WO2022111587A1 - 大麻素类化合物的制备方法 - Google Patents
大麻素类化合物的制备方法 Download PDFInfo
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- WO2022111587A1 WO2022111587A1 PCT/CN2021/133194 CN2021133194W WO2022111587A1 WO 2022111587 A1 WO2022111587 A1 WO 2022111587A1 CN 2021133194 W CN2021133194 W CN 2021133194W WO 2022111587 A1 WO2022111587 A1 WO 2022111587A1
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- side chain
- compound
- amino acid
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 58
- 229930003827 cannabinoid Natural products 0.000 title claims abstract description 27
- 239000003557 cannabinoid Substances 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 16
- -1 triethylsilyl Chemical group 0.000 claims description 44
- 150000001413 amino acids Chemical group 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 229960003767 alanine Drugs 0.000 claims description 23
- 235000004279 alanine Nutrition 0.000 claims description 21
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 18
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 229940024606 amino acid Drugs 0.000 claims description 13
- 235000001014 amino acid Nutrition 0.000 claims description 13
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 10
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 239000004471 Glycine Substances 0.000 claims description 9
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 9
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 9
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 8
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 8
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 150000008575 L-amino acids Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims 3
- 150000001408 amides Chemical class 0.000 claims 3
- 229940009098 aspartate Drugs 0.000 claims 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims 1
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- 235000009582 asparagine Nutrition 0.000 claims 1
- 240000004308 marijuana Species 0.000 claims 1
- 125000001474 phenylpropanoid group Chemical group 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 4
- 229940002612 prodrug Drugs 0.000 abstract description 4
- 239000000651 prodrug Substances 0.000 abstract description 4
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- 235000013350 formula milk Nutrition 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
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- 238000006243 chemical reaction Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 6
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- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 description 5
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- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 5
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- 239000001257 hydrogen Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
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- 238000001308 synthesis method Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 2
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- 239000012074 organic phase Substances 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
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- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
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- LCWXJXMHJVIJFK-UHFFFAOYSA-N Hydroxylysine Natural products NCC(O)CC(N)CC(O)=O LCWXJXMHJVIJFK-UHFFFAOYSA-N 0.000 description 1
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- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
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- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- QJHBJHUKURJDLG-UHFFFAOYSA-N hydroxy-L-lysine Natural products NCCCCC(NO)C(O)=O QJHBJHUKURJDLG-UHFFFAOYSA-N 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/36—Amides thereof
-
- 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 application relates to the field of compound preparation, in particular to a method for preparing cannabinoid compounds.
- Cannabinoids include about 70 components, mainly including cannabidiol (CBD), cannabidiol (CBN), tetrahydrocannabinol (THC) and their homologues, among which cannabidiol ( CBD) has the highest content.
- CBD cannabidiol
- the purpose of the present invention is to provide a novel method for preparing cannabinoid prodrugs, which has the characteristics of good purification effect and suitability for industrial production.
- One or more embodiments of the present application provide a cannabinoid prodrug technology that improves the in vivo absorption, distribution, transport and metabolism of the parent drug, improves bioavailability, improves the selectivity of the drug's action on the target site, reduces the Toxic and side effects of drugs, technical effects of prolonging action time, etc.
- One or more embodiments of the present application provide a compound of formula (III), or a stereoisomer or salt thereof:
- G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
- R is C 1-12 alkyl
- R 2 is C 1-6 alkyl
- R3 and R4 are each independently a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxyl, sulfhydryl or carboxyl group;
- R 5 is selected from C 1-6 alkyl.
- the R and R are each independently a side chain of glycine, a side chain of alanine, a side chain of leucine, a side chain of phenylalanine, asparagine side chain or arginine side chain.
- the R3 and R4 are each independently a side chain of alanine.
