,18.26,15.75,15.41.LCMS：[M-OH]+＝493.50
实施例193
化合物193 2-氟-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-N-甲基苯磺酰胺的制备
第一步 化合物乙酸-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-五甲基-1-[(2R)-4-(甲基氨基)丁-2-基]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(54-1)(100mg,0.23mmol,1.0eq)溶解在二氯甲烷(10mL)中,依次加入2-氟苯磺酰氯(132mg,0.68mmol,3.0eq)和三乙胺(0.094mL,0.68mmol,3.0eq),室温搅拌过夜。LCMS显示，原料点消失。反应液二氯甲烷(50mL)稀释，饱和盐水洗涤，有机相无水硫酸钠干燥，浓缩干得到粗品，粗品用硅胶柱层析纯化得到乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{[(2-氟苯基)二氧亚基-λ6-硫基](甲基)氨基}丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(193-1)(100mg,0.15mmol,收率66％)。
第二步 乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{[(2-氟苯基)二氧亚基-λ6-硫基](甲基)氨基}丁-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(193-1)(50mg,0.10mmol，1.0eq)溶解在无水四氢呋喃(1mL)和甲醇(1mL)的混合溶剂中，随后加入氢氧化锂溶液 (0.5mL,1mo/L)，反应加热到50℃反应3hrs，TLC(石油醚：乙酸乙酯＝3:1)监测反应。反应完全后，用1M的盐酸调pH＝4～5，乙酸乙酯(30mL x2)萃取，有机相合并后饱和盐水洗涤，无水硫酸钠干燥，浓缩干得到粗品，粗品硅胶柱层析纯化(石油醚：乙酸乙酯＝80:20to 60:40)得到白色固体2-氟-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]丁基]-N-甲基苯磺酰胺(193)(32mg,0.05mmol,收率65％)。1H NMR(400MHz,CDCl3)δ7.92-7.86(m,1H),7.58–7.52(m,1H),7.28-7.26(m 1H),7.23–7.16(m,1H),3.31-3.20(m,2H),3.12-3.04(m,1H),2.85(d,J＝1.8Hz,3H),2.07–1.97(m,4H),1.95–1.84(m,1H),1.76–1.45(m,10H),1.22(ddt,J＝17.5,12.4,7.7Hz,4H),1.04(dd,J＝12.6,2.1Hz,1H),0.99(d,J＝8.4Hz,6H),0.89(d,J＝6.0Hz,3H),0.86(s,3H),0.81(s,3H),0.67(d,J＝6.4Hz,3H).13C NMR(101MHz,CDCl3)δ157.59,134.49,134.26,131.22,124.35,124.31,117.26,117.05,78.98,50.40,50.37,49.84,47.79,44.56,38.90,37.03,35.59,34.23,33.94,30.96,30.78,28.24,27.97,27.85,26.49,24.23,20.97,19.16,18.57,18.24,15.72,15.42.LCMS(ESI)[M+H]+＝560.5.
实施例194
化合物194(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(1H-吲唑-6-基)-N-甲基戊酰胺的制备

第一步 将6-硝基-1H-吲唑(500mg,3.07mmol,1eq)分散在DCM(二氯甲烷)(10mL)中，冰浴下加入原料(BoC)2O(碳酸酐二叔丁酯)(875mg,4.01mmol,1.0eq)和TEA(三乙胺)(0.5mL,3.06mmol,1.0eq)，反应液在25℃搅拌12hrs。TLC(石油醚：乙酸乙酯＝1:1)监测反应。反应完成后，反应液浓缩后倒入100mL水，用乙酸乙酯(100mL×2)萃取，合并有机层并且用水(100mL×2)洗涤。有机层用Na2SO4干燥，过滤和浓缩后粗品用柱层析(石油醚：乙酸乙酯＝3:1)分离，收集样品得到白色固体6-硝基吲唑-1-甲酸-2-甲基丙-2-基酯(194-1)(580mg，纯度85％，收率71.9％)。1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.31(s,1H),8.21(dd,J＝8.7,1.9Hz,1H),7.88(d,J＝8.7Hz,1H),5.30(s,0H),1.77(s,9H).
第二步 将6-硝基吲唑-1-甲酸-2-甲基丙-2-基酯(194-1)(200mg,0.857mmol,1.0eq)分散在MeOH(甲醇)(10mL)中，加入原料Pd/C(钯碳)(40mg)，将反应体系置换成氢气氛围，反应液在室温搅拌12hrs。TLC(DCM:MeOH＝15:1)监测反应。反应完成后，反应液经硅藻土过滤后浓缩母液得到白色固体6-氨基吲唑-1-甲酸-2-甲基丙-2-基酯(194-2)(160mg,纯度90％,收率90％)，粗品直接投入下一步 反应。LCMS：[M+H]+＝234.2
第三步 将6-氨基吲唑-1-甲酸-2-甲基丙-2-基酯(194-2)(80mg,0.34mmol,1.0eq),(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]戊酸(VII)(157mg，0.34mmol，1eq)，[(二甲基氨基)([1,2,3]三氮杂环戊熳并[4,5-b]吡啶-3-基氧基)甲亚基]二甲基铵六氟-λ5-甲磷烷负离子(196mg，0.514mmol，1.5eq)，DIEA(乙基[二(丙-2-基)]胺)溶于DMF(氮氮二甲基甲酰胺)(5mL)。反应液在室温下搅拌2hrs。TLC(石油醚：乙酸乙酯＝1:1)监测反应。反应完成后，反应液用乙酸乙酯(20mL×2)萃取。合并有机相，过滤和浓缩后粗品用柱层析(DCM:MeOH＝25:1)分离，收集样品得到白色固体6-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基]氨基}吲唑-1-甲酸-2-甲基丙-2-基酯(194-3)(80mg，纯度85％，收率34.61％)。
第四步 将6-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基]氨基}吲唑-1-甲酸-2-甲基丙-2-基酯(194-3)(80mg，0.119mmol,1.0eq)溶于THF(四氢呋喃)(50mL)，冰浴下加入NaH(钠氢)(5mg,0.178mmol，1.5eq)。反应液在0摄氏度下搅拌0.5hrs后加入CH3I(碘甲烷)(24mg，0.237mmol，2eq)。TLC(石油醚：乙酸乙酯＝2:1)监测。反应完成后，反应液用水(40ml)淬灭，用乙酸乙酯(20mL×2)萃取。合并有机层有机层用无水硫酸钠干燥，浓缩得到白色固体6-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基](甲基)氨基}吲唑-1-甲酸-2-甲基丙-2-基酯(194-4)(60mg,纯度80％，产率73.47％)。LC-MS：[M+H]+＝689.3
