CN105985371B - Prepare key intermediate and its application of limaprost - Google Patents
Prepare key intermediate and its application of limaprost Download PDFInfo
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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
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Abstract
The present invention provides compounds shown in the key intermediate formula B of synthesis limaprost, in formula, R1Selected from t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate, trimethyl silicon substrate or THP trtrahydropyranyl；R2Selected from t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate, trimethyl silicon substrate or THP trtrahydropyranyl；R4Selected from acetyl group, chloracetyl, Methoxyacetyl, benzoyl or substituted benzoyl；And R6Selected from-CH2OH or-CHO.The present invention also provides the routes using the compound synthesis limaprost.The advantages such as the route has the control of preparation process chirality preferably, is reacted by multiple Wittig and constructs double bond structure, processing efficient, and production cost is low.
Description
Technical field
The present invention relates to the field of chemical synthesis.Specifically, the present invention relates to the key for preparing limaprost is intermediate
Body, and using the method and the intermediate that the intermediate prepares limaprost in preparing limaprost
Using.
Background technique
Limaprost (Limaprost) chemical name is (E) -7- [(1R, 2R, 3R) -3- hydroxyl -2- [(3S, 5S) -
(E) -3- hydroxy-5-methyl base -1- nonenyl] -5- oxocyclopentyl] -2- enanthic acid.English language Chemical title: (E) -7- [(1R, 2R,
3R)-3-hydroxy-2-[(3S,5S)-(E)-3-hydroxy-5-methyl-1-noneyl]-5-oxo cyclopentyl]-
2-heptenoic acid, structural formula are as follows:
Limaprost is the derivative of prostaglandin E1, can increase cyclic adenosine monophosphate (cAMP) content, inhibit thrombus
Plain A2 (TXA2) generates, and has the function of blood vessel dilatation, increases blood flow and inhibit platelet aggregation and stick, animal experiments show that
Nerve blood flow can be increased, improve nervous function.Clinically for improving all kinds of ischemics of Buerger's disease initiation
Symptom, such as ulcer, pain, creeping chill；And improve the subjective symptom (pain and feeling of numbness) and row of posteriority lumbar spinal stenosis
Walk ability.
The synthesis of limaprost is started with different chiral starting materials, is synthesized through different paths.Such as
US4294849；JP59128370；Tetrahedron Letters(1993),34(40),6427-30；Chemistry
The preparation method of each route is described in detail in Letters (1992), (10), the documents such as 2095-8.In addition,
CN102875586；The patent documents such as WO2014/040457, which have been made, to be partly improved, and yield is improved.
Process 1
This preparation method originates the supply of chiral raw material commercial-free, and route uses three component couling process, and operating condition is multiple
It is miscellaneous, it is more difficult to control, and three components after reaction dock product, yield is lower, and impurity is more, purifying complex.And every portion is required to
Column chromatographic isolation and purification.Industrialization is relatively difficult to achieve.It is less economical.
Process 2
This preparation process is respectively formed two side chains of α and ω using the two-part reaction of two metal reagents coupling, subsequent
The step of shortened, but the synthesis of starting material and the synthesis of side chain still have a large amount of synthesis step, increase wherein being coupled at two
The synthesis difficulty added to technology controlling and process and operates more demanding.Industrial production amplification is difficult.
Process 3:
It is starting material (having commercial offers) that this route, which is with Coreylactone diol (CAS:32233-40-2), warp
It crosses eight steps to react to obtain intermediate A, reacts to obtain limaprost using ten steps.Obtain during this four it is diastereomeric different
The mixture of structure body composition, the mixture obtain target product by column chromatography separating for several times, and combined coefficient is extremely low and purifying is tired
It is difficult.Process will use two seleno reagent of hexichol being more toxic, and experimental implementation difficulty is big and the feature of environmental protection is poor.
Therefore, this field needs development and production at low cost, and processing efficient is easy to operate, is suitble to Lima of industrialized production
Prostaglandin key intermediate compound, and the synthesis technology of limaprost is prepared accordingly.
