CN115010603A - Synthesis method of misoprostol intermediate - Google Patents

Synthesis method of misoprostol intermediate Download PDF

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CN115010603A
CN115010603A CN202210797387.2A CN202210797387A CN115010603A CN 115010603 A CN115010603 A CN 115010603A CN 202210797387 A CN202210797387 A CN 202210797387A CN 115010603 A CN115010603 A CN 115010603A
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蒋宇扬
刘子建
张存龙
吴伟彬
陈大伟
牛子洲
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Shenzhen Kivita Innovative Drug Institute
SHENZHEN MAIN LUCK PHARMACEUTICALS Inc
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SHENZHEN MAIN LUCK PHARMACEUTICALS Inc
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Abstract

The invention provides a preparation method of a misoprostol key intermediate compound I7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -methyl heptanoate, which takes cyclooctanone as a starting material to prepare the misoprostol key intermediate compound I through 6 steps of mCPBA oxidation, hydrolysis-esterification, dessimutane oxidation, Friedel-crafts reaction, intramolecular rearrangement and isomerization. The method has the advantages of cheap and easily-obtained raw material reagents, low process cost, safety, controllability, good operability and industrial prospect.

Description

Synthesis method of misoprostol intermediate
Technical Field
The invention relates to the field of drug synthesis, in particular to a synthetic method of misoprostol intermediate.
Background
Misoprostol is a derivative of Prostaglandin (PG) E1 synthesized by man, and its structure is shown as the following formula:
Figure BDA0003736225430000011
misoprostol has a strong gastric acid secretion inhibiting effect and also has a contraction effect on pregnant uterus. Misoprostol is the first clinical PGE (prostaglandin E) derivative and has obvious therapeutic effects on various ulcers (except duodenal ulcer). In addition, misoprostol has pharmacological activity of E-type prostaglandins, and can soften cervix, enhance uterine tone and intrauterine pressure. The sequential application of mifepristone and induction of labor is one of the main methods for induction of labor in the middle period at present, can better replace surgical operations such as forceps scraping, amniocentesis and the like, has the abortion success rate of about 96.1 percent, and is a safe and effective induction of labor method.
In the misoprostol synthesis process, the optimal process route is that the intermediate 7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -heptanoic acid methyl ester compound I containing a cyclopentenone structure is subjected to TMS protected hydroxyl, conjugate addition reaction with the copper acid salt of tributyl [1(E) -4-methyl-4- [ (trimethylsilyl) oxy ] -1-octen-1-yl ] -stannane and TMS protection removal to obtain the final product misoprostol. Such as US4904820 and WO2019011668, etc.
Figure BDA0003736225430000012
Therefore, the cyclopentenone intermediate compound I is a key intermediate for synthesizing the misoprostol, and the efficient synthesis of the key intermediate has very important practical significance and production value.
Hem.lett. (1976,1341-1342) reports a method for synthesizing a cyclopentenone intermediate by using lactol as a raw material, wherein the method obtains a final product through multiple redox reactions and rearrangement, but a large amount of an oxidant, especially a chromium-containing Jones reagent, is used in the process, so that the method causes environmental pollution and cannot be applied to an actual industrial production process.
Figure BDA0003736225430000021
A process for the synthesis of methyl 7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -heptanoate is described in j.med.chem.,1977,1152-1159, which uses monomethyl azelate as starting material to finally obtain a cyclopentenone intermediate via an 8-step reaction.
The method has a complex route and cannot be applied to industrial production.
Figure BDA0003736225430000022
Another synthesis method is described in J.org.chem.,1977,175-176, which uses nonanone ester containing methylthio group to obtain cyclopentenone intermediate through three-step reaction, however, the synthesis method introduces lithium-containing reagent many times, which results in high risk of the whole synthesis method and is not suitable for industrial production.
Figure BDA0003736225430000023
In Eur.J.org.chem.1999, 2655-2662 it is described that dimethyl suberate as starting material is subjected to a unilateral hydrolysis with Porcine Pancreatic Lipase (PPL) to give a half-ester which is then subjected to a Friedel-Crafts reaction with furan under boron trifluoride diethyl ether catalysis. After reduction by sodium borohydride, isomerization is carried out to obtain a cyclopentenone intermediate. Although the method adopts dimethyl suberate with simple structure and low price as the starting material, the method uses porcine pancreatic lipase with higher price in the reaction and needs to strictly control the reaction pH, and also uses carbon tetrachloride with hepatotoxicity, thereby limiting the application of the reaction route in industrial production.