第五步 将6-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-乙酰氧基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基](甲基)氨基}吲唑-1-甲酸-2-甲基丙-2-基酯(194-4)(60mg,0.087mmol,1.0eq)溶于MeOH(甲醇)(2mL)，室温下加入LiOH(氢氧化锂)水溶液(2mL,1mol/L)。反应液在50℃下搅拌16hrs。TLC(DCM:MeOH＝10:1，)监测反应。反应完全后，反应液用乙酸乙酯(50mL×2)萃取。合并有机层用无水硫酸钠干燥，旋干得到白色固体品6-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基](甲基)氨基}吲唑-1-甲酸-2-甲基丙-2-基酯(194-5)(50mg，纯度90％，产率90.73％)，粗品直接进行下一步。
第六步 将6-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-1-氧亚基戊基](甲基)氨基}吲唑-1-甲酸-2-甲基丙-2-基酯(194-5)(50mg,0.12mmol,1.0eq)溶入MeOH(甲醇)(1mL)中，0℃下加HCl/MeOH(盐酸/甲醇,2mL 4mol/L)溶液中，升至室温，反应液在室温下搅拌2hrs。TLC(DCM:MeOH＝10:1)监测反应。反应完成后，反应液浓缩后用饱和碳酸氢钠(20mL×4)洗涤，乙酸乙酯(50mL×2)萃取，合并有机层，用无水硫酸钠干燥，浓缩后粗品用柱层析(DCM:MeOH＝10:1)分离，收集样品得 到白色固体(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]-N-(1H-吲唑-6-基)-N-甲基戊酰胺(194)(21mg,纯度95.06％，收率49.70％)。1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.81(d,J＝8.5Hz,1H),7.37(s,1H),7.03(d,J＝8.3Hz,1H),3.33(s,3H),3.23(dd,J＝11.5,4.3Hz,1H),2.25–2.15(m,1H),2.00(dd,J＝20.8,15.4Hz,5H),1.84–1.76(m,2H),1.71–1.47(m,9H),1.24(dd,J＝30.1,10.7Hz,6H),1.10(t,J＝10.4Hz,1H),1.02(dd,J＝12.8,1.8Hz,1H),0.97(d,J＝17.9Hz,6H),0.79(d,J＝8.5Hz,6H),0.67(s,3H),0.60(s,3H).
13C NMR(101MHz,CDCl3)δ173.91,143.39,134.38,134.32,124.83,122.53,121.20,112.74,110.58,78.99,50.39,50.23,49.76,44.42,38.88,37.70,37.00,36.14,35.57,32.05,31.46,30.91,30.76,28.05,27.96,27.83,26.46,24.12,20.93,19.12,18.31,18.23,15.70,15.41.LC-MS：[M+H]+＝546.4
实施例200
化合物200(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(2,5-二氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将溴苯换为2,5-二氟溴苯，得到最终产物白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(2,5-二氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(200)(21.01mg,0.04mmol,纯度90.46％，收率16.41％)。1H NMR(400MHz,CDCl3)δ7.18(ddd,J＝11.8,5.8,3.0Hz,1H),6.94-6.75(m,2H),4.99(dd,J＝12.8,5.7Hz,1H),3.23(dd,J＝11.5,4.5Hz,1H),2.07–1.97(m,4H),1.93–1.94(m,1H),1.77–1.64(m,8H),1.60–1.48(m,9H),1.24–1.13(m,3H),1.00(s,3H),0.98(s,3H),0.90–0.86(m,6H),0.81(s,3H),0.68(d,J＝1.6Hz,3H).
13C NMR(101MHz,CDCl3)δ163.48,160.19,134.42,134.38,124.83,113.65,113.61,109.86,78.99,68.14, 50.48,50.41,49.81,44.49,38.89,37.02,35.59,30.98,30.83,28.22,27.96,27.85,26.50,24.26,22.32,20.99,19.14,18.61,18.25,15.75,15.42.LCMS:[M-OH]+＝511.37
实施例201
化合物201(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(3-氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将溴苯换为间氟溴苯，得到最终产物白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(3-氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(201)(9.79mg,0.02mmol,纯度81.8％，收率8.71％)。
1H NMR(400MHz,CDCl3)δ7.30(dd,J＝13.8,7.9Hz,1H),7.09(dd,J＝12.1,9.3Hz,2H),6.96(ddd,J＝9.7,8.1,3.9Hz,1H),4.67(t,J＝6.6Hz,1H),3.23(dd,J＝11.5,4.5Hz,1H),2.01(d,J＝4.9Hz,4H),1.94–1.84(m,1H),1.75–1.65(m,6H),1.60–1.53(m,9H),1.29–1.21(m,4H),1.00(s,3H),0.98(s,3H),0.89–0.84(m,6H),0.81(s,3H),0.67(d,J＝2.4Hz,3H).LCMS(ESI)[M-OH]+＝493.38
实施例202
化合物202(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(2,6-二氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将溴苯换为2,6-二氟溴苯，得到最终产物白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(2,6-二氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊 并[1,2-a]菲-7-醇(202)(6.99mg,0.03mmol,纯度86.9％，收率5.24％)。
1H NMR(400MHz,CDCl3)δ7.25–7.16(m,1H),6.87(t,J＝8.2Hz,2H),5.04(t,J＝7.3Hz,1H),3.23(dd,J＝11.5,4.5Hz,1H),2.01(d,J＝9.3Hz,5H),1.95–1.85(m,2H),1.79–1.61(m,10H),1.58–1.41(m,＝6H),1.21–1.12(m,2H),0.99(d,J＝8.9Hz,6H),0.87(t,J＝5.8Hz,6H),0.81(s,3H),0.67(d,J＝4.0Hz,3H).
