CN115960154A - 20-hydroxyprogesterone precursor compound and preparation method and application thereof - Google Patents
20-hydroxyprogesterone precursor compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a 20-hydroxyprogesterone precursor compound and a preparation method and application thereof, belonging to the technical field of medicine preparation. The invention provides a 20-hydroxyprogesterone precursor compound, wherein progesterone derivative 20-hydroxyprogesterone is connected with a triglyceride skeleton through different connecting bridges to synthesize 20-hydroxyprogesterone triglyceride prodrugs with different structures, the prodrugs can simulate the specific digestion process of triglyceride in intestinal tracts through gastrointestinal tracts, tend to lymphatic transport and avoid the first pass effect of liver, so that the oral bioavailability of the parent drug 20-hydroxyprogesterone is improved, and the connecting bridges with different structures influence the in-vivo process of the prodrugs, so that the oral bioavailability is influenced.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a 20-hydroxyprogesterone precursor compound and a preparation method and application thereof.
Background
The progestogen is a C-21 structure steroid compound with progestogen activity, and is widely used for treating the gynecological endocrine diseases of women. Progestagens are currently mainly divided into two main groups, natural and synthetic, among which progesterone (pregn-4-ene-3,20-dione, C) 21 H 30 O 2 ，Progesterone，P 4 ) Is the only natural progestogen, secreted by the ovarian corpus luteum, necessary for maintaining pregnancy. Progesterone is the first choice in the aspects of female hormone supplementation therapy, assisted fertility and the like, and no other medicines can replace the progesterone. Currently, the types of preparations commonly used for clinically treating progesterone include intramuscular injections, vaginal administration preparations, oral preparations and the like. Wherein, the oral administration is the most convenient, safe and economical administration route and is the first choice for long-term administration. But because of low solubility and poor absorption in vivo of progesterone, oral administration has strong liver first-pass effect and bioavailability<10 percent. Therefore, how to improve the oral bioavailability of progesterone has become a key problem in progesterone application.
Progesterone is rapidly metabolized in the liver by oral administration via the portal vein and the metabolic reactions are typically 5-position reduction, 3-position hydroxylation and 20-position hydroxylation, the 20-position hydroxylated metabolite being 20 α -hydroxyprogesterone (20 α -hydroxy-4-pregnan-3-one, C) 21 H 31 O 2 20 α -dihydroprogastrone, 20 α -DHP) have progestogen-like effects and play an important role in regulating ovulation and gonadotropin secretion and influencing ovarian-pituitary-hypothalamic interactions, as well as anxiolytic properties. Research also shows that 20 alpha-DHP has the capacity of resisting aromatizing enzyme agent, has antiproliferative effect on breast cancer cells, and can prevent breast cancer.
Disclosure of Invention
In view of the above, the present invention aims to provide a 20-hydroxyprogesterone precursor compound, and a preparation method and applications thereof. The 20-hydroxyprogesterone precursor compound tends to transport lymph by oral administration, so that the first pass effect of the liver can be reduced, and the oral bioavailability can be improved.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a 20-hydroxyprogesterone precursor compound, which has a structure shown in a formula I:
in the formula I, A is a structure shown in formulas 1-3:
in formulas 1 to 3, a connecting site;
the carbon at the carbon-oxygen double bond in the formula 1 is connected with the oxygen at the hydroxyl of 20-hydroxyprogesterone, and n = 1-10;
the carbon at the carbon-oxygen double bond in the formula 2 is connected with the oxygen at the hydroxyl of 20-hydroxyprogesterone, k = 1-10, m = 1-10 3 Is C1-C10 saturated carbon chain or C1-C6 acyl;
in the formula 3, a = 1-10,b = 1-10,R 4 Is H, C-C10 saturated carbon chain or C1-C6 acyl;
in the formula I, R 1 And R 2 Independently a saturated or unsaturated carbon chain of C2-24.
Preferably, n, k, a and b are independently 1 to 5.
Preferably, said R is 1 And R 2 Independently a saturated or unsaturated carbon chain of C10-24.