Figure BDA0003736225430000031
In addition, a method for obtaining 7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -methyl heptanoate by using cyclooctanone as a raw material is reported in Bull, chem, Soc, Jpn, 1988, 2401-one 2404. Although the cyclooctanone used in the method is low in price and easy to obtain, the method uses a strong oxidant silver perchlorate which is unstable twice, so that the method is easy to generate potential safety hazards in the operation process.
Figure BDA0003736225430000032
There is no literature or patent report at home and abroad, and the method has the advantages of safe and simple operation, high yield and direct chemical synthesis of the misoprostol key intermediate under the condition of not depending on bio-enzyme catalysis. At present, domestic synthetic raw materials related to the key intermediate of misoprostol completely depend on import, which not only can cause monopoly of the raw materials, but also can cause the problems of uncontrollable quality, too long period, influence on production and the like. Due to the excellent curative effect of misoprostol in clinical application and potential huge economic and social benefits, a chemical synthesis method of a key intermediate of misoprostol needs to be further optimized.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a synthetic preparation method of the misoprostol intermediate compound I, which has the advantages of low process cost, strong operability, mild reaction conditions and industrial prospect.
The invention provides a synthesis method of a misoprostol intermediate compound I7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -methyl heptanoate, which is characterized by comprising the following steps:
A. oxidizing cyclooctanone to obtain oxacyclononane-2-one, wherein the oxidant is m-chloroperoxybenzoic acid;
Figure BDA0003736225430000041
B. b, adding inorganic acid into the oxacyclononane-2-ketone obtained in the step A in an alcohol solvent to react and open the ring to esterify to obtain 8-hydroxy methyl octanoate;
Figure BDA0003736225430000042
C. b, carrying out oxidation reaction on the 8-hydroxy methyl caprylate obtained in the step B by using a dessimutan reagent to obtain 8-oxo methyl caprylate;
Figure BDA0003736225430000043
D. d, carrying out Friedel-crafts reaction on the 8-oxo methyl caprylate obtained in the step C and furan to obtain 8- (furan-2-yl) -8-hydroxy caprylate under the action of an alkali reagent butyl lithium;
Figure BDA0003736225430000044
E. carrying out intramolecular rearrangement reaction on the 8- (furan-2-yl) -8-hydroxyoctanoate obtained in the step D to obtain 7- (2-hydroxy-5-oxocyclopent-3-en-1-yl) -heptanoic acid methyl ester;
Figure BDA0003736225430000045
F. e, reacting and isomerizing the methyl 7- (2-hydroxy-5-oxocyclopent-3-en-1-yl) -heptanoate obtained in the step E under the action of triethylamine and anhydrous chloral to obtain methyl 7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -heptanoate;
Figure BDA0003736225430000046
Figure BDA0003736225430000051
namely, the reaction route adopted is
Figure BDA0003736225430000052
Wherein, the reaction solvent adopted in the oxidation reaction in the step A is one of dichloromethane, tetrahydrofuran, toluene or acetonitrile, preferably dichloromethane; the dosage of the oxidizing reagent is 1-2 times of the molar quantity of the compound II, and preferably 1.4-1.5 times of the molar quantity; the reaction temperature is 10-40 ℃, and preferably 20-30 ℃.
In the hydrolysis ring-opening and esterification reaction in the step B, the alcohol solvent is methanol or ethanol, preferably methanol; the inorganic acid is one of sulfuric acid, hydrobromic acid or hydrochloric acid, and is preferably sulfuric acid; the amount of the inorganic acid is preferably 2.0 to 10.0 times of the molar amount of the compound III, and preferably 3 to 5 times of the molar amount.
C, the reaction solvent of the Dismetin oxidation reaction in the step C is dichloromethane or tetrahydrofuran, and dichloromethane is preferred; the alkali reagent is one of sodium bicarbonate, sodium carbonate, potassium carbonate or triethylamine, preferably sodium bicarbonate; the dosage of the alkali reagent is 1.8-2.5 times of the molar weight of the compound IV; the dosage of the dessimutan reagent is 1-2 times of the molar weight of the compound IV, and preferably 1.1-1.3 equivalent.
The reaction solvent of the Friedel-crafts reaction is dichloromethane or tetrahydrofuran, preferably tetrahydrofuran; the strong base used is one of n-butyl lithium, tert-butyl lithium or methyl lithium, preferably n-butyl lithium; the amount of the furan is 2-4 times of the molar amount of the compound V, and preferably 2.5 times of the molar amount.