13C NMR(101MHz,CDCl3)δ159.71,134.42,134.40,126.55,118.14,111.85,111.59,79.00,66.75,50.41,49.81,44.49,38.89,37.84,37.02,36.32,35.59,30.98,30.83,28.18,27.96,27.85,26.50,24.25,22.86,22.73,20.99,19.14,18.58,18.55,18.26,15.74,15.41.LCMS:[M-OH]+＝511.37
实施例209
化合物209(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(2,4-二氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将溴苯换为2,4-二氟溴苯，得到最终产物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(2,4-二氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(209)。1H NMR(400MHz,CDCl3)δ7.20(dd,J＝14.9,7.4Hz,1H),6.87(t,J＝8.2Hz,2H),5.03(dd,J＝10.3,4.3Hz,1H),3.23(dd,J＝11.5,4.5Hz,＝1H),2.07–1.98(m,5H),1.94–1.83(m,2H),1.72–1.66(m,4H),1.64–1.57(d,J＝9.4Hz,6H),1.47–1.40(m,3H),1.30–1.24(m,4H),1.20–1.14(m,2H),1.00(s,3H),0.98(s,3H),0.87(s,5H),0.81(s,3H),0.67(d,J＝4.0Hz,3H).13C NMR(101MHz,CDCl3)δ165.41,159.39,134.42,132.47,114.79,111.85,108.35,79.00,72.06,50.42,49.81,44.49,38.90,37.03,36.40,36.33,35.60,30.99,30.84,28.21,27.97,27.86,26.50,24.26,22.86,22.73,21.00,19.15,18.55,18.26,17.53,15.75,15.42.LC-MS:[M+H]+＝511.50
实施例212
化合物212(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(噻吩-2-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将苯基锂换成噻吩-2-基锂，得到产物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(噻吩-2-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(212).1H NMR(400MHz,CDCl3)δ7.26-7.23(m,1H),7.00-6.94(m,2H),4.97–4.89(m,1H),3.27–3.19(m,1H),2.02(dd,J＝11.3,6.8Hz,4H),1.83(d,J＝7.6Hz,3H),1.76–1.63(m,6H),1.48–1.42(m,3H),1.38–1.27(m,4H),1.27–1.14(m,4H),1.07–1.03(m,1H),0.99(d,J＝8.6Hz,6H),0.88(dd,J＝5.6,3.8Hz,6H),0.81(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ134.43,134.39,126.61,126.59,124.51,124.46,123.75,123.62,79.00,70.37,50.42,49.82,44.49,39.78,38.90,37.03,36.37,35.93,35.60,30.91,28.24,27.91,26.51,24.26,22.63,21.00,19.15,18.66,18.26,15.76,15.42.LC-MS:[M-OH]+＝481.45
实施例215
化合215(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-[2-(三氟甲基)苯基]己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将苯基锂换成临三氟甲基苯基锂，得到产物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-[2-(三氟甲基)苯基]己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(215).1H NMR(399MHz,Chloroform-d)δ7.75(d,J＝7.9Hz,1H),7.57(q,J＝8.0Hz,2H),7.34(t,J＝7.7Hz,1H),5.08(d,J＝7.9Hz,1H),3.21(dd,J＝11.6,4.5Hz,1H),1.99(dd,J＝15.4,7.5Hz,4H),1.95–1.78(m,2H),1.74–1.61(m,7H),1.60–1.52(m,4H),1.48–1.37(m,5H),1.34–1.22(m,3H),1.21–1.10(m,3H),1.04–1.00(m,2H),0.96(s,3H),0.86(d,J＝6.5Hz,6H),0.79(s,3H),0.66(d,J＝3.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ134.37,132.24,127.49,127.29,125.37,125.31,78.99, 77.32,77.21,77.15,77.00,76.69,69.68,69.46,50.47,50.38,49.78,44.46,39.69,39.59,38.87,36.99,36.35,36.29,35.97,35.80,35.56,30.97,30.81,28.16,28.13,27.94,27.82,26.90,26.48,24.25,23.07,22.93,20.98,19.12,18.59,18.54,18.23,15.73,15.40.
实施例221
化合物221(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(2-甲氧基苯基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将苯基锂换为邻甲氧基苯基锂，得到产物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(2-甲氧基苯基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(221)1H NMR(400MHz,CDCl3)δ7.30(dd,J＝6.8,5.1Hz,1H),7.23(d,J＝7.6Hz,1H),6.95(t,J＝7.4Hz,1H),6.88(d,J＝8.2Hz,1H),4.85(d,J＝7.7Hz,1H),3.86(s,3H),3.23(dd,J＝11.5,4.5Hz,1H),2.02(dd,J＝13.0,7.4Hz,4H),1.91(dd,J＝13.1,8.0Hz,1H),1.70(ddd,J＝13.7,8.5,3.6Hz,7H),1.56(dd,J＝12.7,9.5Hz,4H),1.44(d,J＝9.7Hz,4H),1.25(s,3H),1.20–1.12(m,2H),1.07–1.02(m,2H),0.99(d,J＝8.4Hz,6H),0.87(s,3H),0.81(s,3H),0.68(d,J＝2.8Hz,3H).13C NMR(101MHz,CDCl3)δ134.42,128.27,128.12,127.09,126.87,120.69,110.57,77.33,77.01,76.70,55.37,55.28,50.42,49.82,44.59,38.99,37.08,35.56,30.95,30.86,30.20,29.67,28.38,27.97,27.81,26.46,24.27,22.86,21.01,19.12,18.55,18.22,15.70,15.35.LC-MS:[M-OH]+＝505
实施例228
化合物228(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(1,3-硫杂氮杂环戊熳-2-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将苯基锂换为1,3-硫杂氮杂环戊熳-2-基锂，得到产物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(1,3-硫杂氮杂环戊熳-2-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(228)1H NMR(400MHz,CDCl3)δ7.77(d,J＝3.3Hz,1H),7.34(d,J＝3.3Hz,1H),5.10-5.03(m,1H),3.23(dd,J＝11.6,4.5Hz,1H),2.03–1.97(m,3H),1.95–1.80(m,4H),1.76–1.64(m,6H),1.60-1.54(m,2H),1.52-1.42(m,3H),1.33(s,2H),1.27(ddd,J＝11.1,10.1,3.6Hz,3H),1.17(s,1H),1.05(dd,J＝12.6,2.1Hz,1H),0.99(d,J＝8.4Hz,6H),0.91–0.85(m,6H),0.81(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ141.95,134.41,118.92,117.01,79.00,72.01,70.42,70.22,50.42,49.82,44.50,39.00–38.55,37.03,36.35(d,J＝6.1Hz,40H),35.93,35.59,30.91,28.22,27.91,26.50,24.26,22.46,22.00,21.00,19.75,19.15,18.65,18.26,15.76,15.42LC-MS:[M+H]+＝500.6
实施例229
化合物229 2-[(5R)-1-羟基-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己基]苯-1-甲腈的制备
参考实施例161，将苯基锂换为邻氰基苯基锂，得到化合物2-[(5R)-1-羟基-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-羟基-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-1-基]己基]苯-1-甲腈(229).1H NMR(400MHz,Methanol-d4)δ8.18(d,J＝8.0Hz,1H),7.96(t,J＝7.6Hz,1H),7.75(t,J＝7.6Hz,1zH),7.57(t,J＝8.1Hz,1H),6.20(dd,J＝8.1,3.8Hz,1H),3.21–3.07(m,1H),2.04(s,4H),1.92(s,2H),1.73(d,J＝14.7Hz,4H),1.65–1.55(m,4H),1.55–1.39(m,4H),1.35–1.25(m,4H),1.23–1.11(m,3H),1.03(dd,J＝12.4,2.1Hz,1H),0.97(d,J＝10.9Hz,6H),0.91–0.85(m,6H),0.78(s,3H),0.72 (t,J＝2.7Hz,3H)LC-MS:[M+H]+＝518.4