Summary of the invention
The object of the present invention is to provide a kind of production cost is low, processing efficient is easy to operate, is suitble to the benefit of industrialized production
Horse prostaglandin key intermediate compound, and the synthesis work of limaprost is prepared using the intermediate accordingly
Skill.
In a first aspect, the present invention provides compound shown in formula B:
In formula,
R1Selected from t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate, trimethyl silicon substrate or tetrahydro pyrrole
It mutters base；
R2Selected from t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate, trimethyl silicon substrate or tetrahydro pyrrole
It mutters base；
R4Selected from acetyl group, chloracetyl, Methoxyacetyl, benzoyl or substituted benzoyl；With
R6Selected from-CH2OH or-CHO.
In second aspect, the present invention provides the preparation method of compound described in first aspect present invention, comprising the following steps:
(1) compound shown in Formula IV reacts to obtain compound shown in Formula VII with WITTIG reagent；With
(2) compound shown in Formula VII obtains compound shown in Formula VIII through acylting agent protection hydroxyl
(3) compound shown in Formula VIII carries out selective double bond reduction and R using catalyst3The removing of protecting group obtains formula
Compound shown in IX, the method is as shown in following formulas:
(4) compound shown in Formula IX obtains compound shown in Formula X after oxidising agent aoxidizes；
In formula,
R1、R2And R4As defined in claim 1；With
R3Selected from benzyl or substituted benzyl.
In a particular embodiment, in step (3), the selectivity double bond reduction and R3The removing of protecting group utilizes
Catalytic hydrogenation carries out, and the catalyst of catalytic hydrogenation is 5%Pd/C or 10%Pd/C, preferably 10%Pd/C；And/or
The selectivity double bond reduction and R3The reaction temperature of the removing of protecting group is controlled at -40 DEG C~-20 DEG C, preferably -
30℃；Reaction pressure is controlled in 0.1~1atm H2, preferably 1atm H2；Reaction carries out in ethyl acetate.
In a particular embodiment, in step (4), the oxidant utilized that aoxidizes is selected from: Dess-Martin examination
Agent, the combination of DMSO- oxalyl chloride, TEMPO-NaOCl, TEMPO-TCCA or TEMPO and other oxidants, preferably Dess-
Martin reagent；And/or
In the oxidation reaction, the molar ratio of compound and oxidant shown in Formula IX is 1:1.2-1:1.5, preferably 1:1.5；
Reaction temperature is controlled at 10~30 DEG C, preferably 20~30 DEG C, most preferably 25 DEG C.
In a preferred embodiment, the Wittig reagent in step (1) is R3O(CH2)3P+Ph3Br-, R3For benzyl or
Substituted benzyl；And/or
The acylting agent in step (2) is acetic anhydride, chloroacetic chloride, chloracetyl chloride, methoxyacetyl chloride, benzoyl
Chlorine；It is preferred that acetic anhydride, chloroacetic chloride or chlorobenzoyl chloride；Most preferably acetic anhydride.
In a preferred embodiment, as shown in following formulas, compound shown in Formula V restores the formula of being made through ester reducing agent
Compound shown in VI:
In a preferred embodiment, the ester reducing agent is selected from diisobutyl aluminium hydride or other aluminum hydride derivatizations try
The combination of agent.
In a preferred embodiment, as shown in following formulas, compound shown in formula IV is protected through hydroxy protecting agent
Obtain compound shown in Formula V:
In a preferred embodiment, the hydroxy protecting agent is tert-butyl chloro-silicane, tert-butyl diphenyl
Chlorosilane, chlorotriethyl silane, trim,ethylchlorosilane or dihydropyran.
In a preferred embodiment, compound shown in Formula V passes through recrystallization, OR2Chiral purity is greater than 99.0%.
In a preferred embodiment, as shown in following formulas, compound shown in formula III and asymmetric reduction reagent are anti-
It should obtain compound shown in formula IV:
In a preferred embodiment, asymmetric reduction reagent is DIP Chloirde or Corey catalyst CBS.
