CN116234812A - Preparation method of cannabinoid compounds - Google Patents

Preparation method of cannabinoid compounds Download PDF

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CN116234812A
CN116234812A CN202180068000.3A CN202180068000A CN116234812A CN 116234812 A CN116234812 A CN 116234812A CN 202180068000 A CN202180068000 A CN 202180068000A CN 116234812 A CN116234812 A CN 116234812A
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side chain
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formula
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amino acid
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孙毅
张靖
许学珍
魏用刚
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Chengdu Baiyu Pharmaceutical Co Ltd
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Abstract

The preparation method of cannabinoid compounds and prodrugs thereof has good purification effect and is suitable for industrial production.

Description

Preparation method of cannabinoid compounds Technical Field
The present application relates to the field of compound preparation, and in particular to a method for preparing cannabinoid compounds.
Background
Cannabinoids include about 70 ingredients, mainly including Cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabinol (THC), and homologs thereof, wherein the Cannabidiol (CBD) is the highest.
At present, a preparation method of cannabinoid compound prodrugs with good purification effect and suitable for industrial production is needed.
Disclosure of Invention
The invention aims 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 cannabinoid prodrug technology that improves the absorption, distribution, transport and metabolic processes of a parent drug in vivo, increases bioavailability, increases selectivity of drug action on a target site, reduces toxic side effects of the drug, prolongs duration of action, and the like.
One or more embodiments of the present application provide a compound of formula (III):
Figure PCTCN2021133194-APPB-000001
wherein the method comprises the steps of
G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
r is C 1-12 An alkyl group;
R 2 is C 1-6 An alkyl group;
R 3 and R is 4 Each independently is a natural amino acid side chain or a pharmaceutically acceptable salt thereofAmino acid side chains; optionally, the amino acid side chain contains an optionally esterified hydroxy, mercapto or carboxyl group;
R 5 selected from C 1-6 An alkyl group.
In one or more embodiments, the R 3 And R is 4 Each independently is a glycine side chain, an alanine side chain, a leucine side chain, a phenylalanine side chain, an asparagine side chain, or an arginine side chain.
In one or more embodiments, the R 3 And R is 4 Each independently is the side chain of alanine.
One or more embodiments of the present application provide a process for preparing a compound of formula (III), or a stereoisomer or salt thereof, comprising reacting a compound of formula (I) with a compound of formula (II) and L-AA under basic conditions to prepare a compound of formula (III):
Figure PCTCN2021133194-APPB-000002
wherein the method comprises the steps of
G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
r is C 1-12 An alkyl group;
R 1 is C 1-6 An alkyl group;
R 2 is C 1-6 An alkyl group;
R 3 and R is 4 Each independently is a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxy, mercapto or carboxyl group;
R 5 is C 1-6 An alkyl group;
L-AA is an L-amino acid.
In one or more embodimentsWherein said R is 3 And R is 4 Each independently is a glycine side chain, an alanine side chain, a leucine side chain, a phenylalanine side chain, an asparagine side chain, or an arginine side chain.
In one or more embodiments, the R 3 And R is 4 Each independently is the side chain of alanine.
One or more embodiments of the present application provide a process for preparing a cannabinoid compound of formula (IV), or a stereoisomer or salt thereof, comprising deprotecting a compound of formula (III) under basic conditions to yield a cannabinoid compound of formula (IV):
Figure PCTCN2021133194-APPB-000003
wherein the method comprises the steps of
G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
r is C 1-12 An alkyl group;
R 2 is C 1-6 An alkyl group;
R 3 and R is 4 Each independently is a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxy, mercapto or carboxyl group;
R 5 selected from C 1-6 An alkyl group.
In one or more embodiments, the R 3 And R is 4 Each independently is a glycine side chain, an alanine side chain, a leucine side chain, a phenylalanine side chain, an asparagine side chain, or an arginine side chain.
In one or more embodiments, the R 3 And R is 4 Each independently is the side chain of alanine.
One or more embodiments of the present application provide a method for preparing a cannabinoid compound of formula (IV), or a stereoisomer or salt thereof, comprising the steps of:
(1) Reacting a compound of the general formula (I-0) with trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl under alkaline conditions to obtain a compound of the general formula (I);
(2) The compound of the general formula (I) is reacted with the compound of the general formula (II) under alkaline conditions
Figure PCTCN2021133194-APPB-000004
Reacting the compound of formula (III) with L-AA to obtain a compound of formula (III);
(3) Removing protecting group G from compound of formula (III) under alkaline condition to obtain cannabinoid compound of formula (IV)