实施例230
化合230(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(2,3-二氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将苯基锂换为2,3-二氟苯基锂，得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(2,3-二氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(230).1H NMR(399MHz,Chloroform-d)δ7.21(s,1H),7.08–7.01(m,2H),5.01(d,J＝6.7Hz,1H),3.21(dd,J＝11.5,4.6Hz,1H),2.03–1.97(m,4H),1.73(d,J＝7.0Hz,2H),1.71–1.62(m,6H),1.43(t,J＝9.1Hz,3H),1.26(d,J＝16.5Hz,4H),1.21(s,1H),1.18–1.12(m,2H),1.03(d,J＝11.9Hz,2H),0.97(d,J＝8.2Hz,6H),0.87(d,J＝4.0Hz,3H),0.85(s,3H),0.79(s,3H),0.66(d,J＝2.2Hz,3H).13C NMR(100MHz,Chloroform-d)δ134.35,110.01,78.97,50.44,49.78,44.45,38.86,38.41,36.99,30.95,28.19,27.82,18.22 19F(376MHz,CDCl3)δ138.92，145.06LC-MS:[M-OH]+＝511.30。
实施例247
化合物247(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(1,3-氧杂氮杂环戊熳-2-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备

第一步 化合物1,3-氧杂氮杂环戊熳(75.61mg,1.095mmol，5.0eq)溶解在无水四氢呋喃(5mL)中，氮气保护，缓缓加入硼烷四氢呋喃溶液(0.219mL,0.219mmol，1.0eq)，室温搅拌1hr，随后反应降温到-70℃，用注射器加入叔丁基锂1.3M正戊烷(0.842mL,1.095mmol，5.0eq)，保温反应40分钟，随后加入)乙酸(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(100mg,0.219mmol，1.0eq)，TLC(石油醚:乙酸乙酯＝5:1)监测反应完全。反应液用冰水淬灭，乙酸乙酯萃取(10mL x2)，有机相饱和盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗品硅胶柱层析纯化(石油醚:乙酸乙酯＝90:10)得到白色固体乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(1,3-氧杂氮杂环戊熳-2-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(247-1)(20mg,0.030mmol,纯度80％收率13.90％)。
1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.59(s,1H),4.71(s,1H),4.51(dd,J＝11.5,4.5Hz,1H),3.66(s,0H),2.65(s,0H),2.08–1.98(m,7H),1.94–1.62(m,13H),1.45-1.42(m,12H),1.01(s,3H),0.89(dd,J＝8.7,4.4Hz,11H),0.68(s,3H).
第二步 乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(1,3-氧杂氮杂环戊熳-2-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(247-1)(20mg,0.038mmol)溶解在甲醇(1mL)和四氢呋喃(1mL)混合溶剂中，加入饱和的氢氧化锂溶液(0.5mL)，室温搅拌，TLC(石油醚:乙酸乙酯＝3:1)监测反应。反应结束后，体系乙酸乙酯稀释，饱和盐水洗涤3次，有机相无水硫酸钠干燥，过滤，滤浓缩干得到粗品，粗品用快速硅胶柱层析纯化(石油醚:乙酸乙酯c＝80：20)得到白色固体(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(1,3-氧杂氮杂环戊熳-2-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(247)(3.5mg,0.006mmol,16.55％)。1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.59(s,1H),4.70(s,1H),3.24(dd,J＝11.5,4.4Hz,1H),2.03(d,J＝10.3Hz,4H),1.74(s,3H),1.69(dd,J＝10.5,6.4Hz,6H),1.56(dd,J＝19.4,6.4Hz,3H),1.46(dd,J＝20.7,11.8Hz,4H),1.33(s,1H),1.28(s,1H),1.21(dd,J＝17.2,7.3Hz,2H),1.05(d,J＝12.6Hz,2H),0.99(d,J＝8.7Hz,6H),0.90(d,J＝2.4Hz,2H),0.87(s,3H),0.81(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ153.24,138.57,134.42,125.18,125.10,79.16,66.96,50.41,49.76,44.46,42.93,38.92,37.03,35.57,28.23,27.97,27.86,26.50,24.27,22.20,22.11,21.00,19.15,18.65,18.23,15.76,15.43.LCMS：[M+H]+＝484.3
实施例256
化合物256(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(吡啶-4-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将溴苯换为4-溴吡啶得到最终产物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(吡啶-4-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(161).1H NMR(400MHz,DMSO)δ8.48(d,J＝5.5Hz,2H),7.31(d,J＝5.3Hz,2H),5.37–5.32(m,1H),4.56–4.48(m,1H),4.32(d,J＝5.1Hz,1H),3.00(dt,J＝10.7,5.5Hz,1H),1.05-1.91(m,4H),1.85(s,2H),1.63(d,J＝12.7Hz,4H),1.52(dd,J＝19.8,8.3Hz,5H),1.41(dd,J＝17.5,8.8Hz,4H),1.30(dd,J＝22.7,12.4Hz,5H),1.15–1.08(m,4H),0.91(d,J＝6.3Hz,6H),0.83(s,3H),0.70(s,3H),0.65(s,3H).LCMS[M+H]+＝494.4
实施例257
化合物257(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(吡啶-3-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将溴苯换为3-溴吡啶得到最终产物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(吡啶-3-基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(257).1H NMR(400MHz,DMSO)δ8.50(s,1H),8.43(d,J＝4.7Hz,1H),7.70(d,J＝8.0Hz,1H),7.37–7.29(m,1H),5.32(s,1H),4.60-4.51(m,1H),4.33(d,J＝5.0Hz,1H),2.99(s,1H),2.01–1.96(m,5H),1.85(s,1H),1.60(dd,J＝24.5,9.4Hz,6H),1.44(dd,J＝21.5,9.2Hz,7H),1.26(s,5H),1.10(d,J＝10.7Hz,3H),0.91(d,J＝6.0Hz,4H),0.82(s,6H),0.70(s,3H),0.64(s,3H).LCMS[M+H]+＝494.4
实施例261
化合物261(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基辛-7-炔-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
第一步 称取乙炔基三甲基甲硅烷(516.24mg,5.256mmol)溶于四氢呋喃(20mL)中，干冰-丙酮降温至-78℃，滴加丁基锂(280.53mg,4.379mmol)，随后在该温度下搅拌30min，随后滴加乙酸-(1R,3aR,7S,9aS,11aR)-1-[(2R)-5-甲酰基戊-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(37-2)(200mg,0.438mmol)的四氢呋喃溶液(5mL)，TLC(石油醚：乙酸乙酯＝3:1)监测完全。加入20.0mL饱和氯化铵水溶液，在以乙酸乙酯10mL*3萃取，有机相合并，干燥，浓缩后经柱层析(石油醚：乙酸乙酯＝30：1～5：1)纯化得(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-8-(三甲基甲硅基)辛-7-炔-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(261-1)(150mg,0.25mmol,56.75％)。1H NMR(399MHz,Chloroform-d)δ4.34(s,1H),3.21(dd,J＝11.5,4.5Hz,1H),2.01(d,J＝11.9Hz,4H),1.89(dd,J＝13.7,8.1Hz,1H),1.79(s,1H),1.66(dt,J＝15.9,5.3Hz,6H),1.55–1.45(m,4H),1.44–1.30(m,5H),1.21(dt,J＝19.9,11.2Hz,4H),1.06–0.99(m,2H),0.97(d,J＝7.3Hz,6H),0.89(d,J＝6.1Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H),0.15(s,9H).