In a preferred embodiment, the selective double bond reduction of compound shown in Formula VIII carries out in ethyl acetate.
In a particular embodiment, as shown in following formulas, chemical combination shown in preparation of compounds of formula X shown in Formula IX is utilized
Object:
Wherein, the Dess-Martin reagent oxidation of compound shown in Formula IX, mole of compound and oxidant shown in Formula IX
Than for 1:1.5；Reaction temperature is controlled at 25 DEG C；Compound shown in Formula X is made.
In the third aspect, the present invention provides the purposes of compound described in first aspect present invention, for synthesizing Lima forefront
Parathyrine.
In fourth aspect, the present invention provides a kind of method for synthesizing limaprost, the described method comprises the following steps:
(1) compound shown in Formula IV reacts to obtain compound shown in Formula VII with WITTIG reagent；
(2) compound shown in Formula VII obtains compound shown in Formula VIII through acylting agent protection hydroxyl；
(3) compound shown in Formula VIII carries out selective double bond reduction and R using catalyst3The removing of protecting group obtains formula
Compound shown in IX；
(4) compound shown in Formula IX obtains compound shown in Formula X after oxidising agent aoxidizes, compound shown in Formula X with
Wittig reagent reacts to obtain compound shown in Formula XI；
(5) limaprost is finally prepared using compound shown in Formula XI；
In formula, R1、R2、R3And R4As defined in claim 1；R5For C1-C4Linear or branched alkyl group.
In a particular embodiment, in step (3), the selectivity double bond reduction and R3The removing of protecting group utilizes
Catalytic hydrogenation carries out, and the catalyst of catalytic hydrogenation is 5%Pd/C or 10%Pd/C, preferably 10%Pd/C；And/or
The selectivity double bond reduction and R3The reaction temperature of the removing of protecting group is controlled at -40 DEG C~-20 DEG C, preferably -
30℃；Reaction pressure is controlled in 0.1~1atm H2, preferably 1atm H2；Reaction carries out in ethyl acetate.
In a particular embodiment, in step (4), the oxidant utilized that aoxidizes is selected from: Dess-Martin examination
Agent, the combination of DMSO- oxalyl chloride, TEMPO-NaOCl, TEMPO-TCCA or TEMPO and other oxidants, preferably Dess-
Martin reagent；And/or
In the oxidation reaction, the molar ratio of compound and oxidant shown in Formula IX is 1:1.2-1:1.5, preferably 1:1.5；
Reaction temperature is controlled at 10~30 DEG C, preferably 20~30 DEG C, most preferably 25 DEG C.
In a preferred embodiment, the selective double bond of compound shown in Formula VIII is restored in acetic acid second in step (3)
It is carried out in ester；WITTIG reagent in step (4) is selected from phosphonoacetate, phosphinylidyne acetic acid methyl ester diethylester, phosphinylidyne
Acetic acid methyl ester diisopropyl ester, phosphoryl allyl acetate diethylester or other phosphinylidyne acetic acid derivatives.
In a preferred embodiment, as shown in following formulas, compound shown in Formula V restores the formula of being made through ester reducing agent
Compound shown in VI:
In a preferred embodiment, the ester reducing agent is selected from diisobutyl aluminium hydride or other aluminum hydride derivatizations try
The combination of agent.
In a preferred embodiment, as shown in following formulas, compound shown in formula IV is protected through hydroxy protecting agent
Obtain compound shown in Formula V:
In a preferred embodiment, the hydroxy protecting agent is tert-butyl chloro-silicane, tert-butyl diphenyl
Chlorosilane, chlorotriethyl silane, trim,ethylchlorosilane or dihydropyran.
In a preferred embodiment, compound shown in Formula V passes through recrystallization, OR2Chiral purity is greater than 99.0%.
In a preferred embodiment, as shown in following formulas, compound shown in formula III and asymmetric reduction reagent are anti-
It should obtain compound shown in formula IV:
In a preferred embodiment, asymmetric reduction reagent is DIP Chloirde or Corey catalyst CBS.