Figure PCTCN2021133194-APPB-000005
Wherein the method comprises the steps of
G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
r is C 1-12 An alkyl group;
R 1 is C 1-6 An alkyl group;
R 2 is C 1-6 An alkyl group;
R 3 and R is 4 Each independently is a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxy, mercapto or carboxyl group;
R 5 selected from C 1-6 An alkyl group;
L-AA is an L-amino acid.
In one or more embodiments, the R 3 And R is 4 Each independently is a glycine side chain, an alanine side chain, a leucine side chain, a phenylalanine side chain, an asparagine side chain, or an arginine side chain.
In one or more embodiments, the R 3 And R is 4 Each independently is the side chain of alanine.
One or more embodiments of the present application provide for the use of a compound of formula (III) or a stereoisomer or salt thereof in the preparation of a cannabinoid compound or a stereoisomer or salt thereof.
In one or more embodiments, the cannabinoid is a cannabinoid of formula (IV).
One or more embodiments of the present application provide for the use of a compound of formula (III) or a stereoisomer or salt thereof, in the conversion to or production of a cannabinoid compound or a stereoisomer or salt thereof.
In one or more embodiments, the cannabinoid is a cannabinoid of formula (IV).
In one or more embodiments, the cannabinoids of formula (IV) are as follows:
Figure PCTCN2021133194-APPB-000006
wherein the method comprises the steps of
R is C 1-12 An alkyl group;
R 2 is C 1-6 An alkyl group;
R 3 and R is 4 Each independently is a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxy, mercapto or carboxyl group;
R 5 selected from C 1-6 An alkyl group.
In one or more embodiments, the R 3 And R is 4 Each independently is glycineThe side chain of an acid, the side chain of alanine, the side chain of leucine, the side chain of phenylalanine, the side chain of asparagine or the side chain of arginine.
In one or more embodiments, the R 3 And R is 4 Each independently is the side chain of alanine.
Detailed Description
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms), preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 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 isomers thereof; when the alkyl group is substituted, it may optionally be further substituted with 1 or more substituents.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.
"Natural amino acid side chain or pharmaceutically acceptable amino acid" means that the basic skeleton of the protein molecule is an amino acid sequence, there are 20 basic amino acids constituting the protein, these 20 basic amino acids are the basis for the organism to carry out the post-modification of the protein, furthermore, on the basis of these basic amino acids, the organism also synthesizes into the amino acid types derived from hydroxyproline, hydroxylysine, etc., these amino acids synthesized by the organism are collectively referred to as "natural amino acids"; the artificial method is to synthesize the non-natural amino acid; "pharmaceutically acceptable amino acid" refers to a natural or unnatural amino acid that is pharmaceutically acceptable.
"side chain of an amino acid" refers to the general formula of an amino acid
Figure PCTCN2021133194-APPB-000007
X substituents in the structure.
Detailed Description
Example 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-alanine salt (Compound 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
Figure PCTCN2021133194-APPB-000008
The first step:
(1 ' R,2' R) -5' -methyl-4-pentyl-2 ' - (prop-1-en-2-yl) -6- ((triethylsilyl) methyl) -1',2',3',4' -tetrahydro- [1,1' -biphenyl ] -2-ol 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
(1 ' R,2' R) -5' -methyl-4-pentyl-2 ' - (prop-1-en-2-yl) -1',2',3',4' -tetrahydro- [1,1' -biphenyl ] -2, 6-diol 1a (0.26 g,0.84 mmol) and imidazole (0.17 g,2.5 mmol) mixed with other impurities were dissolved in dichloromethane (1.8 ml), triethylchlorosilane (320 mg,2.1 mmol) was added at 0 ℃, the temperature was slowly raised to 40 ℃, and the reaction was carried out at 40℃for 3 hours. TLC checked the reaction was complete and stopped. Solvent spin-drying silica gel column chromatography (dichloromethane/n-hexane (v/v) =1/19) gave the title compound (1 ' r,2' r) -5' -methyl-4-pentyl-2 ' - (prop-1-en-2-yl) -6- ((triethylsilyl) methyl) -1',2',3',4' -tetrahydro- [1,1' -biphenyl ] -2-ol 1b (254 mg, 72% yield, light yellow oil).
1 H 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]。
And a second step of:
isopropyl ((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) -L-alanine 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
Ethyl (dichlorophosphoryl) formate (0.31 g,1.6 mmol) was dissolved in dichloromethane (1 mL) in a dry round bottom flask, triethylamine (0.25 mL) was added at-60℃followed by dropwise addition of a solution of L-alanine isopropyl ester hydrochloride (0.16 g,0.95 mmol) dissolved in dichloromethane and stirring at-60℃for 1.5 hours. (1 ' R,2' R) -5' -methyl-4-pentyl-2 ' - (prop-1-en-2-yl) -6- ((triethylsilyl) methyl) -1',2',3',4' -tetrahydro- [1,1' -biphenyl ] -2-ol 1b (678 mg,1.6 mmol) and triethylamine (0.5 mL) were added sequentially to the reaction solution, followed by slow warming to room temperature and stirring overnight. LC-MS detected the end of the reaction. Saturated ammonium chloride solution was added at 0℃and extracted with dichloromethane. The organic phase was dried over sodium sulfate, dried, and the residue was purified by column chromatography over silica gel (petroleum ether/ethyl acetate (v/v) =10:1 to 1:10) to give the title compound isopropyl ((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) -L-alanine 1c (422.7 mg, 38.5% yield as a yellow oil).