- One or more embodiments of the present application provide a method of preparing a compound of formula (III), or a stereoisomer or salt thereof, comprising combining a compound of formula (I) with formula (II) under basic conditions The compound reacts with L-AA to prepare the compound of general formula (III):
- G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
- R is C 1-12 alkyl
- R 1 is C 1-6 alkyl
- R 2 is C 1-6 alkyl
- R3 and R4 are each independently a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxyl, sulfhydryl or carboxyl group;
- R 5 is C 1-6 alkyl
- L-AA is an L-amino acid.
- the R and R are each independently a side chain of glycine, a side chain of alanine, a side chain of leucine, a side chain of phenylalanine, asparagine side chain or arginine side chain.
- the R3 and R4 are each independently a side chain of alanine.
- One or more embodiments of the present application provide a method of preparing a cannabinoid compound of formula (IV), or a stereoisomer or salt thereof, comprising deprotecting the compound of general formula (III) under basic conditions Base G, the cannabinoid compound of general formula (IV) is obtained:
- G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
- R is C 1-12 alkyl
- R 2 is C 1-6 alkyl
- R3 and R4 are each independently a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxyl, sulfhydryl or carboxyl group;
- R 5 is selected from C 1-6 alkyl.
- the R and R are each independently a side chain of glycine, a side chain of alanine, a side chain of leucine, a side chain of phenylalanine, asparagine side chain or arginine side chain.
- the R3 and R4 are each independently a side chain of alanine.
- One or more embodiments of the present application provide a method of preparing a cannabinoid compound of formula (IV), or a stereoisomer or salt thereof, comprising the steps of:
- G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
- R is C 1-12 alkyl
- R 1 is C 1-6 alkyl
- R 2 is C 1-6 alkyl
- R3 and R4 are each independently a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxyl, sulfhydryl or carboxyl group;
- R 5 is selected from C 1-6 alkyl
- L-AA is an L-amino acid.
- the R and R are each independently a side chain of glycine, a side chain of alanine, a side chain of leucine, a side chain of phenylalanine, asparagine side chain or arginine side chain.
- the R3 and R4 are each independently a side chain of alanine.
- One or more embodiments of the present application provide the use of the compound of formula (III) of the present application, or a stereoisomer or salt thereof, in the preparation of a cannabinoid compound or a stereoisomer or salt thereof.
- the cannabinoid is a cannabinoid of formula (IV).
- One or more embodiments of the present application provide the use of a compound of formula (III) of the present application, or a stereoisomer or salt thereof, in the conversion or production of a cannabinoid compound or a stereoisomer or salt thereof.
- the cannabinoid is a cannabinoid of formula (IV).
- the cannabinoids of formula (IV) are as follows:
- R is C 1-12 alkyl
- R 2 is C 1-6 alkyl
- R3 and R4 are each independently a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxyl, sulfhydryl or carboxyl group;
- R 5 is selected from C 1-6 alkyl.
- the R and R are each independently a side chain of glycine, a side chain of alanine, a side chain of leucine, a side chain of phenylalanine, asparagine side chain or arginine side chain.
- the R3 and R4 are each independently a side chain of alanine.
- the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
- isotopes of carbon include 12 C, 13 C
- Alkyl means 1 to 20 carbon atoms (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms) linear or branched saturated aliphatic hydrocarbon group, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms Alkyl of carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched chain isomers thereof; when the alkyl group is substituted, it can be optionally further substituted by one or more substituents.
- Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
- heterocyclyl optionally substituted with an alkyl group means that the alkyl group may, but need not, be present, and the description includes the case where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group happening.
- Natural amino acid side chain or pharmaceutically acceptable amino acid means that the basic skeleton of a protein molecule is an amino acid sequence. There are 20 basic amino acids that make up proteins. These 20 basic amino acids are the basis for later modification of proteins by organisms. In addition, in these basic amino acids On the basis of amino acids, organisms also synthesize amino acid types derived from hydroxyproline, hydroxylysine, etc. These amino acids synthesized by biosynthesis are collectively referred to as “natural amino acids”; those synthesized by artificial methods are “non-natural amino acids”; “Pharmaceutically acceptable amino acid” refers to a pharmaceutically acceptable natural or unnatural amino acid.
