CN112608294B - Preparation method of latanoprost - Google Patents
Preparation method of latanoprost Download PDFInfo
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- CN112608294B CN112608294B CN202011489769.6A CN202011489769A CN112608294B CN 112608294 B CN112608294 B CN 112608294B CN 202011489769 A CN202011489769 A CN 202011489769A CN 112608294 B CN112608294 B CN 112608294B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention provides a preparation method of latanoprost. Compared with the method in the prior art, the method has the advantages of less steps, high yield, high product purity, avoidance of a hydrogenation reduction process and a chiral reduction or chiral resolution process, great reduction in cost, improvement in safety, less three-waste discharge and high environmental friendliness, and is particularly suitable for industrial application to produce latanoprost.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a novel preparation method of latanoprost.
Background
Latanoprost (Latanoprost, also known as Latanoprost), chemical name (Z) -7[ (1R,2R,3R,5S)3, 5-dihydroxy-2- [ (3R) -3-hydroxy-pentylphenyl)]Cyclopentyl group]Isopropyl 5-heptanoate) is a novel phenyl-substituted propyl ester prostaglandin F2αIs selectivity F2αA receptor agonist. It is an inactive substance that can rapidly penetrate into cornea, can be hydrolyzed into active free acid in cornea and blood plasma, and is the first choice drug for treating glaucoma and ocular hypertension.
Many methods for synthesizing latanoprost are known, and mainly involve how to introduce α and ω side chains, how to select protecting groups, and the like, but many methods have problems such as long route, low yield, and difficulty in separating isomer impurities. For example, Karusala Nageswara Rao et al disclose the following synthetic methods,
the whole process is 10 steps, wherein the introduction of the omega side chain requires that the coriolide diol is firstly oxidized into the coriolide aldehyde, then the phenethyl carbonyl double bond is introduced through the Witting reaction, and then the carbonyl and the double bond on the phenethyl carbonyl double bond are respectively reduced, so that the steps are very complicated. Aiming at the defects of the existing method, the method proposes the following synthetic route:
although improvements have been made in lactone oxidation to aldehyde, HWE reaction, reduction of ω side chain, hydrogenation, lactone reduction, Wittig reaction, etc., problems still remain such as long reaction route and low total yield.
Transition metal catalysts are of particular interest in organic transformations involving chemical bond activation and formation events, where the structure of the ligand can be modified to manipulate the linking environment and to tune the electronic properties of the metal center to improve and achieve the desired stability, catalytic reactivity, chemistry and stereoselectivity, and thus the organic reactions of carbon-heteroatom bond and carbon-carbon bond formation catalyzed by transition metal catalysts are the basis and very efficient methods for the preparation of natural compounds, small organic molecule drugs and biomolecules. The cobalt complex has high activity and high selectivity, and the Frederik Freitag and the like research the triazine-based PN5P pincer ligand chromium (III) complex, and its application in primary amine with primary alcohol alkylation, primary amine with amine alkylation, ketone with primary alcohol alkylation, secondary alcohol with primary alcohol alkylation etc. catalysis.
The invention creatively provides a novel preparation method of latanoprost by introducing a transition metal catalyst catalysis method in the preparation process of latanoprost according to the structural characteristics of latanoprost.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of latanoprost, which is characterized in that a method of transition metal catalyst catalysis is used in the process of introducing an omega side chain, and a coriolide diol is directly coupled with 4-phenylbutan-2-ol to introduce the omega side chain.
On the basis, the invention provides a preparation method of latanoprost, which comprises the following steps:
wherein R is1Represents a hydroxyl protecting group, preferably p-phenylbenzoyl (PPB), benzoyl (Bz), benzyl (Bn), tetrahydropyran-2-yl (THP) or diphenyl tert-butylsilyl (TBDPS).
The reaction is carried out in the presence of a chromium (III) complex catalyst, the structure of which is represented by the following formula X:
wherein R' represents H, methyl, isopropyl or phenyl.
The catalyst represented by formula X is a pyridyl PN known in the art3P-type pincer ligand chromium (III) complex catalyst can be used for catalyzing various organic reactions. Frederik Freitag et al reported a series of similar catalysts and concluded that triazine-based catalysts can be used to catalyze the alkylation of secondary alcohols with primary alcohols, but that pyridine-based catalysts do not have this activity. However, the present inventors found in the course of experiments that the catalyst represented by formula X has excellent catalytic activity when applied to the coupling of a coriolis lactone diol with 4-phenylbutan-2-ol, and can obtain an alkylated product in a higher yield, because the introduction of a pyrazolyl group changes the overall structure and properties of the complex.
In one embodiment, the steps include: reacting the compound of formula 1 with (R) -4-phenylbutan-2-ol in an organic solvent in the presence of a catalyst represented by formula X and pyridine, and carrying out aftertreatment to obtain the latanoprost intermediate of formula 2.