LC-MS m/z(ESI)＝678.38[M+1]。
And a third step of:
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-alanine salt (Compound 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
Isopropyl ((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) -L-alanine 1c (578mg, 0.86 mmol) was dissolved in DMF and potassium fluoride (50 mg,0.86 mmol) was added at 0 ℃. Stirred at 0deg.C for 1 hr and monitored by HPLC to complete the reaction. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was dried by spin-drying, and the residue was purified with an ethyl acetate/n-hexane (5% -30%) system to give isomer 1-1 (205 mg,42.3% yield, yellow oil) and isomer 1-2 (151 mg, 31.1% yield, yellow oil) of the title compound 1.
Isomer 1-1
1 H NMR (300 MHz, chloroform-d) delta 6.78 (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).
31 P NMR (121 MHz, chloroform-d): -2.98.
LC-MS m/z(ESI)＝564.19[M+1]。
Isomer 1-2
1 H NMR (300 MHz, chloroform-d) delta 6.68 (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).
31 P NMR (121 MHz, chloroform-d): 3.47.
LC-MS m/z(ESI)＝564.20[M+1]。
Example 2
Isopropyl 2- (((((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) (isopropoxycarbonyl) phosphoryl) amino) -2-methylpropanoate (Compound 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
Figure PCTCN2021133194-APPB-000009
Figure PCTCN2021133194-APPB-000010
First step
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-propanoic acid methyl ester 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
The synthesis of compound 2a was identical to that of compound 1c, affording 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-propanoic acid methyl ester 2a (657 mg, 42.5% yield as a yellow oil).
LC-MS m/z(ESI)＝692.35[M+1]。
And a second step of:
isopropyl 2- (((((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) (isopropoxycarbonyl) phosphoryl) amino) -2-methylpropanoate (Compound 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
The synthesis of compound 2 was the same as that of compound 1, to give isomer 2-1 (205 mg,32.5% yield, yellow oil) and isomer 2-2 (163 mg, 27.4% yield, yellow oil) of the title compound 2.
Isomer 2-1
1 H NMR (300 MHz, chloroform-d) delta 6.81 (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).
31 P NMR (121 MHz, chloroform-d): -3.36.
LC-MS m/z(ESI)＝592.45[M+1]。
Isomer 2-2
1 H NMR (300 MHz, chloroform-d) delta 6.75 (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).
31 P NMR (121 MHz, chloroform-d): -3.39.
LC-MS m/z(ESI)＝592.10[M+1]。
Example 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-alanine salt (Compound 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
Figure PCTCN2021133194-APPB-000011
The first step:
benzyl ((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) -L-alanine 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
The procedure for the synthesis of compound 3a was the same as for compound 1c to give the title compound benzyl ((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) -L-alanine 3a (623 mg, 41.8% yield as yellow oil).
LC-MS m/z(ESI)＝726.32[M+1]。
And a second step of:
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-alanine salt (Compound 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
The synthesis of compound 3 was the same as that of compound 1, to give isomer 3-1 (218 mg,37.8% yield, yellow oil) and isomer 3-2 (254 mg, 43.5% yield, yellow oil) of the title compound 3.
Isomer 3-1
1 H NMR (300 MHz, chloroform-d) delta 7.39-7.29 (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).
31 P NMR (121 MHz, chloroform-d): 3.05.
LC-MS m/z(ESI)＝612.45[M+1]。
Isomer 3-2
1 H NMR (300 MHz, chloroform-d) delta 7.39-7.29 (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).
31 P NMR (121 MHz, chloroform-d): 3.61.
LC-MS m/z(ESI)＝612.53[M+1]。
Example 4
Isopropyl 2- (((((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) (isopropoxycarbonyl) phosphoryl) amino) -2-methylpropanoate (Compound 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
Figure PCTCN2021133194-APPB-000012
The first step:
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-propanoic acid methyl ester 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
The procedure for the synthesis of compound 4a was the same as for compound 1a to give 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-propanoic acid methyl ester 4a (578 mg, 33.8% yield as a yellow oil).
LC-MS m/z(ESI)＝706.28[M+1]。
And a second step of:
isopropyl 2- (((((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) (isopropoxycarbonyl) phosphoryl) amino) -2-methylpropanoate (Compound 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
The synthesis of compound 4 was the same as that of compound 1, to give isomer 4-1 (186 mg,38.6% yield, yellow oil) and isomer 4-2 (215 mg, 41.3% yield, yellow oil) of the title compound 4
Isomer 4-1
1 H NMR (300 MHz, chloroform-d) delta 6.81 (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).
31 P NMR (121 MHz, chloroform-d): -3.36.
LC-MS m/z(ESI)＝592.45[M+1]。
Isomer 4-2
1 H NMR (300 MHz, chloroform-d) delta 6.75 (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).
31 P NMR (121 MHz, chloroform-d): -3.39.
LC-MS m/z(ESI)＝592.10[M+1]。