- Standard chain of an amino acid refers to the general amino acid formula The X substituent in the structure.
- the reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was spin-dried, and the residue was purified with ethyl acetate/n-hexane (5%-30%) system to obtain the isomer 1-1 of the title compound 1 (205 mg, 42.3% yield, yellow oil) and Isomer 1-2 (151 mg, 31.1% yield, yellow oil).
- the synthetic method of compound 2a is the same as that of compound 1c to obtain the title compound isopropyl 2-((((ethoxycarbonyl))(((1'R,2'R)-5'-methyl-4-pentyl -2'-(Prop-1-en-2-yl)-6-((triethylsilyl)oxy)-1',2',3',4'-tetrahydro-[1,1 '-Biphenyl]-2-yl)oxy)phosphoryl)amino)-2-propionic acid methyl ester 2a (657 mg, 42.5% yield, yellow oil).
- the synthetic method of compound 3a is the same as that of compound 1c to obtain the title compound benzyl((ethoxycarbonyl)(((1'R,2'R)-5'-methyl-4-pentyl-2'-(propane) -1-En-2-yl)-6-((triethylsilyl)oxy)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]- 2-yl)oxy)phosphoryl)-L-alanine 3a (623 mg, 41.8% yield, yellow oil).
- the synthetic method of compound 4a is the same as that of compound 1a to obtain the title compound isopropyl 2-(((isopropoxycarbonyl)(((1'R,2'R)-5'-methyl-4-pentyl-2 '-(Prop-1-en-2-yl)-6-((triethylsilyl)oxy)-1',2',3',4'-tetrahydro-[1,1'- Biphenyl]-2-yl)oxy)phosphoryl)amino)-2-propionic acid methyl ester 4a (578 mg, 33.8% yield, yellow oil).
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Abstract
大麻素类化合物及其前药的制备方法,该方法纯化效果好、适用于工业化生产。
Description
本申请涉及化合物制备领域,具体涉及制备大麻素化合物的方法。
大麻素类化合物包括大约70多种成分,主要包括大麻二酚(cannabidiol,CBD)、大麻酚(cannabinol,CBN)、四氢大麻酚(Tetrahydrocannabinol,THC)及其同系物等,其中大麻二酚(CBD)含量最高。
目前需要纯化效果好、适用于工业化生产的大麻素类化合物前药的制备方法。
发明内容
本发明的目的是提供新型制备大麻素前药的方法,本方法具有纯化效果好、适用于工业化生产的特点。
本申请的一个或多个实施方式提供了大麻素前药技术,该技术改善母药在体内的吸收、分布、转运与代谢过程、提高生物利用度、提高药物对靶部位作用的选择性、降低药物的毒副作用、延长作用时间等的技术效果。
本申请的一个或多个实施方式提供了式(III)的化合物或者其立体异构体或盐:
其中
G为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基;
R为C
1-12烷基;
R
2为C
1-6烷基;
R
3和R
4各自独立地为天然氨基酸侧链或可药用氨基酸侧链;任选地,所述氨基酸侧链含有任选地被酯化的羟基、巯基或羧基;
R
5选自C
1-6烷基。
在一个或多个实施方式中,所述R
3和R
4各自独立地为甘氨酸的侧链、丙氨酸的侧链、亮氨酸的侧链、苯丙氨酸的侧链、天冬酰胺的侧链或精氨酸的侧链。
在一个或多个实施方式中,所述R
3和R
4各自独立地为丙氨酸的侧链。