第二步 称取(1R,3aR,7S,9aS,11aR)-1-[(2R)-6-羟基-8-(三甲基甲硅基)辛-7-炔-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(240-1)(150mg,0.292mmol)溶于甲醇(5mL)中，加入碳酸钾(121.25mg,0.877mmol)，室温下搅拌，TLC(石油醚：乙酸乙酯＝3:1)监测反应完全。加入水和乙酸乙酯萃取，有机相分离，干燥，浓缩后经柱层析(石油醚：乙酸乙酯＝10：1～5：1～2：1)纯化得(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基辛-7-炔-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(261)(90mg,0.187mmol,64.11％)白色固体。
1H NMR(399MHz,Chloroform-d)δ5.28(s,0H),4.38–4.33(m,1H),3.22(dd,J＝11.5,4.5Hz,1H),2.45(dd,J＝2.1,1.1Hz,1H),2.07–1.96(m,4H),1.87(s,2H),1.76–1.61(m,8H),1.50–1.12(m,10H),1.03(dd,J＝12.5,2.2Hz,2H),0.97(d,J＝7.5Hz,6H),0.89(d,J＝6.2Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H).13C NMR(100MHz,CDCl3)δ134.37,134.34,106.93,106.84,89.34,89.26,78.98,78.95,62.94,50.46,50.28,49.77,44.44,38.85,38.14,38.05,36.99,36.20,35.62,30.95,28.15,28.02,27.82,26.47,24.33,20.97,18.22,15.66,15.47,0.99,-0.13.LCMS:[M-OH]+＝423.4.
实施例262
化合物(1R,3aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-{2-[(三氟甲基)氧基]苯基}己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将苯基锂换为2-三氟甲氧基苯基锂，得到化合物(1R,3aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-{2-[(三氟甲基)氧基]苯基}己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(262)。1H NMR(399MHz,Chloroform-d)δ7.60–7.55(m,1H),7.31–7.26(m,2H),7.22–7.16(m,1H),5.04(dd,J＝5.3,3.3Hz,1H),3.21(dd,J＝11.5,4.5Hz,1H),2.01(d,J＝8.1Hz,6H),1.88(dd,J＝13.1,8.0Hz,2H),1.76–1.61(m,9H),1.56(d,J＝11.7Hz,2H),1.50(dd,J＝12.9,3.8Hz,2H),1.44(d,J＝9.5Hz,3H),1.41–1.35(m,3H),1.31(s,3H),1.25(d,J＝11.5Hz,4H),1.23–1.15(m,3H),1.03(dd,J＝12.5,2.3Hz,2H),0.97(d,J＝7.3Hz,6H),0.85(q,J＝1.9Hz,6H),0.79(s,3H),0.66(d,J＝1.7Hz,3H).13C NMR(101MHz,CDCl3)δ137.18,134.35,128.41,127.41,126.99,119.90,78.97,68.12,67.92,50.45,50.36,49.76,44.44,38.85,38.52,38.41,36.98,36.33,36.30,35.92,35.78,35.55,30.95,30.79,29.67,28.13,27.92,27.80,26.46,24.22,22.60,22.47,20.96,19.11,18.55,18.52,18.22,15.70,15.39,0.99.19F NMR(376MHz,Chloroform-d)δ-47.51–-69.08(m).LCMS:[M-OH]+＝560.5.
实施例263
化合物263(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(2-甲基苯基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将苯基锂换为2-甲氧基苯基锂，得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-羟基-6-(2-甲基苯基)己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(263)。1H NMR(399MHz,Chloroform-d)δ7.45(d,J＝9.1Hz,1H),7.24–7.08(m,3H),4.96–4.86(m,1H),3.21(dd,J＝11.3,5.0Hz,1H),2.33(s,3H),2.00(s,4H),1.87(d,J＝7.8Hz,2H),1.55–1.35(m,7H),1.34–1.11(m,5H),1.03(d,J＝12.5Hz,2H),0.97(d,J＝7.6Hz,6H),0.92–0.82(m,6H),0.79(s,3H),0.66(s,3H).13C NMR(100MHz,CDCl3)δ143.06,134.35,130.31,127.07,126.24,78.95,50.49,49.77,44.45,38.86,38.62,38.46,36.98,36.38,36.31,35.55,30.96,30.80,28.20,27.81,26.47,24.26,22.99,22.83,20.97,19.13,18.62,18.22,15.73,15.38,0.99.LCMS:[M+Na]+＝529.5.
实施例264
化合物264(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(4-氯苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将苯基锂换为4-氯苯基锂，得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(4-氯苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(264).1H NMR(400MHz,Chloroform-d)δ7.32–7.27(m,3H),7.26(d,J＝6.4Hz,1H),4.64(d,J＝5.3Hz,1H),3.21(d,J＝11.3Hz,1H),2.01(d,J＝12.0Hz,4H),1.96–1.81(m,1H),1.79(s,1H),1.74–1.62(m,6H),1.59(d,J＝15.3Hz,1H),1.54–1.32(m,5H),1.32–1.11(m,6H),1.02(d,J＝12.3Hz,1H),0.97(d,J＝8.9Hz,6H),0.84(d,J＝6.2Hz,6H),0.79(s,3H),0.65(d,J＝2.2Hz,3H).13C NMR(101MHz,CDCl3)δ134.37,134.32,128.52,127.29,127.21,78.97,73.94,50.35,49.77,441.43,39.59,38.86,36.98,36.03,35.92,35.54,30.93,30.79,28.22,27.93,27.80,26.46,24.22,22.49,20.96,19.11,18.62,18.21,15.71,15.40,1.00.
实施例265
化合物265乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(3-氯苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯的制备
参考实施例161，将苯基锂换为3-氯苯基锂，得到化合物乙酸-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(3-氯苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-i]菲-7-基酯(265).1H NMR(399MHz,Chloroform-d)δ7.34(s,1H),7.21(t,J＝8.5Hz,3H),4.63(s,1H),3.21(s,1H),2.01(d,J＝10.1Hz,4H),1.87(s,1H),1.81(s,1H),1.66(dd,J＝16.4,4.4Hz,7H),1.46–1.31(m,5H),1.25(d,J＝12.5Hz,4H),1.16(d,J＝10.9Hz,2H),1.03(d,J＝12.6Hz,1H),0.97(d,J＝8.8Hz,6H),0.86(d,J＝6.7Hz,6H),0.79(s,3H),0.66(d,J＝2.8Hz,3H).13C NMR(100MHz,CDCl3)δ134.34,134.30,110.00,50.43,49.78,44.45,39.58,38.86,36.99,35.55,30.94,30.79,28.22,27.81,26.47,20.96,18.22,15.72,15.38,0.99.