In a preferred embodiment, it includes following for limaprost being finally prepared using compound shown in Formula XI
Step:
As shown in following formulas, compound shown in Formula XI removes carboxylic acid simultaneously under alkaline condition and hydroxyl protection obtains
Compound shown in Formula XII:
As shown in following formulas, compound shown in Formula XII aoxidizes to obtain compound shown in Formula XIII through oxidising agent, after
Continuous removing R1And R2Obtain limaprost:
In a preferred embodiment, the alkaline condition is the alkaline hydrolysis conditions there are sodium hydroxide；The oxidation
Reagent is Dess-Martin reagent.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
Inventor after extensive and in-depth study, it was unexpectedly found that synthesis limaprost is new crucial intermediate
Body and the new limaprost synthetic route for utilizing the intermediate, so as to shorten the synthesis of limaprost
Step, the control of preparation process chirality preferably, by multiple Wittig react building double bond structure, and processing efficient improves synthesis effect
Rate reduces production cost.The present invention is completed on this basis.
In the new synthesis process research of limaprost, the present inventor has synthesized compound shown in formula B:
In formula,
R1Selected from t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate, trimethyl silicon substrate or tetrahydro pyrrole
It mutters base；
R2Selected from t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate, trimethyl silicon substrate or tetrahydro pyrrole
It mutters base；
R4Selected from acetyl group, chloracetyl, Methoxyacetyl, benzoyl or substituted benzoyl；With
R6Selected from-CH2OH or-CHO.
In the above structure compound represented, R1And R2As the protecting group of hydroxyl, limaprost is prepared subsequent
Reaction in need to remove.Therefore, those skilled in the art can independently select specific hydroxyl protection base, as long as the hydroxyl is protected
Shield group can play the role of protecting hydroxyl, readily removed in subsequent reactions step, and to the system of limaprost
It is standby not generate unfavorable negative effect.In a preferred embodiment, R1And R2For t-Butyldimethylsilyl.
Compound shown in formula B of the invention can be prepared by the following method, and the described method comprises the following steps:
(1) compound shown in Formula IV reacts to obtain compound shown in Formula VII with WITTIG reagent；With
(2) compound shown in Formula VII obtains compound shown in Formula VIII through acylting agent protection hydroxyl
(3) compound shown in Formula VIII carries out selective double bond reduction and R using catalyst3The removing of protecting group obtains formula
Compound shown in IX, the method is as shown in following formulas:
(4) compound shown in Formula IX obtains compound shown in Formula X after oxidising agent aoxidizes；
In formula,
R1、R2And R4As defined in claim 1；With
R3Selected from benzyl or substituted benzyl.
In a particular embodiment, in step (3), the selectivity double bond reduction and R3The removing of protecting group utilizes
It is carried out using catalytic hydrogenation, the catalyst of catalytic hydrogenation is 5%Pd/C or 10%Pd/C, preferably 10%Pd/C；And/or
The selectivity double bond reduction and R3The reaction temperature of the removing of protecting group is controlled at -40 DEG C~-20 DEG C, preferably -
30℃；Reaction pressure is controlled in 0.1~1atm H2, preferably 1atm H2；Reaction carries out in ethyl acetate.
In a particular embodiment, in step (4), the oxidant utilized that aoxidizes is selected from: Dess-Martin examination
Agent, the combination of DMSO- oxalyl chloride, TEMPO-NaOCl, TEMPO-TCCA or TEMPO and other oxidants, preferably Dess-
Martin reagent；And/or
In the oxidation reaction, the molar ratio of compound and oxidant shown in Formula IX is 1:1.2-1:1.5；It is preferred that 1:1.5；
Reaction temperature is controlled at 10~30 DEG C, preferably 20~30 DEG C, most preferably 25 DEG C.