本申请的一个或多个实施方式提供了制备式(III)的化合物或者其立体异构体或盐的方法,其包括在碱性条件下将通式(I)的化合物与通式(II)的化合物和L-AA反应,制备得到通式(III)的化合物:
其中
G为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基;
R为C
1-12烷基;
R
1为C
1-6烷基;
R
2为C
1-6烷基;
R
3和R
4各自独立地为天然氨基酸侧链或可药用氨基酸侧链;任选地,所述氨基酸侧链含有任选地被酯化的羟基、巯基或羧基;
R
5为C
1-6烷基;
L-AA为L-氨基酸。
在一个或多个实施方式中,所述R
3和R
4各自独立地为甘氨酸的侧链、丙氨酸的侧链、亮氨酸的侧链、苯丙氨酸的侧链、天冬酰胺的侧链或精氨酸的侧链。
在一个或多个实施方式中,所述R
3和R
4各自独立地为丙氨酸的侧链。
本申请的一个或多个实施方式提供了制备式(IV)的大麻素类化合物或其立体异构体或盐的方法,其包括将通式(III)的化合物在碱性条件下脱去保护基G,得到通式(IV)的大麻素类化合物:
其中
G为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基;
R为C
1-12烷基;
R
2为C
1-6烷基;
R
3和R
4各自独立地为天然氨基酸侧链或可药用氨基酸侧链;任选地,所述氨基酸侧链含有任选地被酯化的羟基、巯基或羧基;
R
5选自C
1-6烷基。
在一个或多个实施方式中,所述R
3和R
4各自独立地为甘氨酸的侧链、丙氨酸的侧链、亮氨酸的侧链、苯丙氨酸的侧链、天冬酰胺的侧链或精氨酸的侧链。
在一个或多个实施方式中,所述R
3和R
4各自独立地为丙氨酸的侧链。
本申请的一个或多个实施方式提供了制备式(IV)的大麻素类化合物或其立体异构体或盐的方法,其包括以下步骤:
(1)将通式(I-0)的化合物在碱性条件下与三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基反应,制备得到通式(I)的化合物;
(3)将通式(III)的化合物在碱性条件下脱去保护基G,得到通式(IV)的大麻素类化合物
其中
G为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基;
R为C
1-12烷基;
R
1为C
1-6烷基;
R
2为C
1-6烷基;
R
3和R
4各自独立地为天然氨基酸侧链或可药用氨基酸侧链;任选地,所述氨基酸侧链含有任选地被酯化的羟基、巯基或羧基;
R
5选自C
1-6烷基;
L-AA为L-氨基酸。
在一个或多个实施方式中,所述R
3和R
4各自独立地为甘氨酸的侧链、丙氨酸的侧链、亮氨酸的侧链、苯丙氨酸的侧链、天冬酰胺的侧链或精氨酸的侧链。
在一个或多个实施方式中,所述R
3和R
4各自独立地为丙氨酸的侧链。
本申请的一个或多个实施方式提供了本申请式(III)的化合物或者其立体异构体或盐在制备大麻素类化合物或其立体异构体或盐中的用途。
在一个或多个实施方式中,所述大麻素类化合物为式(IV)的大麻素类化合物。
本申请的一个或多个实施方式提供了本申请式(III)的化合物或者其立体异构体或盐在转化为或产生大麻素类化合物或其立体异构体或盐中的用途。
在一个或多个实施方式中,所述大麻素类化合物为式(IV)的大麻素类化合物。
在一个或多个实施方式中,式(IV)的大麻素类化合物如下:
其中
R为C
1-12烷基;
R
2为C
1-6烷基;
R
3和R
4各自独立地为天然氨基酸侧链或可药用氨基酸侧链;任选地,所述氨基酸侧链含有任选地被酯化的羟基、巯基或羧基;
R
5选自C
1-6烷基。
在一个或多个实施方式中,所述R
3和R
4各自独立地为甘氨酸的侧链、丙氨酸的侧链、亮氨酸的侧链、苯丙氨酸的侧链、天冬酰胺的侧链或精氨酸的侧链。
在一个或多个实施方式中,所述R
3和R
4各自独立地为丙氨酸的侧链。
发明详述
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括
12C、
13C和
14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括
16O、
17O和
18O,硫的同位素包括
32S、
33S、
34S和
36S,氮的同位素包括
14N和
15N,氟的同位素包括
17F和
19F,氯的同位素包括
35Cl和
37Cl,溴的同位素包括
79Br和
81Br。
“烷基”是指1至20个碳原子(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子)的直链或支链饱和脂肪族烃基,优选为1至8个碳原 子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
“天然氨基酸侧链或可药用氨基酸”是指蛋白质分子的基本骨架是氨基酸序列,组成蛋白质的基本氨基酸有20种,这20种基本氨基酸是生物进行蛋白后期修饰的基础,此外,在这些基本氨基酸的基础上,生物还会合成羟脯氨酸、羟赖氨酸等衍生出来的氨基酸类型,这些由生物合成的氨基酸统称为“天然氨基酸”;用人工方法合成的就是“非天然氨基酸”;“可药用氨基酸”是指在药学上可接受的天然或非天然氨基酸。