Step E, carrying out structural rearrangement on the compound VI to prepare a compound VII, and carrying out two chemical reactions in sequence by adopting a one-pot preparation process, wherein the first chemical reaction is to add the compound VI and zinc oxide into a solvent 1, 4-dioxane and water for reaction, the use amount of the 1, 4-dioxane is 5-10 times of the molar amount of the compound VI, the use amount of the water is 3-5 times of the molar amount of the compound VI, and the use amount of the zinc oxide is 1-2 times of the molar amount of the compound VI, preferably 1.5-1.7 times of the molar amount; and the second chemical reaction is to add an alkali reagent and a methylating reagent into the solvent acetone to react, wherein the alkali reagent is one of sodium bicarbonate, sodium carbonate, potassium carbonate or triethylamine, preferably potassium carbonate, the dosage of the alkali reagent is 1-2 times of the molar quantity of the compound VI, preferably 1.5 equivalent, the methylating reagent is dimethyl sulfate or methyl iodide, preferably dimethyl sulfate, and the dosage of the methylating reagent is 1-2 times of the molar quantity of the compound VI, preferably 1.5 equivalent.
And F, using toluene or ethyl acetate as a reaction solvent, preferably toluene, using triethylamine as an alkali reagent, wherein the using amount of the alkali reagent is 1-2 times of the molar amount of the compound VII, preferably 1.0-1.2 times of the molar amount, and the reaction temperature is 50-80 ℃, preferably 60-70 ℃.
Compared with the prior art, the synthesis preparation method of the misoprostol intermediate compound I has the beneficial effects that:
1. all the raw materials of the reagent are cheap and easy to obtain;
2. expensive biological enzyme catalysis methods such as porcine pancreatic lipase, porcine liver esterase or yeast lipase are avoided, the production cost is obviously reduced, and the operability of the synthesis process is improved;
3. strong oxidants such as silver perchlorate and the like are avoided being used as reaction oxidants, so that the operation difficulty is reduced, and the safety of the synthesis process is improved;
4. avoiding the use of hepatotoxic carbon tetrachloride as a necessary solvent for the reaction.
Therefore, the invention provides a synthesis method of a key intermediate compound I7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -methyl heptanoate of misoprostol, which takes cyclooctanone as a starting material to prepare the key intermediate compound I of misoprostol through 6 steps of mCPBA oxidation, hydrolysis-esterification, dessimutane oxidation, Friedel-crafts reaction, intramolecular rearrangement and isomerization. The method has the advantages of cheap and easily-obtained raw material reagents, low process cost, safety, controllability, good operability and industrial prospect.
The invention is further illustrated by the following examples of specific embodiments.
Detailed Description
Example 1: synthesis of Oxacyclononane-2-one (III)
6g of cyclooctanone (II) was dissolved in 100mL of dichloromethane, 12g of m-chloroperoxybenzoic acid was added, the reaction mixture was stirred at room temperature until TLC monitoring was completed, the reaction mixture was concentrated, and 3.5g of oxacyclononane-2-one (III) was obtained as a yellow oily substance by column chromatography with a yield of 52.0%. ESI-MS [ M + H ]](m/z):143.1；1H-NMR(400MHz,CDCl 3 )δ(ppm):4.17(t,J＝4.0Hz,2H),2.17(t,J＝8.0Hz,2H),1.20-1.80(m,10H)。
Example 2: synthesis of methyl 8-hydroxyoctanoate (IV)
Dissolving 3.2g of oxacyclononane-2-one (III) in 50mL of methanol, adding 5mL of concentrated sulfuric acid, refluxing for 8 hours, concentrating the reaction solution, adding 50mL of water, washing for 3 times, extracting with 50mL of ethyl acetate for 3 times, concentrating the organic layer, and performing column chromatography to obtain 2.7g of colorless oily methyl 8-hydroxyoctanoate (IV) with the yield of 69.0%. ESI-MS [ M + H ]](m/z):175.1；1H-NMR(400MHz,CDCl 3 )δ(ppm):3.63(s,3H),3.58(t,J＝6.6Hz,2H),2.27(t,J＝7.5Hz,2H),1.92(s,1H),1.49-1.60(m,4H),1.22-1.38(m,6H)。
Example 3: synthesis of methyl 8-oxooctanoate (V)
2.5g of methyl 8-hydroxyoctanoate (IV) and 2.4g of sodium hydrogen carbonate were dissolved in 50mL of dichloromethane, and 6g of dessimidine reagent was added thereto under stirring at 0 ℃ to monitor completion of the reaction by TLC, 50mL of water was added thereto, followed by 3-time extraction with 50mL of dichloromethane, concentration of the organic layer and column chromatography to give 2.1g of methyl 8-oxooctanoate (V) as a colorless oily substance in 85.0% yield. ESI-MS [ M + H ]](m/z):173.1；1H-NMR(400MHz,CDCl 3 )δ(ppm):9.68(s,1H),3.58(s,3H),2.36(t,J＝7.2Hz,2H),2.24(t,J＝7.6Hz,2H),1.49-1.60(m,4H),1.24-1.30(m,4H)。