实施例267
化合物267(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(3,5-二氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇的制备
参考实施例161，将苯基锂换为3,5-二氟苯基锂，得到化合物(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(3,5-二氟苯基)-6-羟基己-2-基]-3a,6,6,9a,11a-五甲基-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-十四氢-1H-环戊并[1,2-a]菲-7-醇(267)。1H NMR(400MHz,CDCl3)δ7.21(t,J＝7.8Hz,1H),6.87(t,J＝8.3Hz,2H),5.08–4.96(m,1H),3.23(dd,J＝11.6,4.5Hz,1H),2.01(d,J＝9.4Hz,4H),1.94–1.83(m,2H),1.74–1.52(m, 14H),1.25(s,2H),1.21–1.13(m,2H),0.99(d,J＝8.7Hz,6H),0.89–0.85(m,6H),0.81(s,3H),0.67(d,J＝4.1Hz,3H).13C NMR(101MHz,CDCl3)δ164.31,134.39,131.73,111.85,111.59,106.84,79.00,50.47,50.40,49.81,44.48,41.01,40.82,38.89,37.74,37.02,35.72,35.59,30.98,30.83,28.21,27.96,27.85,26.50,24.25,22.73,20.99,19.14,18.61,18.25,15.74,15.42.LCMS：[M+H]+＝511.5。

Claims (14)

  1. 一种式I所示化合物或其药学上可接受的盐：
    其中，R21为-L1-C(O)RA、-L1-S(O)2RA、-L1-RB、 -L2-RC或-L3-RD；
    每个L1和L2独立地为单键、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分任选被-X-代替；
    L3为-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分被-Y-代替；
    每个X独立地为-CHR5a-、-CR5aR5b-、C3-6环烷基、C3-6氧杂环烷基、C3-6氮杂环烷基或-Y-；
    每个R5a和R5b各自独立地为F或氟代C1-4烷基；
    每个Y独立地为-O-、-NH-、-N(C1-4烷基)-、-CH＝CH-、或-CHRg-；
    Rg为-C1-4亚烷基-OH；
    每个RA独立地为-NR21aR21b；
    RB为-N(R21a)-C(O)R21b或-N(R21a)-S(O)2R21b；
    RD为-OH、-CH2OH、RC、-CH(CH3)-OH或-C(CH3)2-OH；
    每个RC独立地为-C(R21c)(R21d)-OH、-C(R21c)(R21d)-CN、CN、-C(O)RE、NH2、C1-4烷氧基、3-6元杂环烷基或5-10元杂芳基；所述5- 10元杂芳基是未取代的或者被p个Rc取代；
    RE为C1-4烷基、C3-6环烷基或3-6元杂环烷基；其中所述C1-4烷氧基、C3-6环烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
    每个R21a独立地为H、C1-6烷基或3-6元杂环烷基，其中所述C1-6烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
    每个R21b独立地为H、C1-6烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基独立地是未取代的或者被q个Rb取代；
    或者，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成3-10元杂环烷基，其中所述3-10元杂环烷基是未取代的或者被p个Rc取代；
    每个m、p和q各自独立地为1、2、3、4或5；
    每个Ra、Rb和Rc各自独立地为F、Cl、OH、COOH、CN、NO2、C1-4烷基、氟代C1-4烷基、C1- 4烷氧基、
    R21c为H、F、C1-4烷基、氟代C1-4烷基、C2-4烯基或C3-6环烷基；
    R21d为F、C2-4烷基、氟代C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、苯基、5-6元杂芳基或-L4-R21e，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
    或者，R21c和R21d以及连接它们的碳原子一起形成C3-6环烷基或3-6元杂环烷基；
    L4为亚甲基或亚乙基；
    R21e为OH、CN、C1-4烷氧基、苯基或5-6元杂芳基，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
    每个j独立地为1、2、3或4；
    每个r独立地为0、1、2、3或4；
    每个Rd和Rf独立地为F、Cl、OH、CN、NO2、C1-4烷基、氟代C1-4烷基、氟代C1-4烷氧基或C1- 4烷氧基；
    所述杂环烷基和杂芳基中的杂原子个数独立地为1、2、3或4个，每个杂原子独立地为N、O或S；
    式I所示化合物不为：
    式I中*标记的碳原子为S构型、R构型或者两者的混合。
  2. 如权利要求1所述的式I所示化合物或其药学上可接受的盐，其特征在于，
    其中，R21为-L1-C(O)RA、-L1-S(O)2RA、-L1-RB、 -L2-RC或-L3-RD；
    每个L1和L2独立地为单键、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分任选被-X-代替；
    L3为-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分被-Y-代替；
    每个X独立地为-CHR5a-、-CR5aR5b-或-Y-；
    每个R5a和R5b各自独立地为F、C1-4烷基或氟代C1-4烷基；
    每个Y独立地为-O-、-NH-、-N(C1-4烷基)-、-CH＝CH-、 或-CHRg-；
    Rg为-C1-4亚烷基-OH；
    每个RA独立地为-NR21aR21b；
    RB为-N(R21a)-C(O)R21b；
    RD为-OH、-CH2OH、RC、-CH(CH3)-OH或-C(CH3)2-OH；
    每个RC独立地为-C(R21c)(R21d)-OH、CN、-C(O)RE、NH2、C1-4烷氧基、 3-6元杂环烷基或5-10元杂芳基；所述5-10元杂芳基是未取代的或者被p个Rc取代；
    RE为C1-4烷基、C1-4烷氧基、C3-6环烷基或3-6元杂环烷基；其中所述C1-4烷基、C1-4烷氧基、C3- 6环烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
    每个R21a独立地为H、C1-6烷基、C3-6环烷基或3-6元杂环烷基，其中所述C1-6烷基、C3-6环烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
    每个R21b独立地为H、C1-6烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基独立地是未取代的或者被q个Rb取代；
    或者，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成3-10元杂环烷基，其中所述3-10元杂环烷基是未取代的或者被p个Rc取代；