实施例1
异丙基((乙氧基羰基)(((1’R,2’R)-6-羟基-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物1)
isopropyl((ethoxycarbonyl)(((1’R,2’R)-6-hydroxy-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
第一步:
(1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)甲基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-醇1b
(1’R,2’R)-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-6-((triethylsilyl)methyl)-1’,2’,3’,4’-tetrah ydro-[1,1’-biphenyl]-2-ol
将混有其他杂质的(1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2,6-二醇1a(0.26g,0.84mmol)和咪唑(0.17g,2.5mmol)溶解于二氯甲烷(1.8ml)中,在0℃下加入三乙基氯硅烷(320mg,2.1mmol),温度缓慢升致40℃,在40℃下反应3小时。TLC检测反应完全,停止反应。将溶剂旋干硅胶柱色谱分离提纯(二氯甲烷/正己烷(v/v)=1/19),得到标题化合物(1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)甲基)-1’,2’,3‘,4’-四氢-[1,1’-联苯]-2-醇1b(254mg,产率72%,淡黄色油状物)。
1H NMR(300MHz,cdcl3)δ6.27(s,1H),6.16(s,1H),5.89(s,1H),5.53(s,1H),4.54(s,1H),4.42(s,1H),3.91(d,1H),2.44-2.41(m,3H),2.19-2.04(m,2H),1.77-1.64(m,4H),1.64(s,3H),1.57-1.54(m,3H),1.35-1.22(m,4H),0.99-0.96(m,9H),0.87(t,J=6.9Hz,3H),0.80-0.68(m,6H)。
LC-MS m/z(ESI)=429.33[M+1]。
第二步:
异丙基((乙氧羰基)(((1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)-L-丙氨酸1c
isopropyl((ethoxycarbonyl)(((1’R,2’R)-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-6-((triethyl silyl)oxy)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
在干燥的圆底烧瓶中将(二氯磷酰基)甲酸乙酯(0.31g,1.6mmol)溶解于二氯甲烷(1ml),在-60℃下加入三乙胺(0.25mL),然后滴加L-丙氨酸异丙酯盐酸盐(0.16g,0.95mmol,)溶解于二氯甲烷的溶液,-60℃下搅拌1.5小时。(1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)甲基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-醇1b(678mg,1.6mmol)和三乙胺(0.5mL)依次加到反应溶液中,然后缓慢升温至室温,搅拌过夜。LC-MS检测至反应结束。在0℃下加入氯化铵饱和溶液,在用二氯甲烷萃取。有机相用硫酸钠干燥、旋干,残留物使用硅胶柱色谱分离提纯,(石油醚/乙酸乙酯(v/v)=10:1~1:10),得到标题化合物异丙基((乙氧羰基)(((1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)-L-丙氨酸1c(422.7mg,产率38.5%,黄色油状物)。
LC-MS m/z(ESI)=678.38[M+1]。
第三步:
异丙基((乙氧基羰基)(((1’R,2’R)-6-羟基-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物1)
isopropyl((ethoxycarbonyl)(((1’R,2’R)-6-hydroxy-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
将异丙基((乙氧羰基)(((1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)-L-丙氨酸1c(572mg,0.86mmol)溶解于DMF中,在0℃下加入氟化钾(50mg,0.86mmol)。在0℃下搅拌1小时,HPLC监测至反应完全。加入水淬灭反应,用乙酸乙酯萃取,有机相旋干,残留物用乙酸乙酯/正己烷(5%-30%)体系纯化,得到标题化合物1的异构体1-1(205mg,42.3%产率,黄色油状物)和异构体1-2(151mg,产率31.1%,黄色油状物)。