Preferably, the 20-hydroxyprogesterone precursor compound has a structure represented by formulas II-V:
the invention also provides a preparation method of the 20-hydroxyprogesterone precursor compound, which comprises the following steps:
mixing fatty acid and 1,3-dihydroxyacetone for condensation reaction to obtain a condensation product; the fatty acid comprises C2-24 saturated or unsaturated fatty acid;
hydrogenating and reducing the condensation product to obtain 1,3-diglyceride;
the 1,3-diglyceride has the structure shown in formula a:
when the A is the structure shown in the formula 1, the preparation method comprises the following steps:
mixing 1,3-diglyceride, pyridine and dibasic fatty acid anhydride to perform a first esterification reaction to obtain a first esterification product; the binary fatty acid anhydride is malonic anhydride, succinic anhydride, glutaric anhydride, adipic anhydride, pimelic anhydride, suberic anhydride, azelaic anhydride or sebacic anhydride;
mixing the first esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a second esterification reaction to obtain a 20-hydroxyprogesterone precursor compound;
when A is a structure shown in formula 2, R 3 When the carbon chain is a saturated carbon chain of C1-C10, the preparation method comprises the following steps:
carrying out acyl chloride reaction on the dibasic fatty acid to obtain an acyl chloride product; the dibasic fatty acid is malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid or sebacic acid;
mixing the 1,3-diglyceride, pyridine and acyl chloride products to perform a third esterification reaction to obtain a third esterification product;
mixing the third esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a fourth esterification reaction to obtain a 20-hydroxyprogesterone precursor compound;
when A is a structure shown in formula 2, R 3 When the acyl is C1-C6 acyl, the preparation method comprises the following steps:
mixing fatty acid benzyl ester with alpha-amino with sodium nitrite for diazotization reaction to obtain diazotization products; the fatty acid benzyl ester with alpha-amino is 2-amino-malonic acid benzyl ester, 2-amino-succinic acid benzyl ester, 2-amino-glutaric acid benzyl ester, 2-amino-adipic acid benzyl ester, 2-amino-pimelic acid benzyl ester, 2-amino-suberic acid benzyl ester, 2-amino-azelaic acid benzyl ester or 2-amino-sebacic acid benzyl ester;
mixing the diazotization product with fatty acyl chloride to perform a fifth esterification reaction to obtain a fifth esterification product; the fatty acyl chloride is acetyl chloride, propionyl chloride, 2-methyl propionyl chloride or trimethyl acetyl chloride;
mixing the 1,3-diglyceride, pyridine and a fifth esterification product to carry out a sixth esterification reaction to obtain a sixth esterification product;
mixing the sixth esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a seventh esterification reaction to obtain a 20-hydroxyprogesterone precursor compound;
when the A is the structure shown in the formula 3, the preparation method comprises the following steps:
modifying 20-hydroxyprogesterone with dimethyl sulfoxide, and mixing with SO 2 Cl 2 Reacting to obtain 20-hydroxyprogesterone methylthio methyl ether;
and mixing the first esterification product, 20-hydroxyprogesterone methylthiomethyl ether and 4-dimethylaminopyridine to perform an eighth esterification reaction to obtain the 20-hydroxyprogesterone precursor compound.
Preferably, the 20-hydroxyprogesterone is obtained by reduction of progesterone.
Preferably, the reducing agent used for the reduction comprises lithium aluminum hydride and/or lithium bis-trimethylsilyl amide.
Preferably, the reduction also comprises oxidation, and the oxidant used in the oxidation comprises one or more of pyridinium chlorochromate, manganese dioxide, silver carbonate and 2,3-dichloro-5,6-dicyan-p-benzoquinone.
Preferably, the condensation reaction is carried out under condensing agent conditions, the condensing agent comprising dicyclohexylcarbodiimide and/or 4-dimethylaminopyridine.
The invention also provides application of the 20-hydroxyprogesterone precursor compound in the technical scheme in preparation of progesterone medicaments.
The invention provides a 20-hydroxyprogesterone precursor compound, wherein a progesterone derivative 20-hydroxyprogesterone is connected with a triglyceride skeleton through different connecting bridges to synthesize 20-hydroxyprogesterone triglyceride prodrugs with different structures, the prodrugs can simulate the specific digestion process of triglyceride in intestinal tracts through gastrointestinal tracts, tend to lymphatic transport and avoid the first pass effect of liver, so that the oral bioavailability of the parent drug 20-hydroxyprogesterone is improved, and the connecting bridges with different structures influence the in-vivo process of the prodrugs and have different oral utilizations.
The invention also provides a preparation method of the 20-hydroxyprogesterone precursor compound, which is simple and suitable for industrial production.
Drawings
FIG. 1 is a graph of the effect of the 20-hydroxyprogesterone precursor compound prepared in example 1, wherein A is 20 α -DHP and B is 20 β -DHP.
Detailed Description
The invention provides a 20-hydroxyprogesterone precursor compound, which has a structure shown in a formula I:
in the formula I, A is a structure shown in formulas 1-3:
in formulas 1 to 3, a connection site;
the carbon at the carbon-oxygen double bond in the formula 1 is connected with the oxygen at the hydroxyl of 20-hydroxyprogesterone, and n = 1-10;
the carbon at the carbon-oxygen double bond in the formula 2 is connected with the oxygen at the hydroxyl of 20-hydroxyprogesterone, k = 1-10, m = 1-10 3 Is a C1-C10 saturated carbon chain or a C1-C6 acyl group;
in the formula 3, a = 1-10, b = 1-10 4 Is H, C-C10 saturated carbon chain or C1-C6 acyl;
in the formula I, R 1 And R 2 Independently a saturated or unsaturated carbon chain of C2-24.
In the present invention, the configuration of the carbon at the 20-position of the steroid ring moiety in the 20-hydroxyprogesterone precursor compound may be alpha configuration (S type) or beta configuration (R type), and the 20-hydroxyprogesterone precursor compound of the present invention is a mixture of alpha configuration (S type) and beta configuration (R type).
In the present invention, the structure of the α configuration is represented by formula I-1:
the structure of the beta configuration is shown as a formula I-2:
in the present invention, n, k, a and b are independently preferably 1 to 5.
In the present invention, said R 1 And R 2 Independently, a saturated or unsaturated carbon chain having 10 to 24 carbon atoms is preferred.