    每个m、p和q各自独立地为1、2、3、4或5；
    每个Ra、Rb和Rc各自独立地为F、Cl、OH、COOH、CN、NO2、C1-4烷基、氟代C1-4烷基、C1- 4烷氧基、
    R21c为H、F、C1-4烷基、氟代C1-4烷基、C2-4烯基或C3-6环烷基；
    R21d为F、C2-4烷基、氟代C1-4烷基、C2-4烯基、C3-6环烷基、苯基、5-6元杂芳基或-L4-R21e，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
    或者，R21c和R21d以及连接它们的碳原子一起形成C3-6环烷基或3-6元杂环烷基；
    L4为C1-4亚烷基；
    R21e为OH、CN、C1-4烷氧基、苯基或5-6元杂芳基，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
    每个j独立地为1、2、3或4；
    每个r独立地为0、1、2、3或4；
    每个Rd和Rf独立地为F、Cl、OH、CN、NO2、C1-4烷基、氟代C1-4烷基或C1-4烷氧基；
    所述杂环烷基和杂芳基中的杂原子个数独立地为1、2、3或4个，每个杂原子独立地为N、O或S；
    式I中*标记的碳原子为S构型、R构型或者两者的混合。
  3. 如权利要求1所述的式I所示化合物或其药学上可接受的盐，其特征在于，
    其中，R21为-L1-C(O)RA、-L1-S(O)2RA、-L1-RB、 -L2-RC或-L3-RD；
    每个L1和L2独立地为单键、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分任选被-X-代替；
    L3为-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-或-(CH2)6-，其中所述-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-和-(CH2)6-中的一个-CH2-部分被-Y-代替；
    每个X独立地为-CHR5a-、-CR5aR5b-或-Y-；
    每个R5a和R5b各自独立地为F、C1-4烷基或氟代C1-4烷基；
    每个Y独立地为-O-、-NH-、-N(C1-4烷基)-、-CH＝CH-、 或-CHRg-；
    Rg为-C1-4亚烷基-OH；
    每个RA独立地为-NR21aR21b；
    RB为-N(R21a)-C(O)R21b或-N(R21a)-S(O)2R21b；
    RD为-OH、-CH2OH、RC、-CH(CH3)-OH或-C(CH3)2-OH；
    每个RC独立地为-C(R21c)(R21d)-OH、CN、-C(O)RE、NH2、C1-4烷氧基、 3-6元杂环烷基或5-10元杂芳基；所述5-10元杂芳基是未取代的或者被p个Rc取代；
    RE为C1-4烷基、C1-4烷氧基、C3-6环烷基或3-6元杂环烷基；其中所述C1-4烷基、C1-4烷氧基、C3- 6环烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
    每个R21a独立地为H、C1-6烷基、C3-6环烷基或3-6元杂环烷基，其中所述C1-6烷基、C3-6环烷基和3-6元杂环烷基独立地是未取代的或者被m个Ra取代；
    每个R21b独立地为H、C1-6烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基独立地是未取代的或者被q个Rb取代；
    或者，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成3-10元杂环烷基，其中所述3-10元杂环烷基是未取代的或者被p个Rc取代；
    每个m、p和q各自独立地为1、2、3、4或5；
    每个Ra、Rb和Rc各自独立地为F、Cl、OH、COOH、CN、NO2、C1-4烷基、氟代C1-4烷基、C1- 4烷氧基、
    R21c为H、F、C1-4烷基、氟代C1-4烷基、C2-4烯基或C3-6环烷基；
    R21d为F、C2-4烷基、氟代C1-4烷基、C2-4烯基、C3-6环烷基、苯基、5-6元杂芳基或-L4-R21e，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
    或者，R21c和R21d以及连接它们的碳原子一起形成C3-6环烷基或3-6元杂环烷基；
    L4为C1-4亚烷基；
    R21e为OH、CN、C1-4烷氧基、苯基或5-6元杂芳基，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；
    每个j独立地为1、2、3或4；
    每个r独立地为0、1、2、3或4；
    每个Rd和Rf独立地为F、Cl、OH、CN、NO2、C1-4烷基、氟代C1-4烷基或C1-4烷氧基；
    所述杂环烷基和杂芳基中的杂原子个数独立地为1、2、3或4个，每个杂原子独立地为N、O或S；
    式I中*标记的碳原子为S构型、R构型或者两者的混合。
  4. 如权利要求1-3任一项所述的式I所示化合物或其药学上可接受的盐，其特征在于，其满足以下条件中的一种或多种：
    (1)R21为-L1-C(O)RA、-L1-RB、-L2-RC或-L3-RD；
    (2)L1为单键、-CH2-、-(CH2)2-或-(CH2)3-；
    (3)每个R21a独立地为H或C1-6烷基，其中所述C1-6烷基是未取代的或者被m个Ra取代；每个R21b独立地为H、C1-6烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基独立地是未取代的或者被q个Rb取代；或者，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成3-10元杂环烷基，其中所述3-10元杂环烷基是未取代的或者被p个Rc取代；
    (4)每个m、p和q各自独立地为1或2；
    (5)L2为-CH2-、-(CH2)2-、-(CH2)3-或-(CH2)4-；其中所述-CH2-、-(CH2)2-、-(CH2)3-和-(CH2)4-中的一个-CH2-部分任选被-X-代替；每个X独立地为-CHR5a-，每个R5a和R5b各自独立地为F；较佳的，L2为-(CH2)3-；
    (6)每个RC独立地为-C(R21c)(R21d)-OH、CN、-C(O)RE、NH2、C1-4烷氧基、 3-6元杂环烷基或5-10元杂芳基；所述5-10元杂芳基是未取代的或者被p个Rc取代；
    (7)R21c为H或C1-4烷基；R21d为F、C2-4烷基、氟代C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、苯基、5-6元杂芳基或-L4-R21e，其中所述苯基和5-6元杂芳基独立地是未取代的或者被j个Rd取代；或者，R21c和R21d以及连接它们的碳原子一起形成C3-6环烷基或3-6元杂环烷基；
    (8)Rd独立地为F、Cl、OH、CN、C1-4烷基、氟代C1-4烷基、氟代C1-4烷氧基或C1-4烷氧基；
    (9)RE为C1-4烷基或C3-6环烷基；
    (10)RD为-OH、-CH2OH或-C(CH3)2-OH；
    (11)每个j独立地为1或2；和
    (12)每个r独立地为0。
  5. 如权利要求1-3任一项所述的式I所示化合物或其药学上可接受的盐，其特征在于，其满足以下条件中的一种或多种：
    (1)每个X独立地为-CHR5a-或-CR5aR5b-，例如-CHR5a-；
    (2)L1的定义如下任一组中所述：
    a)L1为单键；
    b)L1为-(CH2)2-或-CH2-CHR5a-；
    c)每个R5a和R5b各自独立地为F、甲基、乙基或三氟甲基；