异构体1-1
1H NMR(300MHz,氯仿-d)δ6.78(s,1H),6.49(s,1H),6.04(s,1H),5.54(s,1H),5.07-4.99(m,1H),4.66(s,1H),4.21(s,1H),4.31–4.08(m,3H),3.84–3.77(m,2H),2.49–2.44(m,3H),2.19–2.11(m,1H),2.04-1.55(m,10H),1.39–1.21(m,16H),0.87(t,3H)。
31P NMR(121MHz,氯仿-d):-2.98。
LC-MS m/z(ESI)=564.19[M+1]。
异构体1-2
1H NMR(300MHz,氯仿-d)δ6.68(s,1H),6.47(s,1H),6.12(s,1H),5.55(s,1H),5.02-4.94(m,1H),4.52(s,1H),4.35(s,1H),4.28–4.04(m,3H),3.87–3.72(m,2H),2.45–2.40(m,3H),2.19–2.08(m,1H),1.79-1.46(m,10H),1.39–1.21(m,16H),0.84(t,3H)。
31P NMR(121MHz,氯仿-d):-3.47。
LC-MS m/z(ESI)=564.20[M+1]。
实施例2
异丙基2-(((((1’R,2’R)-6-羟基-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)氨基)-2-甲基丙酸酯(化合物2)
isopropyl 2-(((((1’R,2’R)-6-hydroxy-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetr ahydro-[1,1’-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)amino)-2-methylpropanoate
第一步
异丙基2-((((乙氧基羰基))(((1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)氨基)-2-丙酸甲酯2a
isopropyl 2-(((ethoxycarbonyl)(((1’R,2’R)-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-6-((triethylsil yl)oxy)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate
化合物2a的合成方法与化合物1c相同,得到标题化合物异丙基2-((((乙氧基羰基))(((1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)氨基)-2-丙酸甲酯2a(657mg,产率42.5%,黄色油状物)。
LC-MS m/z(ESI)=692.35[M+1]。
第二步:
异丙基2-(((((1’R,2’R)-6-羟基-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)氨基)-2-甲基丙酸酯(化合物2)
isopropyl 2-(((((1’R,2’R)-6-hydroxy-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetr ahydro-[1,1’-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)amino)-2-methylpropanoate
化合物2的合成方法与化合物1相同,得到标题化合物2的异构体2-1(205mg,32.5%产率,黄色油状物)和异构体2-2(163mg,产率27.4%,黄色油状物)。
异构体2-1
1H NMR(300MHz,氯仿-d)δ6.81(s,1H),6.46(s,1H),6.04(s,1H),5.53(s,1H),5.18–5.09(m,1H),5.07-4.99(m,1H),4.62(s,1H),4.40(s,1H),4.19(d,1H),3.86(d,1H),2.47–2.42(m,3H),2.21-2.03(m,2H),1.81–1.21(m,32H),0.85(t,3H)。
31P NMR(121MHz,氯仿-d):-3.36。
LC-MS m/z(ESI)=592.45[M+1]。
异构体2-2
1H NMR(300MHz,氯仿-d)δ6.75(s,1H),6.47(s,1H),6.04(s,1H),5.58(s,1H),5.29–5.12(m,1H),5.06-4.98(m,1H),4.55(s,1H),4.38(s,1H),4.12(d,1H),3.87(d,1H),2.48–2.43(m,3H),2.20-2.04(m,2H),1.83–1.20(m,32H),0.86(t,3H)。