In a preferred embodiment, the Wittig reagent in step (1) is R3O(CH2)3P+Ph3Br-, R3For benzyl or
Substituted benzyl；And/or
The acylting agent in step (2) is without being particularly limited to, and effect is protection hydroxyl, as long as the hydroxyl protection
Group can play the role of protecting hydroxyl, readily removed in subsequent reactions step, and the preparation to limaprost
Unfavorable negative effect is not generated.In a particular embodiment, the acylting agent is selected from acetic anhydride, chloroacetic chloride,
Chloracetyl chloride, methoxyacetyl chloride, chlorobenzoyl chloride；It is preferred that acetic anhydride, chloroacetic chloride or chlorobenzoyl chloride；Most preferably acetic anhydride.
In a preferred embodiment, as shown in following formulas, compound shown in Formula V restores the formula of being made through ester reducing agent
Compound shown in VI:
In a preferred embodiment, the ester reducing agent is selected from diisobutyl aluminium hydride or other aluminum hydride derivatizations try
The combination of agent.
In a preferred embodiment, as shown in following formulas, compound shown in formula IV is protected through hydroxy protecting agent
Obtain compound shown in Formula V:
In a preferred embodiment, the hydroxy protecting agent is tert-butyl chloro-silicane, tert-butyl diphenyl
Chlorosilane, chlorotriethyl silane, trim,ethylchlorosilane or dihydropyran.
In a preferred embodiment, compound shown in Formula V passes through recrystallization, OR2Chiral purity is greater than 99.0%.
In a preferred embodiment, as shown in following formulas, compound shown in formula III and asymmetric reduction reagent are anti-
It should obtain compound shown in formula IV:
In a preferred embodiment, asymmetric reduction reagent is DIP Chloirde or Corey catalyst CBS.
In a preferred embodiment, the selective double bond reduction of compound shown in Formula VIII carries out in ethyl acetate.
In a preferred embodiment, as shown in following formulas, chemical combination shown in preparation of compounds of formula X shown in Formula IX is utilized
Object:
Wherein, the Dess-Martin reagent oxidation of compound shown in Formula IX, mole of compound and oxidant shown in Formula IX
Than for 1:1.5；Reaction temperature is controlled at 25 DEG C；Compound shown in Formula X is made.
Compound described in formula B of the invention can be used for synthesizing limaprost.
On the basis of the compound shown in formula B, the present invention provides a kind of method for synthesizing limaprost, the sides
Method the following steps are included:
(1) compound shown in Formula IV reacts to obtain compound shown in Formula VII with WITTIG reagent；
(2) compound shown in Formula VII obtains compound shown in Formula VIII through acylting agent protection hydroxyl；
(3) compound shown in Formula VIII carries out selective double bond reduction and R using catalyst3The removing of protecting group obtains formula
Compound shown in IX；
(4) compound shown in Formula IX obtains compound shown in Formula X after oxidising agent aoxidizes, compound shown in Formula X with
Wittig reagent reacts to obtain compound shown in Formula XI；
(5) limaprost is finally prepared using compound shown in Formula XI；
In formula, R1、R2、R3And R4As defined above；R5For C1-C4Linear or branched alkyl group.
In a preferred embodiment, in step (3), the selectivity double bond reduction and R3The removing of protecting group utilizes
Catalytic hydrogenation carries out, and the catalyst of catalytic hydrogenation is 5%Pd/C or 10%Pd/C, preferably 10%Pd/C；And/or
The selectivity double bond reduction and R3The reaction temperature of the removing of protecting group is controlled at -40 DEG C~-20 DEG C, preferably -
30℃；Reaction pressure is controlled in 0.1~1atm H2, preferably 1atm H2；Reaction carries out in ethyl acetate.
In a preferred embodiment, in step (4), the oxidant utilized that aoxidizes is selected from: Dess-Martin examination
Agent, the combination of DMSO- oxalyl chloride, TEMPO-NaOCl, TEMPO-TCCA or TEMPO and other oxidants；It is preferred that Dess-
Martin reagent
In the oxidation reaction, the molar ratio of compound and oxidant shown in Formula IX is 1:1.2-1:1.5, preferably 1:1.5；
Reaction temperature is controlled at 10~30 DEG C, preferably 20~30 DEG C, most preferably 25 DEG C.
