CN107778168B - Synthesis method of cis-3-hydroxy-cyclopentane carboxylate or cyclohexane carboxylate and derivatives thereof - Google Patents
Synthesis method of cis-3-hydroxy-cyclopentane carboxylate or cyclohexane carboxylate and derivatives thereof Download PDFInfo
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Abstract
The invention discloses a method for synthesizing cis-3-hydroxy-cyclopentane carboxylate or cyclohexane carboxylate and derivatives thereof, which takes a compound III as a raw material and can prepare the cis-3-hydroxy-cyclopentane carboxylate or cyclohexane carboxylate and the derivatives thereof through one-step ring opening reaction with hydrogen in a solvent in the presence of alkali and a catalyst. The method is simple, convenient and feasible, and the obtained product has high yield and is suitable for large-scale production.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a synthesis method of 1-substituted cis-3-hydroxy-cyclopentane carboxylate or cyclohexane carboxylate.
Background
Cis-structured 3-hydroxy-cyclopentanecarboxylates or cyclohexanecarboxylates and derivatives thereof are central building templates or direct precursors of a class of important pharmaceutically active compounds, which are capable of therapeutically regulating the metabolism of lipids and/or carbohydrates, and are therefore suitable for the prevention and/or treatment of type II diabetes and atherosclerosis.
However, regarding the preparation of the cis methyl 3-hydroxy-cyclopentanecarboxylate derivative, WO2014159218A1 patent specification discloses the preparation of the following compound I-1:
reagents and conditions: (a) phenylacetic acid, dicyclohexylcarbodiimide, 4-dimethylaminopyridine and dichloromethane at room temperature for 17 hours, 99 percent; (b)1, 4-dioxane, LiHMDS, room temperature, 1 hour, 53%; (c)4M HCl, methanol, 1, 4-dioxane, room temperature, 17 hours; 59 percent.
The method has the advantages that the market supply of the raw material compound IV is rare and expensive, strong base LiHMDS is required to be used in the step b, the yield of the step b and the yield of the step c are low, and the total yield is 30.9%.
In addition, chinese invention patent CN101815717B discloses the synthesis of the following compound VIII:
reagents and conditions: (d) TMS-Br, dimethyl sulfoxide, N-diisopropylethylamine, chloroform, yield: 57 percent; (e) azobisisobutyronitrile, tris (trimethylsilyl) silane, 80 ℃ for 5 hours, yield 53%.
The method has the advantages that the yield of the steps d and e is low, the total yield is 30.2%, the temperature of the step e is high, only halogen can be removed, and the ring-opening reaction cannot be completed.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of 1-substituted cis-3-hydroxy-cyclopentane carboxylate or cyclohexane carboxylate, which has the advantages of cheap and easily obtained raw materials, short reaction steps, simple and convenient operation and high yield.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a process for the preparation of a compound of formula I:
wherein:
x is Br or I;
n is 1 or 2;
r is selected from H, fluorine, alkyl, phenyl and benzyl;
R1selected from methyl or ethyl, and when R is1When the methyl is adopted, the solvent is methanol; r1In the case of ethyl, the solvent is ethanol.
Further, the compound III can be prepared by the following method:
wherein R, n, X, R1The definition of (A) is as above.
The alkyl group is methyl, ethyl, n-propyl, isopropyl, tert-butyl according to the definition of the R group.
In the process of preparing the compound III from the compound II, the base is selected from triethylamine, tripropylamine, tributylamine or N, N-diisopropylethylamine.
In the process of preparing the compound III from the compound II, the halogenating agent is selected from trimethyl bromine silane, trimethyl iodine silane or potassium iodide/iodine.
In the process of preparing the compound I by using the compound III, the catalyst is selected from Raney nickel, palladium hydroxide carbon, palladium/kieselguhr or rhodium-palladium carbon; palladium on carbon and rhodium on palladium on carbon are preferred.
In the process of preparing the compound I from the compound III, the weight ratio of the compound III to the catalyst is 1: 0.05-1: 0.5.
Compound III in the preparation of compound I, the base is selected from triethylamine, tripropylamine, tributylamine, N-dimethylaniline, N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate.
In the process of preparing the compound I from the compound III, the reaction temperature is 20-75 ℃; the reaction pressure is 0.1 MPa-4 MPa.