31P NMR(121MHz,氯仿-d):-3.39。
LC-MS m/z(ESI)=592.10[M+1]。
实施例3
苄基((乙氧羰基)(((1’R,2’R)-6-羟基-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物3)
benzyl((ethoxycarbonyl)(((1’R,2’R)-6-hydroxy-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
第一步:
苄基((乙氧基羰基)(((1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)-L-丙氨酸3a
benzyl((ethoxycarbonyl)(((1’R,2’R)-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-6-((triethylsil yl)oxy)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
化合3a的合成方法与化合物1c相同,得到标题化合物苄基((乙氧基羰基)(((1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)-L-丙氨酸3a(623mg,产率41.8%,黄色油状物)。
LC-MS m/z(ESI)=726.32[M+1]。
第二步:
苄基((乙氧羰基)(((1’R,2’R)-6-羟基-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物3)
benzyl((ethoxycarbonyl)(((1’R,2’R)-6-hydroxy-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
化合物3的合成方法与化合物1相同,得到标题化合物3的异构体3-1(218mg,37.8%产率,黄色油状物)和异构体3-2(254mg,产率43.5%,黄色油状物)。
异构体3-1
1H NMR(300MHz,氯仿-d)δ7.39-7.29(m,5H),6.78(s,1H),6.49(s,1H),6.04(s,1H),5.53(s,1H),5.21–5.11(m,2H),4.63(s,1H),4.41(s,1H),4.33-4.10(m,3H),3.87–3.74(m,2H),2.46(t,3H),2.22–2.04(m,2H),1.83–1.20(m,20H),0.86(t,3H)。
31P NMR(121MHz,氯仿-d):-3.05。
LC-MS m/z(ESI)=612.45[M+1]。
异构体3-2
1H NMR(300MHz,氯仿-d)δ7.39-7.29(m,5H),6.70(s,1H),6.49(s,1H),6.09(s,1H),5.55(s,1H),5.18–5.09(m,2H),4.54(s,1H),4.36(s,1H),4.27-4.20(m,3H),3.87–3.71(m,2H),2.45(t,3H),2.26–2.10(m,2H),1.83–1.18(m,20H),0.86(t,3H)。
31P NMR(121MHz,氯仿-d):-3.61。
LC-MS m/z(ESI)=612.53[M+1]。
实施例4
异丙基2-(((((1’R,2’R)-6-羟基-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)氨基)-2-甲基丙酸酯(化合物4)
isopropyl 2-(((((1’R,2’R)-6-hydroxy-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetr ahydro-[1,1’-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)amino)-2-methylpropanoate
第一步:
异丙基2-(((异丙氧羰基)(((1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)氨基)-2-丙酸甲酯4a
isopropyl 2-(((isopropoxycarbonyl)(((1’R,2’R)-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-6-((triethylsilyl)oxy)-1’,2’,3’,4’-tetrahydro-[1,1’-biphenyl]-2-yl)oxy)phosphoryl)amino)-2-methylp ropanoate