In a preferred embodiment, the selective double bond of compound shown in Formula VIII is restored in acetic acid second in step (3)
It is carried out in ester；WITTIG reagent in step (4) is selected from phosphonoacetate, phosphinylidyne acetic acid methyl ester diethylester, phosphinylidyne
Acetic acid methyl ester diisopropyl ester, phosphoryl allyl acetate diethylester or other phosphinylidyne acetic acid derivatives.
In a particular embodiment, it includes following for limaprost being finally prepared using compound shown in Formula XI
Step:
As shown in following formulas, compound shown in Formula XI removes carboxylic acid simultaneously under alkaline condition and hydroxyl protection obtains
Compound shown in Formula XII:
As shown in following formulas, compound shown in Formula XII aoxidizes to obtain compound shown in Formula XIII through oxidising agent, after
Continuous removing R1And R2Obtain limaprost:
In a preferred embodiment, the alkaline condition is that there are sodium hydroxide, the alkaline hydrolysis conditions of potassium hydroxide；
The oxidising agent is Dess-Martin, DMSO- oxalyl chloride, TEMPO-NaOCl, TEMPO-TCCA or TEMPO and other oxidations
The combination of agent.
Advantages of the present invention:
1. the present invention provides the new intermediates of synthesis limaprost；
2. the present invention provides the new limaprost synthetic route using the intermediate；
3. the method for synthesis limaprost of the invention has the control of preparation process chirality preferably, by multiple
Wittig reaction building double bond structure, processing efficient, production cost are low.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.
Embodiment
The preparation of compound shown in 1. formula III of embodiment
Compound shown in Formulas I (143.0g, 0.5mol) [is synthesized from (-)-coreylactone diol by universal method and is tied
Structure formula (I)] it is dissolved in methylene chloride (1430.0ml), it cools to 0 DEG C, stirring addition Dess-Martin reagent (255.0g,
0.6mol), -5 to 0 DEG C of reactions detect fully reacting to TLC, pour Na2S2O3/NaHCO3The aqueous solution of (700g/260g)
In (3000L), layering, water layer is extracted with methylene chloride, merges dichloromethane layer, and anhydrous magnesium sulfate dries, filters, filtrate concentration
The dichloromethane solution of compound shown in Formula II is obtained to volume 1000.0ml.
Phosphoric acid ester side chain (150.0g, 0.6mol) is dissolved in methylene chloride (1500.0ml), is cooled to 0 DEG C, is dripped
Add 30% sodium hydroxide solution (87.0g, 0.65mol), continue after 0 to 5 DEG C is stirred 30 minutes, compound shown in Formula II is added dropwise
Dichloromethane solution (1000.0ml).It finishes, terminates in 0 to 5 DEG C of reaction to TLC detection reaction.Reaction solution is poured into ice
In saturated ammonium chloride solution (3000.0ml), stirring layering, water layer is extracted with methylene chloride, is successively washed with water, salt washing, point
Layer, organic layer anhydrous magnesium sulfate dries, filters, and filtrate is concentrated to dryness to obtain compound shown in formula III: 144.0g (two step yields
70.6%).