In the present invention, the 20-hydroxyprogesterone precursor compound preferably has a structure represented by formulas II to V:
the invention also provides a preparation method of the 20-hydroxyprogesterone precursor compound, which comprises the following steps:
mixing fatty acid and 1,3-dihydroxyacetone for condensation reaction to obtain a condensation product; the fatty acid comprises C2-24 saturated or unsaturated fatty acid;
hydrogenating and reducing the condensation product to obtain 1,3-diglyceride;
the 1,3-diglyceride has the structure shown in formula a:
when the A is the structure shown in the formula 1, the preparation method comprises the following steps:
mixing the 1,3-diglyceride, pyridine and dibasic fatty acid anhydride to perform a first esterification reaction to obtain a first esterification product; the binary fatty acid anhydride is malonic anhydride, succinic anhydride, glutaric anhydride, adipic anhydride, pimelic anhydride, suberic anhydride, azelaic anhydride or sebacic anhydride;
mixing the first esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a second esterification reaction to obtain a 20-hydroxyprogesterone precursor compound;
when A is a structure shown in formula 2, R 3 When the carbon chain is a saturated carbon chain of C1-C10, the preparation method comprises the following steps:
carrying out acyl chloride reaction on the dibasic fatty acid to obtain an acyl chloride product; the dibasic fatty acid is malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid or sebacic acid;
mixing the 1,3-diglyceride, pyridine and acyl chloride products to perform a third esterification reaction to obtain a third esterification product;
mixing the third esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a fourth esterification reaction to obtain the 20-hydroxyprogesterone precursor compound;
when A is a structure shown in formula 2, R 3 When the acyl is C1-C6 acyl, the preparation method comprises the following steps:
mixing fatty acid benzyl ester with alpha-amino with sodium nitrite for diazotization reaction to obtain diazotization products; the fatty acid benzyl ester with alpha-amino is 2-amino-malonic acid benzyl ester, 2-amino-succinic acid benzyl ester, 2-amino-glutaric acid benzyl ester, 2-amino-adipic acid benzyl ester, 2-amino-pimelic acid benzyl ester, 2-amino-suberic acid benzyl ester, 2-amino-azelaic acid benzyl ester or 2-amino-sebacic acid benzyl ester;
mixing the diazotization product with fatty acyl chloride to perform a fifth esterification reaction to obtain a fifth esterification product; the fatty acyl chloride is acetyl chloride, propionyl chloride, 2-methyl propionyl chloride or trimethyl acetyl chloride;
mixing the 1,3-diglyceride, pyridine and a fifth esterification product to perform a sixth esterification reaction to obtain a sixth esterification product;
mixing the sixth esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a seventh esterification reaction to obtain the 20-hydroxyprogesterone precursor compound;
when the A is the structure shown in the formula 3, the preparation method comprises the following steps:
modifying 20-hydroxyprogesterone with dimethyl sulfoxide, and mixing with SO 2 Cl 2 Reacting to obtain 20-hydroxyprogesterone methylthio methyl ether;
and mixing the first esterification product, 20-hydroxyprogesterone methylthiomethyl ether and 4-dimethylaminopyridine to perform an eighth esterification reaction to obtain the 20-hydroxyprogesterone precursor compound.
In the present invention, unless otherwise specified, all the raw materials used are commercially available in the art.
In the present invention, the 20-hydroxyprogesterone (20-DHP) is preferably obtained by reduction of progesterone.
In the present invention, the reducing agent used for the reduction preferably includes lithium aluminum hydride and/or lithium bistrimethylsilyl amide.
In the present invention, the reduction preferably further comprises oxidation, and the oxidizing agent used in the oxidation preferably comprises one or more of pyridinium chlorochromate, manganese dioxide, silver carbonate and 2,3-dichloro-5,6-dicyan-p-benzoquinone.
In the present invention, the 20-hydroxyprogesterone has different configurations of α -type, β -type or a mixture of α and β, and the resulting prodrug 20-hydroxyprogesterone precursor compound also has different configurations.
In the present invention, the preparation of the 20-hydroxyprogesterone preferably comprises the following:
a) Progesterone (P) 4 ) Lithium aluminum hydride (LiAlH) 4 ) Reducing to 3,20-hydroxyprogesterone, and adding manganese dioxide (MnO) 2 ) Oxidizing to obtain the 20-hydroxyprogesterone (20-DHP) according to the following reaction principle:
b) Progesterone (P) 4 ) Lithium aluminum hydride (LiAlH) 4 ) Reducing to 3,20-hydroxyprogesterone, and oxidizing with pyridinium chlorochromate (PCC) to obtain the 20-hydroxyprogesterone (20-DHP), wherein the reaction principle is as follows:
c) Progesterone (P) 4 ) Via bisamidolithium (LiHMDS), lithium aluminium hydride (LiAlH) 4 ) Reducing to obtain the 20-hydroxyprogesterone (20-DHP) according to the following reaction principle:
d) Progesterone (P) 4 ) Lithium aluminum hydride (LiAlH) 4 ) Reducing to 3,20-hydroxyprogesterone, and oxidizing with silver carbonate to obtain 20-hydroxyprogesterone (20-DHP), wherein the reaction principle is as follows:
e) Progesterone (P) 4 ) Lithium aluminum hydride (LiAlH) 4 ) Reducing to 3,20-hydroxyprogesterone, and oxidizing with 2,3-dichloro-5,6-dicyan p-benzoquinone (DDQ) to obtain the 20-hydroxyprogesterone (20-DHP), wherein the reaction principle is as follows:
mixing fatty acid and 1,3-dihydroxyacetone for condensation reaction to obtain a condensation product; the fatty acid comprises C2-24 saturated or unsaturated fatty acid.
In the present invention, the condensation reaction is preferably carried out under the conditions of a condensing agent, and the condensing agent is preferably Dicyclohexylcarbodiimide (DCC) and/or 4-Dimethylaminopyridine (DMAP).
After the condensation product is obtained, the invention carries out hydrogenation reduction on the condensation product to obtain 1,3-diglyceride (1,3-DG).
In the present invention, sodium borohydride is preferably used for the hydrogenation reduction.