化合4a的合成方法与化合物1a相同,得到标题化合物异丙基2-(((异丙氧羰 基)(((1’R,2’R)-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-6-((三乙基甲硅烷基)氧基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)磷酰基)氨基)-2-丙酸甲酯4a(578mg,产率33.8%,黄色油状物)。
LC-MS m/z(ESI)=706.28[M+1]。
第二步:
异丙基2-(((((1’R,2’R)-6-羟基-5’-甲基-4-戊基-2’-(丙-1-烯-2-基)-1’,2’,3’,4’-四氢-[1,1’-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)氨基)-2-甲基丙酸酯(化合物4)
isopropyl 2-(((((1’R,2’R)-6-hydroxy-5’-methyl-4-pentyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetr ahydro-[1,1’-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)amino)-2-methylpropanoate
化合物4的合成方法与化合物1相同,得到标题化合物4的异构体4-1(186mg,38.6%产率,黄色油状物)和异构体4-2(215mg,产率41.3%,黄色油状物)
异构体4-1
1H NMR(300MHz,氯仿-d)δ6.81(s,1H),6.46(s,1H),6.04(s,1H),5.53(s,1H),5.18–5.09(m,1H),5.07-4.99(m,1H),4.62(s,1H),4.40(s,1H),4.19(d,1H),3.86(d,1H),2.47–2.42(m,3H),2.21-2.03(m,2H),1.81–1.21(m,32H),0.85(t,3H)。
31P NMR(121MHz,氯仿-d):-3.36。
LC-MS m/z(ESI)=592.45[M+1]。
异构体4-2
1H NMR(300MHz,氯仿-d)δ6.75(s,1H),6.47(s,1H),6.04(s,1H),5.58(s,1H),5.29–5.12(m,1H),5.06-4.98(m,1H),4.55(s,1H),4.38(s,1H),4.12(d,1H),3.87(d,1H),2.48–2.43(m,3H),2.20-2.04(m,2H),1.83–1.20(m,32H),0.86(t,3H)。
31P NMR(121MHz,氯仿-d):-3.39。
LC-MS m/z(ESI)=592.10[M+1]。
Claims (10)
- 如权利要求1所述的化合物或者其立体异构体或盐,其中所述R 3和R 4各自独立地为甘氨酸的侧链、丙氨酸的侧链、亮氨酸的侧链、苯丙氨酸的侧链、天冬酰胺的侧链或精氨酸的侧链;优选地为丙氨酸的侧链。
- 如权利要求3所述的方法,其中所述R 3和R 4各自独立地为甘氨酸的侧链、丙氨酸的侧链、亮氨酸的侧链、苯丙氨酸的侧链、天冬酰胺的侧链或精氨酸的侧链;优选地为丙氨酸的侧链。
- 如权利要求5所述的方法,其中所述R 3和R 4各自独立地为甘氨酸的侧链、丙氨酸的侧链、亮氨酸的侧链、苯丙氨酸的侧链、天冬酰胺的侧链或精氨酸的侧链;优选地为丙氨酸的侧链。
- 制备式(IV)的大麻素类化合物或其立体异构体或盐的方法,其包括以下步骤:(1)将通式(I-0)的化合物在碱性条件下与三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基反应,制备得到通式(I)的化合物;(3)将通式(III)的化合物在碱性条件下脱去保护基G,得到通式(IV)的大麻素类化合物其中G为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基;R为C 1-12烷基;R 1为C 1-6烷基;R 2为C 1-6烷基;R 3和R 4各自独立地为天然氨基酸侧链或可药用氨基酸侧链;任选地,所述氨基酸侧链含有任选地被酯化的羟基、巯基或羧基;R 5选自C 1-6烷基;L-AA为L-氨基酸。
- 如权利要求7所述的方法,其中所述R 3和R 4各自独立地为甘氨酸的侧链、丙氨酸的侧链、亮氨酸的侧链、苯丙氨酸的侧链、天冬酰胺的侧链或精氨酸的侧链;优选地为丙氨酸的侧链。
- 权利要求1或2所述的式(III)的化合物或者其立体异构体或盐在制备大麻素类化合物或其立体异构体或盐中的用途;优选地,所述大麻素类化合物为式(IV)的大麻素类化合物。
- 权利要求1或2所述的式(III)的化合物或者其立体异构体或盐在转化为或产生大麻素类化合物或其立体异构体或盐中的用途;优选地,所述大麻素类化合物为式(IV)的大麻素类化合物。
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CN113087741A (zh) * | 2020-01-08 | 2021-07-09 | 成都百裕制药股份有限公司 | 大麻二酚衍生物及其制备方法和在医药上的应用 |
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