    d)L1为-(CH2)3-；
    e)L1为-(CH2)4-；
    f)L1为-(CH2)5-；和
    g)L1为-(CH2)6-；
    (3)R21的定义如下任一组中所述：
    a)R21为-L1-C(O)RA；
    b)R21为-L1-S(O)2RA；
    c)R21为-L1-RB；
    d)R21为-L2-RC；
    e)R21为-L3-RD；
    f)R21为
    g)R21为
    h)R21为
    i)R21为和
    j)R21为
    (4)每个R21a独立地为H、C1-6烷基或C3-6环烷基，其中所述C1-6烷基和C3-6环烷基独立地是未取代的或者被m个Ra取代；每个R21b独立地为H、C1-6烷基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C6-10芳基和5-10元杂芳基独立地是未取代的或者被q个Rb取代；或者，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成 其中所述是未取代的或者被p个Rc取代；较佳的，在-NR21aR21b中，R21a和R21b以及连接它们的氮原子一起形成
    (5)m为1、2或3
    (6)每个Ra独立地为F、OH、CN或甲氧基；
    (7)q为1、2或3；
    (8)每个Rb独立地为F、Cl、OH、COOH、CN、NO2、甲基、三氟甲基、甲氧基、
    (9)p为1、2或3；
    (10)每个Rc各自独立地为F、OH、CN、C1-4烷基或氟代C1-4烷基；较佳的，每个Rc各自独立地为F、OH、CN、甲基或三氟甲基；
    (11)L2的定义如下任一组中所述：
    a)L2为单键；
    b)L2为-CH2-；
    c)L2为-(CH2)2-；
    d)L2为-(CH2)3-；
    e)L2为-(CH2)4-；
    f)L2为-(CH2)5-；和
    g)L2为-(CH2)6-；
    (12)RC的定义如下任一组中所述：
    a)每个RC独立地为-C(R21c)(R21d)-OH；
    b)RC为CN；
    c)RC为-C(O)RE；
    d)RC为NH2；
    e)RC为C1-4烷氧基，例如甲氧基；
    f)RC为例如
    g)RC为例如
    h)RC为例如
    i)RC为5-10元杂芳基，所述5-10元杂芳基是未取代的或者被p个Rc取代；较佳的，RC为和
    j)，RC为3-6元杂环烷基；
    (13)当RC为-C(R21c)(R21d)-OH时，R21c和R21d的定义如下任一组中所述：
    a)R21c为H，R21d为C2-4烷基、氟代C1-4烷基、C3-6环烷基、苯基、5-6元杂芳基或-L4-R21e，其中，苯基任选被1个或2个Rd取代，每个Rd独立地为F、OH、CN或C1-4烷氧基；例如，R21c为H，R21d为C2-4烷基、氟代C1-4烷基、C3-6环烷基、苯基、氟代苯基、5-6元杂芳基或-L4-R21e；较佳的，RC中的-C(R21c)(R21d)-OH为
    b)R21c为F，R21d为C2-4烷基(例如乙基)；较佳的，RC中的-C(R21c)(R21d)-OH为
    c)R21c为CH3或三氟甲基，R21d为C2-4烷基(例如乙基)或三氟甲基；较佳的，RC中的-C(R21c)(R21d)-OH为
    d)R21c为C2-4烷基、C2-4烯基(例如)或C3-6环烷基(例如环丙基)，R21d为C2-4烷基、C2-4烯基(例如)或C3-6环烷基(例如环丙基)；较佳的，R21c为乙基、正丙基、异丙基、或环丙基，R21d为乙基、正丙基、异丙基、或环丙基；更佳的，RC中的-C(R21c)(R21d)-OH为和
    e)R21c和R21d以及连接它们的碳原子一起形成C3-6环烷基或3-6元杂环烷基(例如)；较佳的，R21c和R21d以及连接它们的碳原子一起形成环丙基、环丁基或
    (14)R21e为OH、CN、C1-4烷氧基、苯基或
    (15)RE为C1-4烷基或C3-6环烷基；较佳的，RE为甲基、乙基或环己基；
    (16)RC定义中的5-10元杂芳基为
    (17)RC定义中的3-6元杂环烷基为
    (18)L3为 上述结构的b端与RD连接；和
    (19)RD为-OH、-CH2OH、-CH(CH3)-OH或-C(CH3)2-OH。
  6. 如权利要求1-3任一项所述的式I所示化合物或其药学上可接受的盐，其特征在于，其满足以下条件中的一种或多种：
    (1)每个R21a独立地为H、C1-4烷基、-C1-4亚烷基-OH、-C1-4亚烷基-OC1-4烷基、氟代C1-4烷基或环丙基；较佳的，每个R21a独立地为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、环丙基或三氟甲基；
    (2)每个R21b独立地为H、-C1-4亚烷基-OH、-C1-4亚烷基-OC1-4烷基、氟代C1-4烷基、四氢吗啉基、苯基、吡啶基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噻二唑基、嘧啶基或苯并吡唑基，其中所述苯基、吡啶基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噻二唑基、嘧啶基和苯并吡唑基独立地是未取代的或者被q个Rb取代；较佳的，每个R21b独立地为H、-C1-4亚烷基-OH、-C1-4亚烷基-OC1-4烷基、氟代C1-4烷基、四氢吗啉基、苯基、 其中所述苯基、 独立地是未取代的或者被q个Rb取代；更佳的，每个R21b独立地为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、苯基、 进一步优选的，每个R21b独立地为和
    (3)RC中的-C(R21c)(R21d)-OH为 较佳的，RC中的-C(R21c)(R21d)-OH为 更佳的，RC中的-C(R21c)(R21d)-OH为
  7. 如权利要求1-3任一项所述的式I所示化合物或其药学上可接受的盐，其特征在于，其满足以下条件中的一种或多种：
    (1)每个RA独立地为-NH2、 较佳的，每个RA独立地为 更佳的，每个RA独立地 和
    (2)RB为 较佳的，RB为
  8. 如权利要求1-3任一项所述的式I所示化合物或其药学上可接受的盐，其特征在于，其满足以下条件中的一种或多种：
    (1)-L1-C(O)RA为
    (2)-L1-RB为
    (3)-L2-RC为 较佳的，-L2-RC为 和
    (4)R21中的-L3-RD为 较佳的，R21中的-L3-RD为 更佳的，R21中的-L3-RD为
  9. 如权利要求1-3任一项所述的式I所示化合物或其药学上可接受的盐，其特征在于，R21为

  10. 如权利要求1-3任一项所述的式I所示化合物或其药学上可接受的盐，其特征在于，式I所示化合物为如下式I-1或I-2所示化合物：
    其中，R21的定义如权利要求1-9任一项所述。
  11. 如权利要求1-3任一项所述的式I所示化合物或其药学上可接受的盐，其特征在于，式I所示化合物为如下任一化合物：













  12. 一种药物组合物，其包含如权利要求1-11中任一项所述的式I所示化合物或其药学上可接受的盐，以及至少一种药用辅料。
  13. 一种如权利要求1-11中任一项所述的式I所示化合物或其药学上可接受的盐或如权利要求12所述的药物组合物在制备用于预防和/或治疗疾病的药物中的应用，其中所述疾病为肥胖、高脂血症、脂肪肝、糖尿病、动脉粥样硬化症、心脑血管疾病、肝癌或皮肤损伤。
  14. 一种如权利要求1-11中任一项所述的式I所示化合物或其药学上可接受的盐或如权利要求12所述的药物组合物在制备用于抑制SREBP通路的药物中的应用。
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