Claims (10)

  1. A compound of formula (III) or a stereoisomer or salt thereof:
    Figure PCTCN2021133194-APPB-100001
    wherein the method comprises the steps of
    G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
    r is C 1-12 An alkyl group;
    R 2 is C 1-6 An alkyl group;
    R 3 and R is 4 Each independently is a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxy, mercapto or carboxyl group;
    R 5 selected from C 1-6 An alkyl group.
  2. The compound of claim 1, or a stereoisomer or salt thereof, wherein the R 3 And R is 4 Each independently glycine side chain, alanine side chain, leucine side chain, phenylalanine side chain, asparagine side chain or arginine side chain; preferably alanine.
  3. A process for preparing a compound of formula (III), or a stereoisomer or salt thereof, comprising reacting a compound of formula (I) with a compound of formula (II) and L-AA under basic conditions to prepare a compound of formula (III):
    Figure PCTCN2021133194-APPB-100002
    wherein the method comprises the steps of
    G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
    r is C 1-12 An alkyl group;
    R 1 is C 1-6 An alkyl group;
    R 2 is C 1-6 An alkyl group;
    R 3 and R is 4 Each independently is a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the ammoniaThe side chain of the acid contains an optionally esterified hydroxyl, thiol or carboxyl group;
    R 5 is C 1-6 An alkyl group;
    L-AA is an L-amino acid.
  4. A method according to claim 3, wherein said R 3 And R is 4 Each independently glycine side chain, alanine side chain, leucine side chain, phenylalanine side chain, asparagine side chain or arginine side chain; preferably alanine.
  5. A process for preparing a cannabinoid compound of formula (IV) or a stereoisomer or salt thereof, comprising deprotecting a compound of formula (III) under basic conditions to give a cannabinoid compound of formula (IV):
    Figure PCTCN2021133194-APPB-100003
    wherein the method comprises the steps of
    G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
    r is C 1-12 An alkyl group;
    R 2 is C 1-6 An alkyl group;
    R 3 and R is 4 Each independently is a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxy, mercapto or carboxyl group;
    R 5 selected from C 1-6 An alkyl group.
  6. The method of claim 5, wherein said R 3 And R is 4 Each independently glycine side chain, alanine side chain, leucine side chainA chain, a side chain of phenylalanine, a side chain of asparagine or a side chain of arginine; preferably alanine.
  7. A process for preparing a cannabinoid compound of formula (IV), or a stereoisomer or salt thereof, comprising the steps of:
    (1) Reacting a compound of the general formula (I-0) with trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl under alkaline conditions to obtain a compound of the general formula (I);
    (2) The compound of the general formula (I) is reacted with the compound of the general formula (II) under alkaline conditions
    Figure PCTCN2021133194-APPB-100004
    Reacting the compound of formula (III) with L-AA to obtain a compound of formula (III);
    (3) Removing protecting group G from compound of formula (III) under alkaline condition to obtain cannabinoid compound of formula (IV)
    Figure PCTCN2021133194-APPB-100005
    Wherein the method comprises the steps of
    G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
    r is C 1-12 An alkyl group;
    R 1 is C 1-6 An alkyl group;
    R 2 is C 1-6 An alkyl group;
    R 3 and R is 4 Each independently is a natural amino acid side chain or a pharmaceutically acceptable amino acid side chain; optionally, the amino acid side chain contains an optionally esterified hydroxy, mercapto or carboxyl group;
    R 5 selected from C 1-6 An alkyl group;
    L-AA is an L-amino acid.
  8. The method of claim 7, wherein the R 3 And R is 4 Each independently glycine side chain, alanine side chain, leucine side chain, phenylalanine side chain, asparagine side chain or arginine side chain; preferably alanine.
  9. Use of a compound of formula (III) according to claim 1 or 2, or a stereoisomer or salt thereof, for the preparation of a cannabinoid compound, or a stereoisomer or salt thereof; preferably, the cannabinoid is a cannabinoid of formula (IV).
  10. Use of a compound of formula (III) or a stereoisomer or salt thereof according to claim 1 or 2 for the conversion to or production of a cannabinoid compound or stereoisomer or salt thereof; preferably, the cannabinoid is a cannabinoid of formula (IV).
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