Example 4: synthesis of 8- (furan-2-yl) -8-hydroxyoctanoate (VI)
2g of furan was dissolved in 20mL of tetrahydrofuran, 16mmol of butyllithium reagent was added at-10 ℃ and after stirring for 30 minutes at 0 ℃ 1.5g of anhydrous magnesium chloride was added and the reaction was stirred at room temperature for 1.5 hours and then cooled to-25 ℃.2g of methyl 8-oxooctanoate (V) was dissolved in 5mL of tetrahydrofuran, and slowly added dropwise to the reaction solution, after completion of dropwise addition, the mixture was stirred at-25 ℃ for 30 minutes, quenched with a saturated aqueous ammonium chloride solution, 50mL of water was added, and then extracted with 50mL of ethyl acetate 3 times, the organic layer was concentrated, and column chromatography was performed to obtain 1.5g of colorless oily 8- (furan-2-yl) -8-hydroxyoctanoate (VI), with a yield of 55.0%. ESI-MS [ M + H ]](m/z):241.1；1H-NMR(400MHz,CDCl 3 )δ(ppm):7.27(brs,1H),6.23(d,J＝4.0Hz,1H),6.13(brs,1H),4.55(t,J＝6.2Hz,1H),3.57(s,3H),2.12-2.30(m,2H),1.68-1.80(m,2H),1.46-1.58(m,2H),1.09-1.44(m,6H)。
Example 5: synthesis of methyl 7- (2-hydroxy-5-oxocyclopent-3-en-1-yl) -heptanoate (VII)
1.4g of 8- (furan-2-yl) -8-hydroxyoctanoate (VI) and 1.2g of zinc chloride are dissolved in 15mL of 1, 4-dioxane, and 10mL of water are added. The reaction was refluxed for 22 hours and the reaction was complete by TLC. Cooling, concentrating the reaction solution, adding 50mL of water, extracting for 3 times by using 50mL of dichloromethane, and concentrating an organic layer; dissolving the concentrate in 30mL acetone, adding 1.2g potassium carbonate and 1.1g dimethyl sulfate, refluxing for 6 hr, concentrating the reaction solution, adding 50mL water, extracting with 50mL dichloromethane for 3 times, concentrating the organic layer, and separating by column chromatographyThis gave 0.49g of methyl 7- (2-hydroxy-5-oxocyclopent-3-en-1-yl) -heptanoate (VII) as a colorless oil in a yield of 35.0%. ESI-MS [ M + H ]](m/z):241.1；1H-NMR(400MHz,CDCl 3 )δ(ppm):7.52(dd,J＝5.8,2.2Hz,1H),6.20(dd,J＝5.8,1.4Hz,1H),5.25-5.55(m,2H),4.71(m,1H),3.66(s,3H),3.13(d,J＝6.7Hz,1H),2.16-2.58(m,7H),1.95(m,1H),1.50(m,1H)。
Example 6: synthesis of methyl 7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -heptanoate (I)
0.48g of methyl 7- (2-hydroxy-5-oxocyclopent-3-en-1-yl) -heptanoate (VII), 0.2g of triethylamine and 20mg of anhydrous chloral were dissolved in 20mL of toluene, and the mixture was heated at 65 ℃ for 6 hours to complete the TLC detection reaction, 50mL of water was added thereto, followed by extraction with 50mL of dichloromethane for 3 times, concentration of the organic layer and column chromatography to give 0.36 g of methyl 7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -heptanoate (I) as a colorless oily substance with a yield of 75.0%. ESI-MS [ M + H ]](m/z):355.2；1H-NMR(400MHz,CDCl 3 )δ(ppm):7.15(dt,J＝2.7,1.5Hz,1H),4.93(dt,J＝5.9,2.0Hz,1H),3.65(s,3H),2.79(dd,J＝18.6,6.0Hz,1H),2.25-2.34(m,3H),2.16(tt,J＝8.4,1.5Hz,2H),1.54-1.64(m,2H),1.43-1.51(m,2H),1.25-1.38(m,4H)。

Claims (12)

1. A synthetic method of misoprostol intermediate compound I7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -methyl heptanoate is characterized by comprising the following steps:
A. oxidizing cyclooctanone to obtain oxacyclononane-2-one, wherein the oxidant is m-chloroperoxybenzoic acid;
Figure FDA0003736225420000011
B. b, adding inorganic acid into the oxacyclononane-2-ketone obtained in the step A in an alcohol solvent to react and open the ring to esterify to obtain 8-hydroxy methyl octanoate;
Figure FDA0003736225420000012
C. b, carrying out oxidation reaction on the 8-hydroxy methyl caprylate obtained in the step B by using a dessimutan reagent to obtain 8-oxo methyl caprylate;
Figure FDA0003736225420000013
D. c, carrying out Friedel-crafts reaction on the 8-oxo methyl octanoate obtained in the step C and furan to obtain 8- (furan-2-yl) -8-hydroxy octanoate under the action of an alkali reagent butyl lithium;
Figure FDA0003736225420000014
E. carrying out intramolecular rearrangement reaction on the 8- (furan-2-yl) -8-hydroxyoctanoate obtained in the step D to obtain 7- (2-hydroxy-5-oxocyclopent-3-en-1-yl) -heptanoic acid methyl ester;
Figure FDA0003736225420000015
F. and E, reacting and isomerizing the methyl 7- (2-hydroxy-5-oxocyclopent-3-en-1-yl) -heptanoate obtained in the step E under the action of triethylamine and anhydrous chloral to obtain the methyl 7- (3-hydroxy-5-oxocyclopent-1-en-1-yl) -heptanoate.