In the present invention, the preparation principle of 1,3-diglyceride is shown as the following formula:
the fatty acid is preferably dissolved in dioxane and thionyl chloride (SOCl) 2 ) Reacting to obtain fatty acid chloride, reacting the fatty acid chloride with 1,3-dihydroxyacetone under the condition of pyridine to obtain 2-oxygen-1,3-palmitoyl propylene diester, and then reacting with sodium borohydride (NaBH) 4 ) Hydrogenation reaction to obtain 1,3-diglyceride (1,3-DG), and the preparation principle is shown as the following formula:
after 1,3-diglyceride is obtained, when a is a structure represented by formula 1, the preparation method comprises the following steps:
mixing the 1,3-diglyceride, pyridine and dibasic fatty acid anhydride to perform a first esterification reaction to obtain a first esterification product; the binary fatty acid anhydride is malonic anhydride, succinic anhydride, glutaric anhydride, adipic anhydride, pimelic anhydride, suberic anhydride, azelaic anhydride or sebacic anhydride;
and mixing the first esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine for a second esterification reaction to obtain the 20-hydroxyprogesterone precursor compound.
In the present invention, it is preferable that 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is further added for the second esterification reaction.
Taking glutaric anhydride as an example, when a is a structure shown in formula 1, the preparation method preferably comprises the following steps of reacting glutaric anhydride with 1,3-DG in the presence of DMAP and pyridine to obtain an intermediate 1, and reacting with 20-hydroxyprogesterone (20-DHP) under catalysis of 4-Dimethylaminopyridine (DMAP) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) to obtain the 20-hydroxyprogesterone precursor compound, and the principle is shown in the following formula:
when A is a structure shown in formula 2, R 3 When the carbon chain is a saturated carbon chain of C1-C10, the preparation method comprises the following steps:
carrying out acyl chloride reaction on the dibasic fatty acid to obtain an acyl chloride product; the dibasic fatty acid is malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid or sebacic acid;
mixing the 1,3-diglyceride, pyridine and acyl chloride products to perform a third esterification reaction to obtain a third esterification product;
mixing the third esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a fourth esterification reaction to obtain the 20-hydroxyprogesterone precursor compound.
With R 3 ＝CH 3 For example, A is formula 2In the case of the structure shown, the production method preferably includes the steps of: 3-methylglutaric acid, N-Dimethylformamide (DMF), thionyl chloride (SOCl) 2 ) Refluxing and heating to obtain diacid chloride, esterifying the diacid chloride with 1,3-DG to generate an intermediate product 2 under the catalysis of 4-Dimethylaminopyridine (DMAP) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), and then esterifying the intermediate product with 20-hydroxyprogesterone (20-DHP) under the conditions of 4-Dimethylaminopyridine (DMAP) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) to obtain the 20-hydroxyprogesterone precursor compound, wherein the principle is shown as the following formula:
when A is a structure shown in formula 2, R 3 When the acyl is C1-C6 acyl, the preparation method comprises the following steps:
mixing fatty acid benzyl ester with alpha-amino with sodium nitrite to carry out diazotization reaction to obtain a diazotization product;
mixing the diazotization product with acyl chloride to perform fifth esterification reaction to obtain a fifth esterification product;
mixing the 1,3-diglyceride, pyridine and a fifth esterification product to perform a sixth esterification reaction to obtain a sixth esterification product;
and mixing the sixth esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a seventh esterification reaction to obtain the 20-hydroxyprogesterone precursor compound.
With R 3 ＝-O-COC(CH 3 ) 3 M =0, the preparation method preferably comprises the following steps: dissolving L-glutamic acid-gamma-benzyl ester in a mixed solvent of glacial acetic acid and water, reacting with sodium nitrite to obtain an intermediate 3, reacting the intermediate 1 with trimethylacetyl chloride in the presence of 4-Dimethylaminopyridine (DMAP) to obtain an intermediate 4, esterifying the intermediate 4 with 1,3-DG under the catalysis of 4-Dimethylaminopyridine (DMAP) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) to obtain an intermediate 5, and performing hydrogen catalytic reduction to obtain a neutral intermediateAnd (3) carrying out esterification reaction on the intermediate 6 and 20-hydroxyprogesterone (20-DHP) under the conditions of 4-Dimethylaminopyridine (DMAP) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) to obtain the 20-hydroxyprogesterone precursor compound, wherein the principle is shown as the following formula:
when the A is the structure shown in the formula 3, the preparation method comprises the following steps:
modifying 20-hydroxyprogesterone with dimethyl sulfoxide, and mixing with SO 2 Cl 2 Reacting to obtain 20-hydroxyprogesterone methylthio methyl ether;
and mixing the first esterification product, 20-hydroxyprogesterone methylthiomethyl ether and 4-dimethylaminopyridine to perform an eighth esterification reaction to obtain the 20-hydroxyprogesterone precursor compound.
Taking R4= H as an example, the preparation method preferably includes the steps of: dissolving the hydroxyprogesterone (20-DHP) in dimethyl sulfoxide (DMSO), stirring with acetic acid and acetic anhydride at room temperature to obtain 20-hydroxyprogesterone methylthiomethyl (20-DHP-MTM) ether, and mixing with sulfuryl chloride (SO) 2 Cl 2 ) After the reaction, the intermediate 1, 1,8-diazabicycloundec-7-ene (DBU) is reacted in toluene (PhMe) to obtain the 20-hydroxyprogesterone precursor compound, the principle is shown as the following formula:
the amount of the reaction principle in the preparation process is not particularly limited, and the reaction is preferably carried out according to the proportion in the reaction principle.
The invention also provides application of the 20-hydroxyprogesterone precursor compound in the technical scheme in preparation of progesterone medicaments.
The invention is not particularly limited to the specific forms of use described, and may be practiced in a manner well known to those skilled in the art.