Preferably, in this step, the molar ratio of the compound of formula 1 to (R) -4-phenylbutan-2-ol is 1:1.1 to 1.5, preferably 1:1.2 to 1.3; the amount of the catalyst represented by the formula X is 1 to 10 mol%, preferably 3 to 8 mol%, and more preferably 5 mol% of the compound of the formula 1.
Preferably, in the step, the reaction temperature is 70-150 ℃, preferably 100-120 ℃.
Preferably, in this step, the catalyst represented by formula X is selected from:
preferably, in this step, the post-processing includes: after the reaction is finished, deionized water is added to quench the reaction, the organic phases are extracted and combined by toluene or ethyl acetate, the solvent is evaporated off under reduced pressure after drying, and the residue is separated by a silica gel column.
The invention further provides a preparation method of latanoprost, which comprises the following steps:
or optionally, the method comprises the steps of:
or optionally, the method comprises the steps of:
wherein R is2Represents a hydroxyl protecting group, preferably tetrahydropyran-2-yl (THP), diphenyl tert-butylsilyl (TBDPS), dimethyl tert-butylsilyl (TBDMS).
The above methods for the preparation of latanoprost 8 from compound 2 are well known in the art and can be found by those skilled in the art in WO2010109476A1, CN1774417A, EP2143712A, Access to a Key Building Block for the Prostaglandin Family via stereocotrol d organic catalytic Baeyer-Villiger Oxidation, Kejie Zhu et al, Angewandte Chemie, International Edition, Volume58, Issue29, Pages 9923-. The above documents are hereby incorporated by reference in their entirety.
The method of the invention has the following advantages:
1. the method of the invention omits the steps of oxidizing the colactone diol into aldehyde, HWE reaction, reducing omega side chain and the like, can obtain the key intermediate 2 of latanoprost from the colactone diol in one step, and has the advantages of simple and easy operation and no need of hydrogenation reduction process due to few steps, thereby greatly improving the safety.
2. The 4-phenylbutan-2-ol with the R-configuration is directly used, so that the step of reducing the side chain carbonyl group of omega into hydroxyl with a specific chiral configuration is omitted, the expensive and inefficient chiral reduction or chiral resolution process is avoided, the cost is reduced, and the purity of the target compound with the required configuration in the product is improved.
3. The omega side chain adduct of formula 2 has a high yield, on average up to over 70%, whereas in the prior art the total yield of analogous compounds obtained from the steps of oxidation of the colelactone diol to aldehyde, HWE reaction, carbonyl reduction, double bond reduction, etc. does not exceed 50%.
In a word, the method has the advantages of few steps, high yield, high product purity, avoidance of a hydrogenation reduction process and a chiral reduction or chiral resolution process, great reduction of cost, improvement of safety, less three-waste discharge and high environmental friendliness, and is particularly suitable for industrial application to produce latanoprost.
Detailed Description
The preparation process of the present invention will be further illustrated with reference to the following examples, but the present invention is not limited to these examples.
Example 1:
(-) PhenylbenzoylCorylactone diol ((3aR,4S,5R,6aS) - (-) -hexahydro 4- (hydroxymethyl) -2-oxo-2H-cyclopenta [ b ] furan-5-yl 1,1' -biphenyl-4-carboxylate) (5mmol, 1.00eq), (R) -4-phenylbutan-2-ol (6mmol, 1.20eq), chromium (III) complex X1 (250. mu. mol, 5 mol%), pyridine (1mL) and toluene (10mL) were charged in a pressure tube under nitrogen atmosphere in a glove box, sealed and heated to 110 ℃ for 15H. After the reaction was completed, the mixture was quenched with 10mL of deionized water, the mixture was extracted with toluene (3 × 20mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed on a silica gel column using acetonitrile, petroleum ether 4:96 as a mobile phase to obtain 1.90g of the objective product with a purity of 99.2% and a yield of 78.5%.
Mass spectrum m/z is theoretical value 484.2250; measured value: 484.2289, identified as the target compound.
Example 2:
a pressure tube was charged with Corlide diol (3aR,4S,5R,6aS) - (-) -hexahydro-4- (hydroxymethyl) -2-oxo-2H-cyclopenta [ b ] furan-5-yl 1,1' -biphenyl-4-carboxylate (5mmol, 1.00eq), (R) -4-phenylbutan-2-ol (6mmol, 1.20eq), chromium complex X2 (250. mu. mol, 5 mol%), pyridine (1mL) and toluene (10mL) under a nitrogen atmosphere in a glove box, sealed and heated to 110 ℃ for 18H. After the reaction was completed, the mixture was quenched with 10mL of deionized water, the mixture was extracted with toluene (3 × 20mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed on a silica gel column using acetonitrile, petroleum ether 4:96 as a mobile phase to obtain 1.82g of the objective product with a purity of 99.3% and a yield of 75.2%.