In the process of preparing the compound I from the compound III, the crude product of the compound I is purified by column chromatography to obtain a pure product of the compound I, wherein the eluent is petroleum ether and ethyl acetate in a ratio of 10: 1-2 or the petroleum ether, the ethyl acetate and ethanol are in a ratio of 20: 3: 0.5-1 or the petroleum ether and dichloromethane are in a ratio of 5: 1-2.
Has the advantages that:
the raw material 3-carboxyl-3-substituted cyclopentene (hexene) is cheap and easy to obtain, the market supply is sufficient, the compound III can simultaneously complete dehalogenation and ester exchange through one-step reaction, the yield of the compound I prepared from the compound III can reach 70%, the total yield of the two-step reaction can reach 46.2%, and the method is simple and convenient to operate, mild in reaction condition, stable in process and suitable for large-scale production.
The reagents and abbreviations referred to in the specification are as follows:
DMSO dimethyl sulfoxide
TMS-Br trimethyl bromine silane
KI potassium iodide
I2Iodine
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications may be effected therein by one of ordinary skill in the art without departing from the spirit and scope of the invention, which is encompassed by the claims.
Example 1
1. Preparation of Compound I-1 from Compound III-1
Compound III-1(223.3g, 1.09mol, 1.0eq.) was added to an autoclave, 3000mL of methanol, triethylamine (166.0g, 1.64mol, 1.5eq.) and 67.0g of palladium on carbon were added, hydrogen substitution was completed three times, 1.5MPa and reaction was performed at 60 ℃ for 12 hours, after completion of the reaction, the solvent was removed, washing was performed with 5000mL of 1N diluted hydrochloric acid, extraction was performed twice with 3000mL × 2 EA, the organic phases were combined, washed once with 1000mL of saturated brine, and after removal of the solvent, column chromatography was performed with sand column (petroleum ether: ethyl acetate: 10: 2) to obtain a pale yellow oil I-1, 120.7g, with a yield of 70.0%.
Example 2
1. Preparation of Compound I-2 from Compound III-2
Compound III-2(132.1g, 0.692mol, 1.0eq.) was added to an autoclave, 2500mL of methanol, sodium carbonate (110.0g, 1.04mol, 1.5eq.) and 52.8g of palladium hydroxide carbon were added, hydrogen substitution was completed three times, 1.0MPa and 50 ℃ were reacted for 14 hours, after the reaction was completed, the solvent was removed, washing was performed with 4500mL of 1N diluted hydrochloric acid, extraction was performed twice with 3000mL × 2 EA, the organic phases were combined, washed once with 1000mL of saturated brine, the organic phase was removed from the solvent, and then subjected to sand column chromatography (petroleum ether: dichloromethane: 5: 1) to obtain a pale yellow oily substance I-2, 68.6g, with a yield of 68.8%.
Example 3
1. Preparation of Compound I-3 from Compound III-3
Compound III-3(183.4g, 0.652mol, 1.0eq.) was added to an autoclave, 2500mL of ethanol, 2500mL of tripropylamine (140.1g, 0.978mol, 1.5eq.) and 91.7g of palladium/diatomaceous earth were added, hydrogen was substituted three times, reaction was carried out at 20 ℃ under 0.5MPa, the solvent was removed after completion of the reaction, washing was carried out with 4000mL of 1N diluted hydrochloric acid, extraction was carried out twice with 3000mL of × 2 EA, the organic phases were combined, washed once with 1000mL of saturated brine, and after removal of the solvent, column chromatography was carried out by sand column chromatography (petroleum ether: ethyl acetate: ethanol: 20: 3: 0.75) to obtain I-3, 102.2g as a yellow oily substance with a yield of 63.1%.
Example 4
1. Preparation of Compound I-4 from Compound III-4
Compound III-4(143.9g, 0.562mol, 1.0eq.) was added to an autoclave, 2200mL of ethanol, tributylamine (156.3g, 0.843mol, 1.5eq.) and 7.20g of rhodium-palladium-on-carbon were added, hydrogen substitution was completed three times, reaction was performed at 70 ℃ for 15 hours under 2.0MPa, the solvent was removed after the reaction was completed, washed with 3500mL of 1N diluted hydrochloric acid, extracted twice with 3000mL × 2 EA, the organic phases were combined, washed once with 1000mL of saturated brine, and subjected to sand column chromatography (petroleum ether: dichloromethane: 5: 1.8) after the solvent was removed to obtain a pale yellow oil I-4, 64.7g, with a yield of 65.3%.