In order to further illustrate the present invention, the 20-hydroxyprogesterone precursor compounds provided by the present invention, as well as the preparation method and use thereof, are described in detail below with reference to examples, which should not be construed as limiting the scope of the present invention.
Example 1
Synthesis of 20-DHP-5C-TG
Synthesis of 20-DHP
1) Preparation of 3,20-hydroxyprogesterone (Compound 1)
Progesterone (2.5g, 8 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and the solution was added dropwise to 1.0 mol. L in an ice bath -1 A solution of lithium aluminum hydride (20mL, 20mmol) in tetrahydrofuran was heated at reflux for 90 minutes. After the reflux was completed, ethyl acetate was added to quench. And (4) carrying out suction filtration, drying the filtrate by using anhydrous sodium sulfate, then carrying out reduced pressure concentration to remove the solvent, and drying to obtain a white solid, thus obtaining an intermediate 3,20-hydroxyprogesterone.
(2) Preparation of 20-hydroxyprogesterone (Compound 2)
Compound 1 (1.2 g), freshly prepared manganese dioxide (7.0 g, 80mmol) was weighed out and heated under reflux in dichloromethane (40 mL) for 6 hours. After the reflux was complete, the mixture was filtered through celite, and washed with dichloromethane, and the filtrate was dried over anhydrous sodium sulfate overnight. And (4) carrying out suction filtration, carrying out reduced pressure concentration on the filtrate to remove the solvent, and drying to obtain a white solid. Obtaining 20-hydroxyprogesterone, namely a compound 2, by silica gel column chromatography, wherein the reaction principle is as follows:
synthesis of 1,3-diglycerol dipalmitate
(1) Synthesis of palmitoyl chloride (Compound 3)
Palmitic acid (10.25g, 40mmol) was weighed, anhydrous dioxane (100 mL) was weighed, 3 drops of N, N-dimethylformamide were added, thionyl chloride (3 mL, 41mmol) was added dropwise, and the mixture was refluxed for 4 hours under nitrogen. And after the reflux is finished, cooling the system to room temperature, and concentrating under reduced pressure to remove the solvent to obtain a light yellow oily substance, namely palmitoyl chloride.
(2) Synthesis of 2-oxo-1,3-dipalmitoyl propylene diester (Compound 4)
At room temperature, 1,3-dihydroxyacetone (1.1g, 12mmol), anhydrous pyridine (2mL, 2g, 24mmol) was dissolved in anhydrous dichloromethane (36 mL) under nitrogen, palmitoyl chloride (6.47g, 24mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with 15mL of methanol and 30mL of water, and stirred for another 30 minutes. After separation, the aqueous layer was extracted once with chloroform, and the chloroform layer was combined with the previous organic layer. The organic layer was washed once with saturated sodium chloride solution. The organic layer was concentrated to dryness under reduced pressure to give a white solid.
(3) Synthesis of 1,3-Glycerol dipalmitate (Compound 5)
synthesis of 20-DHP-5C-TG
(1) Synthesis of Compound 6
1,3-Glycerol dipalmitate (500mg, 0.88mmol) was dissolved in 10mL of anhydrous dichloromethane, tetrahydrofuran (10 mL), 4-dimethylaminopyridine (DMAP, 104mg,0.9 mmol), glutaric anhydride (200mg, 1.75mmol) were added, and anhydrous pyridine (10 mL) was slowly added dropwise and reacted at room temperature for 48 hours. After the reaction is finished, the reaction solution is sequentially used with 1mol and L -1 The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to obtain a solid. And performing silica gel column chromatography to obtain a compound 6.
(2) Synthesis of Compound 7
Chemical combination ofSubstance 6 (560mg, 0.83mmol) was dissolved in anhydrous dichloromethane (30 mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 175mg, 0.9mmol), 4-dimethylaminopyridine (DMAP, 45mg, 0.36mmol) and 20-hydroxyprogesterone (316 mg, 1mmol) were added and reacted at room temperature for 48 hours. After the reaction is finished, the reaction solution is sequentially used by 1 mol.L -1 The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to obtain a solid. And (3) obtaining a compound 7, namely a 20-hydroxyprogesterone precursor compound with a structure shown in a formula II by silica gel column chromatography, wherein the compound is white pasty semisolid, and the specific synthetic principle is shown in the following formula:
compound 7 comprises two configurations, an α configuration and a β configuration, which are enantiomers of each other, and is a mixture of the two isomers when structurally characterized.
And (3) characterization: TLC: n-hexane-ethyl acetate system (v/v = 3:1), rf =0.38.
IRν(KBr):2936,1751,1673,1619,1454cm -1 . 1 H-NMR(600MHz,CDCl 3 ):δ5.76–5.70(m,1H),5.26(tt,J＝5.8,4.3Hz,1H),4.87(dq,J＝10.4,6.1Hz,1H),4.30(ddd,J＝11.9,4.3,2.1Hz,2H),4.14(ddt,J＝11.9,5.9,1.4Hz,2H),2.47–2.22(m,12H),2.05-1.99(m,1H),1.95(p,J＝7.3Hz,2H),1.84(ddt,J＝12.6,9.4,3.5Hz,2H),1.76–1.66(m,3H),1.64–1.56(m,5H),1.55–1.51(m,1H),1.42(dd,J＝7.0,2.7Hz,1H),1.38(dd,J＝6.3,4.5Hz,1H),1.25(s,50H),1.18(d,J＝3.2Hz,3H),1.15(d,J＝6.1Hz,3H),1.06(tdd,J＝15.2,9.3,4.3Hz,2H),0.88(t,J＝7.0Hz,8H),0.86–0.81(m,13H),0.70(d,J＝29.8Hz,3H). 13 C-NMR(150MHz,CDCl 3 ):δ199.53,173.23,172.01,171.96,171.26,123.79,72.79,69.12,61.93,55.19,54.83,53.77,42.18,39.03,38.55,35.64,35.41,33.98,33.93,33.51,33.16,32.81,31.95,31.89,29.67,29.63,29.59,29.45,29.33,29.24,29.09,25.37,24.81,24.15,22.66,20.88,19.94,19.90,17.33,14.09,12.47.HRMS：m/z:981.77376([M+H] + ,C 61 H 105 O 9 Theoretical value981.77531).