Figure FDA0003736225420000021
2. The method according to claim 1, wherein the oxidation reaction in step a is carried out by using one of dichloromethane, tetrahydrofuran, toluene or acetonitrile as a reaction solvent, using 1-2 times of the molar amount of the compound II as an oxidation reagent, and controlling the reaction temperature to 10-40 ℃.
3. The method according to claim 2, wherein the reaction solvent used in the oxidation reaction in step A is dichloromethane, the amount of the oxidation reagent is 1.4 to 1.5 times of the molar amount of the compound II, and the reaction temperature is 20 to 30 ℃.
4. The method according to claim 1, wherein the alcohol solvent in step B is methanol or ethanol, the inorganic acid is one of sulfuric acid, hydrobromic acid or hydrochloric acid, and the amount of the inorganic acid is preferably 2.0-10.0 times the molar amount of compound III.
5. The method according to claim 4, wherein the alcohol solvent in step B is methanol, the inorganic acid is sulfuric acid, and the amount of the inorganic acid is preferably 3 to 5 times the molar amount of the compound III.
6. The method according to claim 1, wherein the reaction solvent in step C is dichloromethane or tetrahydrofuran, the alkali reagent is one of sodium bicarbonate, sodium carbonate, potassium carbonate or triethylamine, the dosage of the dessamidine reagent is 1-2 times of the molar amount of the compound IV, and the dosage of the alkali reagent is 1.8-2.5 times of the molar amount of the compound IV.
7. The method according to claim 6, wherein the reaction solvent in step C is dichloromethane, the alkali reagent is sodium bicarbonate, and the amount of the dessimutan reagent is 1.1-1.3 times of the molar amount of the compound IV.
8. The method according to claim 1, wherein the reaction solvent of the Friedel-crafts reaction in step D is dichloromethane or tetrahydrofuran, the strong base used is one of n-butyllithium, t-butyllithium or methyllithium, and the amount of the furan used is 2-4 times of the molar amount of the compound V.
9. The process according to claim 8, wherein the solvent for Friedel-crafts reaction in step D is tetrahydrofuran, the strong base used is n-butyllithium, and the amount of furan used is 2.5 times the molar amount of compound V.
10. The method as claimed in claim 1, wherein the step E is a one-pot method, the compound VI and zinc oxide are added into a solvent 1, 4-dioxane and water to react, acetone as a solvent, an alkali reagent and a methylating reagent are added into the reaction concentrate to react, the alkali reagent is one of sodium bicarbonate, sodium carbonate, potassium carbonate or triethylamine, the methylating reagent is dimethyl sulfate or methyl iodide, the amount of the alkali reagent is 1-2 times of the compound VI, and the amount of the methylating reagent is 1-2 times of the compound VI.
11. The method of claim 10, wherein the base reagent is potassium carbonate and the methylating agent is dimethyl sulfate.
12. The method according to claim 1, wherein the reaction solvent in the step F is toluene or ethyl acetate, the used base reagent is triethylamine, the used amount of the base reagent is 1-2 times of the molar amount of the compound VII, and the reaction temperature is 50-80 ℃.
CN202210797387.2A 2022-07-08 2022-07-08 Synthesis method of misoprostol intermediate Pending CN115010603A (en)

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