Example 5
1. Preparation of Compound I-5 from Compound III-5
Compound III-5(165.9g, 0.528mol, 1.0eq.) was added to an autoclave, 2000mL of methanol, potassium bicarbonate (79.3g, 0.792mol, 1.5eq.) and 33.2g of Raney-Ni were added, hydrogen substitution was completed three times, reaction was performed at 40 ℃ under 2.5MPa, 18 hours was performed, the solvent was removed after the reaction was completed, washing was performed with 3000mL of 1N diluted hydrochloric acid, extraction was performed twice with 3000mL of 2 EA, the organic phases were combined, washed once with 1000mL of saturated brine, and subjected to column chromatography (petroleum ether: ethyl acetate: ethanol: 20: 3: 0.5) to obtain brown-yellow oily substance I-5, 77.1g, and yield was 66.3%.
Example 6
1. Preparation of Compound I-6 from Compound III-6
Compound III-6(216.1g, 0.812mol, 1.0eq.) was added to an autoclave, 3000mL of methanol, N-dimethylaniline (147.6g, 1.218mol, 1.5eq.) and 21.6g of palladium on charcoal were added, hydrogen was added three times for replacement, reaction was carried out at 30 ℃ for 20 hours under 3.0MPa, the solvent was removed after completion of the reaction, washing was carried out with 3000mL of 1N diluted hydrochloric acid, extraction was carried out twice with 3000m L × 2 EA, the organic phases were combined, washing was carried out with 1000mL of saturated brine once, the organic phase was removed with the solvent, and then subjected to sand column chromatography (petroleum ether: ethyl acetate: 10: 1.7) to give I-6 as a pale yellow oil, 95.1g, and a yield of 68.0%.
Example 7
1. Preparation of Compound I-7 from Compound III-7
Compound III-7(149.8g, 0.606mol, 1.0eq.) was added to an autoclave along with 2500mL of ethanol, N-diisopropylethylamine (117.5g, 0.909mol, 1.5eq.) and 13.5g of palladium on carbon hydroxide, hydrogen was added three times to complete the replacement, the reaction was carried out at 55 ℃ for 18 hours under 3.5MPa, the solvent was removed after the completion of the reaction, the mixture was washed with 3000mL of 1N diluted hydrochloric acid, extracted twice with 3000mL × 2 EA, the organic phases were combined, washed once with 1000mL of saturated brine, and subjected to solvent removal to preparative sand column chromatography (petroleum ether: ethyl acetate: 10: 1.5) to obtain I-7 as a yellow oil, 84.3g, and the yield was 64.9%.
Example 8
1. Preparation of Compound III-8 from Compound II-8
150mL of DMSO and 2200mL of chloroform are added into a reaction flask, TMS-Br (194.7g, 1.27mol, 1.2eq.) and tributylamine (235.4g, 1.27mol, 1.2eq.) are added dropwise at 5 ℃, after stirring, 500mL of a chloroform solution of compound II-8 (137.9g, 1.06mol, 1.0eq.) are added dropwise, and after the addition, the temperature is raised to 70 ℃ for reaction for 15 hours.
The reaction mixture was washed with 1N HCl 2.0L, then with 1L saturated brine, dried to remove the solvent and chromatographed (PE: EA 5: 1) to give 139.4g of compound III-8 as a brown liquid with a yield of 62.9%.
2. Preparation of Compound I-8 from Compound III-8
In an autoclave, compound III-8(139.4g, 0.667mol, 1.0eq.), 2500mL of ethanol, cesium carbonate (325.8g, 1.00mol, 1.5eq.) and 11.2g of Raney-Ni were added, hydrogen substitution was completed three times, reaction was performed at 65 ℃ for 16 hours under 4.0MPa, after completion of the reaction, the solvent was removed, washing was performed with 3000mL of 1N diluted hydrochloric acid, extraction was performed twice with 3000m L × 2 EA, the organic phases were combined, washing was performed once with 1000mL of saturated brine, and after removal of the solvent, column chromatography was performed with sand column chromatography (petroleum ether: dichloromethane: 5: 1.5) to obtain yellow oily substance I-8, 80.0g, and yield 68.1%.