Determination of transport pathway of 20-DHP-5C-TG in rat
Ovariectomized female rats were randomly assigned to the normal dosing group (gavage dosing with prodrug in oil 400mg kg) -1 ) Lymph blocking group (intraperitoneal injection 3mg kg) -1 Cycloheximide, 1h post-gavage administration of 400mg kg prodrug oil solution -1 ) 3 in each group. Collecting blood from fundus venous plexus 10min before administration, 5min after administration, 15min, 0.5h, 1h, 2h, 4h, 8h and 12h respectively, collecting blood from 1.5mLEP tube containing EDTA anticoagulation, centrifuging to obtain blood plasma, measuring the concentration of 20-hydroxyprogesterone in the blood plasma by high performance liquid chromatography, drawing a pharmaceutical time curve, and calculating the area under the curve (AUC) by using software GraphPad Prism. AUC by lymph blocking group and normal administration group 0-t The ratio of (A) to (B) can be calculated by calculating the ratio of 20-DHP-5C-TG absorbed through the lymphatic pathway, and the calculation formula is shown as formula 1:
the results of blood concentration measurement are shown in tables 1-2, the time curve of drug is shown in FIG. 1, A in FIG. 1 is the time curve of 20 alpha-DHP, B is the time curve of 20 beta-DHP, the results show that the 20-DHP-5C-TG prodrug can release corresponding parent drug after entering into systemic circulation, and the calculated lymphatic transport ratio of 20 alpha-DHP-5C-TG is 90.065%, and the lymphatic transport ratio of 20 beta-DHP-5C-TG is 84.950%. The difference between the lymph blocking group of 20-DHP-5C-TG and the normal administration group by independent sample t test has statistical significance (P < 0.05).
Table 1 20 α -DHP concentration-time data in rat plasma after oral prodrug administration (n = 3)
Table 2 concentration of 20 β -DHP in rat plasma after oral prodrug-time data (n = 3)
Example 2
Synthesis of 20-DHP-5C (-R) -TG
Synthesis of 20-hydroxyprogesterone and 1,3-diglyceride Using the same method as in example 1
Synthesis of Compound 8
3-methylglutaric acid (500mg, 3.42mmol), N-dimethylformamide (two drops), thionyl chloride (2.48mL, 34.2mmol), and heated under reflux for 2 hours. The reaction was cooled to room temperature, diluted with toluene (5 mL), and concentrated under reduced pressure to give the diacid chloride as a yellow oil, based on the following formula:
synthesis of Compound 9
1,3-DG (50.0mg, 0.088mmol), pyridine (71.1. Mu.L, 0.88 mmol) was added to a solution of compound 8 (80.4mg, 0.44mmol) in dichloromethane (3.5 mL) and refluxed for 2 hours. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with 1M HCl. The aqueous layer was further extracted with ethyl acetate, and the organic phase was washed successively with 1M HCl and brine, and dried (MgSO 4) 4 ) And concentrating under reduced pressure to obtain a crude product. Purifying by silica gel column chromatography to obtain compound 9 as colorless solid according to the following formula:
synthesis of 20-DHP-5C-beta Me-TG
4- (dimethylamino) pyridine (DMAP, 6.1mg, 0.05mmol), EDCI (23.8mg, 0.12mmol), 20-hydroxyprogesterone (28.2mg, 0.09mmol), compound 9 (34.6mg, 0.05mmol), and dichloromethane (2 mL), and the mixture was stirred at room temperature for 19 hours. Diluting the reaction system with dichloromethane (15 mL), concentrating under reduced pressure to obtain a crude product, and purifying by silica gel chromatography to obtain a compound 10, namely a 20-hydroxyprogesterone precursor compound with a structure shown in formula III, wherein the property is colorless solid, and the principle is as follows:
structural characterization: 1 H-NMR(400MHz,CDCl 3 ):δ5.85(m,2H),4.57(m,1H),4.30(d,J＝11.9,4.3Hz,2H),4.14(d,J＝11.9,5.9Hz,2H),2.97–2.86(m,3H,2.27–2.42(m,10H),1.9–1.56(m,12H),1.56–1.26(m,61H),1.04–0.98(m,4H),0.88–0.84(m,9H). 13 C-NMR(100MHz,CDCl 3 ):δ198.9,173.1,170.2,124.0,73.1,69.0,62.7,56.2,55.2,53.7,42.3,39.5,38.6,35.2,34.1,33.9,31.9,31.6,29.6,29.3,29.0,27.7,27.3,25.9,25.1,25.0,22.7,21.1,20.2,19.0,14.9,14.1.ESI-MS:m/z:993.78([M+H] + ,C 62 H 105 O 9 theoretical value 993.78).