Example 3:
(3aR,4S,5R,6aS) - (-) -hexahydro-4- (hydroxymethyl) -2-oxo-2H-cyclopenta [ b ] furan-5-yl 1,1' -biphenyl-4-carboxylate (5mmol, 1.00eq), (R) -4-phenylbutan-2-ol (7.5mmol, 1.50eq), chromium (III) complex X1 (250. mu. mol, 5 mol%), pyridine (1mL) and toluene (10mL) were charged in a pressure tube under nitrogen atmosphere in a glove box, sealed and heated to 115 ℃ for 12H. After the reaction was completed, the mixture was quenched with 10mL of deionized water, the mixture was extracted with toluene (3 × 20mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed on a silica gel column using acetonitrile, petroleum ether 4:96 as a mobile phase to obtain 1.73g of the objective product with a purity of 99.1% and a yield of 71.6%.
Example 4:
(3aR,4S,5R,6aS) - (-) -hexahydro-4- (hydroxymethyl) -2-oxo-2H-cyclopenta [ b ] furan-5-yl 1,1' -biphenyl-4-carboxylate (5mmol, 1.00eq), (R) -4-phenylbutan-2-ol (7.5mmol, 1.20eq), chromium (III) complex X1 (400. mu. mol, 8 mol%), pyridine (1mL) and toluene (10mL) were charged in a pressure tube under nitrogen atmosphere in a glove box, sealed and heated to 100 ℃ for 18H. After the reaction was completed, the mixture was quenched with 10mL of deionized water, the mixture was extracted with toluene (3 × 20mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed on a silica gel column using acetonitrile, petroleum ether 4:96 as a mobile phase to obtain 1.77g of the objective product with a purity of 98.9% and a yield of 73.2%.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (13)
1. A method for preparing latanoprost, comprising the steps of:
wherein R is1Represents a hydroxyl protecting group;
the reaction is carried out in the presence of a chromium (III) complex catalyst, the structure of which is represented by the following formula X:
wherein R' represents H, methyl, isopropyl or phenyl.
2. The method of claim 1, wherein R is1Represents p-phenylbenzoyl (PPB), benzoyl (Bz), benzyl (Bn), tetrahydropyran-2-yl (THP) or diphenyl tert-butylsilyl (TBDPS).
3. The method according to claim 1, wherein the catalyst represented by formula X is selected from the group consisting of:
4. the method of claim 1, wherein the steps comprise: reacting the compound of formula 1 with (R) -4-phenylbutan-2-ol in an organic solvent in the presence of a catalyst represented by formula X and pyridine, and carrying out aftertreatment to obtain the latanoprost intermediate of formula 2.
5. The preparation method according to claim 4, wherein the molar ratio of the compound of formula 1 to (R) -4-phenylbutan-2-ol is 1: 1.1-1.5; the amount of the catalyst represented by the formula X is 1-10 mol% of the compound represented by the formula 1.
6. The preparation method according to claim 4, wherein the molar ratio of the compound of formula 1 to (R) -4-phenylbutan-2-ol is 1: 1.2-1.3; the catalyst represented by formula X is used in an amount of 3 to 8 mol% based on the compound of formula 1.
7. The method according to claim 1, wherein the reaction temperature is 70 to 150 ℃.
8. The method according to claim 1, wherein the reaction temperature is 100 to 120 ℃.
9. The method for preparing according to claim 1, characterized in that it comprises the steps of:
wherein R is2Represents a hydroxyl protecting group.
10. The method of claim 9, wherein R is2Represents tetrahydropyran-2-yl (THP), diphenyl tert-butylsilyl (TBDPS) or dimethyl tert-butylsilyl (TBDMS).
11. The method for preparing according to claim 1, characterized in that it comprises the steps of:
12. the method for preparing according to claim 1, characterized in that it comprises the steps of:
wherein R is2Represents a hydroxyl protecting group.
13. The method of claim 12, wherein R is2Represents tetrahydropyran-2-yl (THP), diphenyl tert-butylsilyl (TBDPS) or dimethyl tert-butylsilyl (TBDMS).
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Citations (7)
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| WO2003008368A1 (en) * | 2001-07-17 | 2003-01-30 | Pharmacia & Upjohn Company | Process and intermediates to prepare latanoprost |
| EP1721894A1 (en) * | 2005-05-13 | 2006-11-15 | Technopharma S.A. | Process for the synthesis of prostaglandin derivatives |
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| EP2495235A1 (en) * | 2011-03-04 | 2012-09-05 | Newchem S.p.A. | Process for the synthesis of prostaglandins and intermediates thereof |
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| CN102627517A (en) * | 2012-03-23 | 2012-08-08 | 温州大学 | Alkylation method for beta- of secondary alcohol |
| GB201522437D0 (en) * | 2015-12-18 | 2016-02-03 | Univ Leeds | Tethered ligands |
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| CN1533372A (en) * | 2001-07-17 | 2004-09-29 | �������Ŷ���Լ��������˾ | Process and intermediates for the preparation of latanoprost |
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| WO2010109476A2 (en) * | 2009-01-19 | 2010-09-30 | Matrix Laboratories Ltd | Improved process for the preparation of prostaglandins and analogues thereof |
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