Example 9
1. Preparation of Compound I-9 from Compound III-9
After the completion of the replacement with hydrogen three times, compound III-9(244.6g, 0.779mol, 1.0eq.), 2500mL of ethanol, potassium carbonate (161.7g, 1.17mol, 1.5eq.) and 17.1g of palladium/diatomaceous earth were added to an autoclave, and the reaction was carried out at 45 ℃ for 20 hours under 1.0MPa, followed by removal of the solvent after the completion of the reaction, washing with 3000mL of 1N diluted hydrochloric acid, extraction with 3000mL of 2 EA twice, combining the organic phases, washing with 1000mL of saturated brine once, and chromatography with a sand column (petroleum ether: ethyl acetate: ethanol: 20: 3: 0.70) after removal of the solvent to give I-9 as a pale yellow oil, 119.2g, and a yield of 65.3%.
Example 10
1. Preparation of Compound I-10 from Compound III-10
In an autoclave, compound III-10(191.1g, 0.932mol, 1.0eq.) was added, 2500mL of methanol, sodium bicarbonate (117.6g, 1.40mol, 1.5eq.) and 11.5g of palladium on carbon were added, hydrogen was added for three times, the mixture was reacted at 55 ℃ under 2.0MPa, the solvent was removed after the reaction was completed, 3000mL of 1N diluted hydrochloric acid was used for washing, 3000mL of 2 × EA was used for extraction twice, the organic phases were combined, washed once with 1000mL of saturated brine, and subjected to sand column chromatography (petroleum ether: ethyl acetate: ethanol: 20: 3: 0.6) after the solvent was removed to obtain a brown oil I-10,93.3g, and the yield was 63.3%.
Example 11
1. Preparation of Compound III-11 Compound I-11
Compound III-11(125.7g, 0.574mol, 1.0eq.) was added to an autoclave, 2500mL of methanol, tripropylamine (123.4g, 0.861mol, 1.5eq.) and 56.6g of palladium on carbon hydroxide were added, hydrogen was added to the mixture to displace three times, the mixture was reacted at 50 ℃ for 14 hours under 1.5MPa, the solvent was removed after the reaction, the mixture was washed with 3000mL of 1N diluted hydrochloric acid, extracted twice with 3000mL of 2 EA, the organic phases were combined, washed with 1000mL of saturated brine once, and subjected to column chromatography (petroleum ether: dichloromethane: 5: 1.6) to give I-11 as a brown oil, 64.4g, and yield 61.5%.
Example 12
1. Preparation of Compound I-12 from Compound III-12
Compound III-12(117.2g, 0.434mol, 1.0eq.) was added to an autoclave, 2300mL of ethanol, tributylamine (120.7g, 0.651mol, 1.5eq.) and 17.6g of rhodium-palladium-on-carbon were added, hydrogen was added three times to replace them, the reaction was carried out at 60 ℃ for 14 hours under 2.5MPa, the solvent was removed after the reaction was completed, 3000mL of 1N diluted hydrochloric acid was used for washing, 3000mL of 2 EA was used for extraction twice, the organic phases were combined and washed once with 1000mL of saturated brine, the organic phase was removed of the solvent and subjected to sand column chromatography (petroleum ether: dichloromethane: 5: 1.6) to obtain brown oil I-12, 52.2g, and yield 63.2%.
Example 13
1. Preparation of Compound II-13 Compound III-13
150mL of DMSO and 2000mL of chloroform were added to a reaction flask, and KI/I (373.6g, 0.890mol, 1.2eq.) was added dropwise at 5 ℃2And (90.1g, 0.890mol, 1.2eq.) triethylamine, stirring, adding (150.0g, 0.742mol, 1.0eq.) 500mL of chloroform solution of compound II-13 dropwise, heating to 70 deg.C after adding, and refluxing for 15 hours.
The reaction mixture was washed with 1N HCl 2.0L, then 1L saturated brine, dried to remove the solvent and chromatographed (PE: EA 5: 1) to give 161.4g of compound III-13 as a brown liquid with a yield of 66.3%.