Example 3
20-DHP-5C-α-OCOC(CH3) 3 -TG synthesis
Synthesis of Compound 11
L-glutamic acid-gamma-benzyl ester (1.5g, 6.33mmol) was dissolved in acetic acid (10 mL), water (10 mL) was added, stirring was performed in an ice bath for 20min, sodium nitrite (3.45g, 50mmol) was added, and after 2 hours of ice bath reaction, the reaction was performed at room temperature overnight. Extracting the reaction solution by ethyl acetate, washing an organic layer for 1 time, combining the organic layers, drying by anhydrous sodium sulfate, and removing the solvent by rotary evaporation to obtain a compound 11 according to the following principle:
synthesis of Compound 12
Compound 11 (1 g) was redissolved in anhydrous dichloromethane (30 mL), 4- (dimethylamino) pyridine (DMAP, 100mg, 0.8mmol) was added, pivaloyl chloride (770mg, 6.28mmol) was added dropwise, and the mixture was reacted overnight at room temperature under vacuum with nitrogen protection with Bi Chou. Removing the solvent by rotary evaporation, and purifying by silica gel column chromatography to obtain a compound 12, wherein the principle is as follows:
synthesis of Compound 13
Compound 12 (500 mg) was dissolved in anhydrous dichloromethane, 4- (dimethylamino) pyridine (DMAP, 200mg,1.6 mmol), EDCI (700mg, 3.66mmol), 1,3-DG (900mg, 1.58mmol) were added, and the mixture was reacted at room temperature for 48 hours under vacuum with nitrogen gas. Removing the solvent by rotary evaporation, and purifying by silica gel column chromatography to obtain a compound 13, wherein the principle is as follows:
synthesis of Compound 14
Dissolving compound 13 (600 mg) in tetrahydrofuran (30 mL), adding palladium on carbon (60 mg), reacting at room temperature for 4 hours under hydrogen conditions, filtering off the palladium on carbon, and removing the solvent by rotary evaporation to obtain compound 14, wherein the principle is as follows:
20-DHP-5C-α-OCOC(CH 3 ) 3 synthesis of-TG
Compound 14 (600 mg) was dissolved in anhydrous dichloromethane (30 mL), 4- (dimethylamino) pyridine (DMAP, 45mg, 0.36mmol), EDCI (175mg, 0.91mmol), and 20-hydroxyprogesterone (316 mg, 1mmol) were added, and the mixture was reacted at room temperature for 48 hours under vacuum with nitrogen gas. Removing the solvent by rotary evaporation, and purifying by column chromatography to obtain a compound 15, namely a 20-hydroxyprogesterone precursor compound with a structure shown in formula IV, wherein the principle is shown in the following formula:
structural characterization: 1 H-NMR(400MHz,CDCl 3 ):δ5.85(m,2H),5.40(m,1H),4.57(m,1H),4.30(d,J＝11.9,4.3Hz,2H),4.14(d,J＝11.9,5.9Hz,2H),2.97–2.86(m,2H)2.35–2.31(m,10H),1.62–1.20(m,83H),0.88–0.84(m,9H). 13 C-NMR(100MHz,CDCl 3 ):δ198.9,177.9,173.1,170.8,170.2,124.0,82.9,73.1,69.0,62.7,56.2,55.2,53.7,42.3,39.5,38.7,38.6,35.7,35.2,34.1,32.5,31.6,29.6,29.3,27.4,25.5,25.1,25.0,22.7,21.1,20.2,19.0,14.9,14.1.ESI-MS:m/z:1080.82([M+H] + ,C 66 H 112 O 11 theoretical 1080.82).
Example 4
20-DHP-CH 2 Synthesis of O-5C-TG
Synthesis of 20-hydroxyprogesterone and 1,3-diglyceride the same as in example 1
Synthesis of 20-hydroxyprogesterone methylthiomethyl ether (20-DHP-MTM)
Acetic acid (44. Mu.L, 0.769 mmol), acetic anhydride (140. Mu.L, 1.48 mmol), dimethyl sulfoxide (216. Mu.L, 3.04 mmol), 20-hydroxyprogesterone (39.5 mg, 0.125mmol), and the mixture was stirred at room temperature for 66 hours. The reaction mixture is diluted with water and is 10% by weight 2 CO 3 Neutralizing the solution. The aqueous phase was extracted with ethyl acetate, the organic layers were combined, washed successively with saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product. Purification by silica gel column chromatography gave the compound 20-hydroxyprogesterone methylthiomethyl ether.
20-DHP-CH 2 Synthesis of O-5C-TG
A solution of sulfuryl chloride (10.7. Mu.L), methylene chloride (2.2 mL) and compound 15 (38.9mg, 0.112mmol) was stirred at 0 ℃ for 30 minutes, and then at room temperature for another 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting crude residue was azeotroped with toluene and then redissolved in toluene (1.1 mL). Intermediate 1 (49.9mg, 0.0770mmol) and DBU (16.4. Mu.L, 0.110 mmol) were pre-stirred in toluene (1.1 mL) for 40 min, and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, saturated sodium bicarbonate, and saturated brine in this order and dried (MgSO) 4 ) Concentrating under reduced pressure to obtain crude product, and purifying with silica gel column chromatography to obtain compound 16, which is 20-hydroxyprogesterone precursor compound with structure shown in formula V, and has the following principle:
structural characterization: 1 H-NMR(400MHz,CDCl 3 ):δ6,16(s,2H),5.85(m,2H),4.30(d,J＝11.9,4.3Hz,4H),4.14(d,J＝11.9,5.9Hz,2H),3.2(m,1H),2.97–2.86(m,2H)2.42–2.25(m,12H),1.97–1.65(m,10H),1.56–1.26(m,56H),1.45–1.04(m,8H),0.88–0.84(m,9H). 13 C-NMR(100MHz,CDCl 3 ):δ198.9,173.1,170.2,124.0,90.9,80.4,69.0,62.7,56.5,56.0,53.7,42.4,39.8,38.6,35.7,35.2,34.1,33.9,33.3,32.5,31.9,31.6,29.6,29.3,29.0,26.2,25.2,25.0,22.7,21.1,20.0,19.2,19.0,15.2,14.1.ESI-MS:m/z:1010.78([M+H] + ,C 2 H 106 O 10 theoretical value 1010.78).