2. Preparation of Compound I-13 from Compound III-13
Compound III-13(161.4g, 0.492mol, 1.0eq.) was added to an autoclave, 2500mL of ethanol, sodium carbonate (78.2g, 0.738mol, 1.5eq.) and 40.4g of Raney-Ni were added, hydrogen substitution was completed three times, reaction was performed at 70 ℃ for 10 hours under 3.0MPa, the solvent was removed after completion of the reaction, washing was performed with 3000mL of 1N diluted hydrochloric acid, extraction was performed twice with 3000mL of × 2 EA, the organic phases were combined, washed once with 1000mL of saturated brine, and subjected to column chromatography (petroleum ether: ethyl acetate: ethanol: 20: 3: 0.70) to obtain tan oily substance I-13, 75.0g, and yield was 61.8%.
Example 14
1. Preparation of Compound I-3 from Compound III-3
After the completion of the reaction with hydrogen gas for three times, the compound III-14(137.7g, 0.466mol, 1.0eq.), 2500mL of methanol, potassium carbonate (96.6g, 0.699mol, 1.5eq.) and 48.2g of palladium/diatomaceous earth were added to an autoclave, and the reaction was carried out at 75 ℃ for 12 hours under 3.5MPa, the solvent was removed, the reaction was washed with 3000mL of 1N diluted hydrochloric acid, twice with 3000mL of EA × 2, the organic phases were combined, washed with 1000mL of saturated brine once, and subjected to sand column chromatography (petroleum ether: ethyl acetate: ethanol: 20: 3: 0.75) to obtain I-14 as a yellow oil, 75.3g, and the yield was 65.1%.
Claims (6)
1. A process for the preparation of a compound of formula I:
wherein:
x is Br or I;
n is 1 or 2;
r is selected from H, fluorine, alkyl, phenyl and benzyl;
R1selected from methyl or ethyl, and when R is1When the methyl is adopted, the solvent is methanol; r1When the solvent is ethyl, the solvent is ethanol;
compound III in the preparation of compound I, the base is selected from triethylamine, tripropylamine, tributylamine, N-dimethylaniline, N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate;
in the process of preparing the compound I from the compound III, the catalyst is selected from Raney nickel, palladium hydroxide carbon, palladium/kieselguhr or rhodium palladium carbon.
2. The method of claim 1, wherein:
wherein R, n, X, R1Is as defined in claim 1;
in the process of preparing the compound III from the compound II, the halogenating agent is selected from trimethyl bromosilane, trimethyl iodosilane or potassium iodide/iodine;
in the process of preparing the compound III from the compound II, the base is selected from triethylamine, tripropylamine, tributylamine or N, N-diisopropylethylamine.
3. The process according to claim 1 or 2, wherein the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, and tert-butyl.
4. The preparation method according to claim 1, wherein in the preparation of the compound I from the compound III, the weight ratio of the compound III to the catalyst is 1: 0.05-1: 0.5.
5. The preparation method according to claim 1 or 2, wherein the reaction temperature is 20-75 ℃ in the preparation of the compound I from the compound III; the reaction pressure is 0.1 MPa-4 MPa.
6. The preparation method according to claim 1 or 2, wherein in the preparation of the compound I from the compound III, the crude compound I is purified by column chromatography to obtain a pure compound I.
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| WO2015004455A2 (en) * | 2013-07-09 | 2015-01-15 | Isomerase Therapeutics Limited | Novel compounds |
Non-Patent Citations (3)
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| 1-(Trifluoromethyl)cyclopent-3-enecarboxylic Acid Derivatives: Platforms for Bifunctional Cyclic Trifluoromethyl Building Blocks;Fabienne Grellepois et al.;《European Journal of Organic Chemistry》;20111123;第2012卷(第3期);第509-517页 * |
| Regio- and diastereoselective fluorination of alicyclic β-amino acids;Lorand Kiss et al.;《Organic Biomolecular Chemistry》;20110616;第9卷(第19期);第6528-6534页 * |
| Synthesis of 3- and 4-Hydroxy-2-aminocyclohexanecarboxylic Acids by Iodocyclization;Zsolt Szakonyi et al.;《European Journal of Organic Chemistry》;20050804;第2005卷(第18期);第4017-4023页 * |
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