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be construed as the protection scope of the present invention.
Claims (10)
1. A 20-hydroxyprogesterone precursor compound having a structure according to formula I:
in the formula I, A is a structure shown in formulas 1-3:
in formulas 1 to 3, a connection site;
the carbon at the carbon-oxygen double bond in the formula 1 is connected with the oxygen at the hydroxyl of 20-hydroxyprogesterone, and n = 1-10;
the carbon at the carbon-oxygen double bond in the formula 2 is connected with the oxygen at the hydroxyl of 20-hydroxyprogesterone, k = 1-10, m = 1-10 3 Is a C1-C10 saturated carbon chain or a C1-C6 acyl group;
formula 3 a =1 &10，b＝1～10，R 4 Is H, C-C10 saturated carbon chain or C1-C6 acyl;
in the formula I, R 1 And R 2 Independently a saturated or unsaturated carbon chain of C2-24.
2. The 20-hydroxyprogesterone precursor compound of claim 1, wherein n, k, a, and b are independently 1 to 5.
3. The 20-hydroxyprogesterone precursor compound of claim 1, wherein said R is 1 And R 2 Independently a saturated or unsaturated carbon chain of C10-24.
4. The 20-hydroxyprogesterone precursor compound of claim 1, wherein the 20-hydroxyprogesterone precursor compound has a structure according to formulas II-V:
5. the process for the preparation of the 20-hydroxyprogesterone precursor compound according to any of claims 1 to 4, comprising the steps of:
mixing fatty acid and 1,3-dihydroxyacetone for condensation reaction to obtain a condensation product; the fatty acid comprises C2-24 saturated or unsaturated fatty acid;
hydrogenating and reducing the condensation product to obtain 1,3-diglyceride;
the 1,3-diglyceride has the structure shown in formula a:
when the A is the structure shown in the formula 1, the preparation method comprises the following steps:
mixing the 1,3-diglyceride, pyridine and dibasic fatty acid anhydride to perform a first esterification reaction to obtain a first esterification product; the binary fatty acid anhydride is malonic anhydride, succinic anhydride, glutaric anhydride, adipic anhydride, pimelic anhydride, suberic anhydride, azelaic anhydride or sebacic anhydride;
mixing the first esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a second esterification reaction to obtain a 20-hydroxyprogesterone precursor compound;
when A is a structure shown in formula 2, R 3 When the carbon chain is a saturated carbon chain of C1-C10, the preparation method comprises the following steps:
carrying out acyl chloride reaction on the dibasic fatty acid to obtain an acyl chloride product; the dibasic fatty acid is malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid or sebacic acid;
mixing the 1,3-diglyceride, pyridine and acyl chloride products to perform a third esterification reaction to obtain a third esterification product;
mixing the third esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a fourth esterification reaction to obtain a 20-hydroxyprogesterone precursor compound;
when A is a structure shown in formula 2, R 3 When the acyl is C1-C6 acyl, the preparation method comprises the following steps:
mixing fatty acid benzyl ester with alpha-amino with sodium nitrite for diazotization reaction to obtain diazotization products; the fatty acid benzyl ester with alpha-amino is 2-amino benzyl malonate, 2-amino benzyl succinate, 2-amino benzyl glutarate, 2-amino benzyl adipate, 2-amino benzyl pimelate, 2-amino benzyl suberate, 2-amino benzyl azelate or 2-amino benzyl sebacate;
mixing the diazotization product with fatty acyl chloride to perform fifth esterification reaction to obtain a fifth esterification product; the fatty acyl chloride is acetyl chloride, propionyl chloride, 2-methylpropionyl chloride or trimethylacetyl chloride;
mixing the 1,3-diglyceride, pyridine and a fifth esterification product to perform a sixth esterification reaction to obtain a sixth esterification product;
mixing the sixth esterification product, 20-hydroxyprogesterone and 4-dimethylaminopyridine to perform a seventh esterification reaction to obtain the 20-hydroxyprogesterone precursor compound;
when the A is the structure shown in the formula 3, the preparation method comprises the following steps:
modifying 20-hydroxyprogesterone with dimethyl sulfoxide, and mixing with SO 2 Cl 2 Reacting to obtain 20-hydroxyprogesterone methylthio methyl ether;
and mixing the first esterification product, 20-hydroxyprogesterone methylthiomethyl ether and 4-dimethylaminopyridine to perform an eighth esterification reaction to obtain the 20-hydroxyprogesterone precursor compound.
6. The method according to claim 5, wherein the 20-hydroxyprogesterone is obtained by reduction of progesterone.
7. The method according to claim 6, wherein the reducing agent used for the reduction comprises lithium aluminum hydride and/or lithium bis-trimethylsilyl amide.
8. The method of claim 6, wherein the reduction further comprises oxidation using an oxidizing agent comprising one or more of pyridinium chlorochromate, manganese dioxide, silver carbonate, and 2,3-dichloro-5,6-dicyan-p-benzoquinone.
9. The production method according to claim 5, wherein the condensation reaction is carried out under a condensing agent condition, and the condensing agent includes dicyclohexylcarbodiimide and/or 4-dimethylaminopyridine.
10. Use of a 20-hydroxyprogesterone precursor compound according to any of claims 1 to 4 for the preparation of a progestin drug.
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