The preparation of compound shown in 2. Formula V of embodiment
Under argon gas protection, compound (204.0g, 0.5mol), THF (2000.0ml) shown in formula III are added in reaction flask,
Stirring and dissolving is cooled to -25 DEG C, and the mixed liquor of (-)-DIPCl (1233.0g, 2.5mol) and THF (500.0ml) is added dropwise, and is added dropwise
Process control temp is between -30--20 DEG C.Reaction detects fully reacting to TLC, controls in -25 DEG C of dropwise addition methanol
(300.0ml) terminates reaction, is concentrated to dryness to obtain residue and pours saturated ammonium chloride water after the dissolution of residue ethyl acetate
Solution, layering, aqueous layer with ethyl acetate extract, and merge organic layer, are successively washed with water, salt washing, layering, organic layer anhydrous slufuric acid
Magnesium dries, filters, and filtrate decompression is concentrated to give compound shown in formula IV.Compound shown in formula IV is dissolved in DMF (1000.0ml), stirring
Dissolution is added imidazoles (102.0g, 1.5mol), is cooled to 5 DEG C, is added tert-butyl chloro-silicane (120.0g, 0.8mol),
It is stirred at room temperature to TLC and detects fully reacting.Reaction solution is poured in ice water, methylene chloride is added and extracts completely, organic layer is successively
It is washed, is washed with 0.1mol/L aqueous hydrochloric acid solution, saturated salt washing is layered, and organic layer anhydrous magnesium sulfate dries, filters, and filtrate subtracts
Pressure is concentrated to give crude compound shown in Formula V, and crude product obtains compound shown in Formula V: 168.0g (two after being recrystallized with 8 times of anhydrous methanols
Walk yield 64.1%).It restores hydroxyl chiral purity and is greater than 99.0%.
The preparation of compound shown in 3. Formula VII of embodiment
Under argon gas protection, compound shown in Formula V (104.8g, 0.2mol) is dissolved in dry toluene (2000ml), is cooled down
It to -30 DEG C, is added dropwise 1mol/L diisobutyl aluminium hydride (600.0ml, 0.6mmol), < -25 DEG C of holding interior temperature is anti-to TLC detection
It should be complete.Methanol (500ml) is added dropwise and destroys reaction, adds and is warmed to room temperature stirring 2 hours, diatomite 50g agitation and filtration, filter is added
The elution of cake toluene, filtrate decompression are concentrated to give grease, and silica gel column purification obtains compound shown in Formula IV on grease.
Under argon gas protection, by BnO (CH2)3PPh3 +Br-(467.0g, 1.0mol) is dissolved in THF (1000ml), is cooled to 10
℃.It is added 0.5mol/L KHMDS toluene solution (3600ml, 1.8mol), after being stirred at room temperature 1 hour, is cooled to -30 DEG C, is added dropwise
The THF solution (1000ml) of compound shown in Formula IV is added dropwise and detects fully reacting in -30 DEG C of reactions to TLC.Post-processing:
Saturated ammonium chloride solution 8000ml stirring will be added in reaction solution, methyl tertiary butyl ether(MTBE) is added and extracts 3 times, merges organic layer.It is full
It is washed 4 times with ammonium chloride solution, saturated salt washing, organic layer is dry, and filtrate decompression is concentrated to give grease, and silicagel column is pure on grease
Change, collects target components and compound shown in Formula VII, 109.5g (yield 83.2%) is concentrated under reduced pressure to obtain.
The preparation of compound shown in 4. Formula IX of embodiment
Compound shown in Formula VII (65.8g, 0.1mol) is dissolved in methylene chloride (500.0ml), addition pyridine (40.0g,
0.5mol) stirring is cooled to -10 DEG C, is added dropwise aceticanhydride (20.5g, 0.2mol), is stirred at room temperature to TLC and detects fully reacting.It will be anti-
Liquid is answered to pour in ice water, stirring layering, water layer is extracted with methylene chloride, is merged organic layer and is successively used 0.1mol/L dilute hydrochloric acid solution
It washes, saturated sodium bicarbonate solution is washed, saturated salt washing, layering, and organic layer anhydrous magnesium sulfate dries, filters, filtrate decompression concentration
Obtain structure formula (VIII).Structure formula (VIII) is dissolved in ethyl acetate (1000.0ml), is added 10%Pd/C (20.0g), stirs
It mixes and is cooled to -30 DEG C, lead to 1atmH2, stirring detects fully reacting, filtering to TLC at -30 DEG C, and filtrate decompression is concentrated to give structure
Formula (IX), 52.6g (yield 85.8%).
MS(ES+):635(M+Na)+。
1H-NMR(CDCl3): δ 0.03 (m, 12H), 0.85-0.88 (m, 24H), 0.90-1.61 (m, 21H), 2.03 (s,
3H),2.25(m,1H),3.61-3.64(t,2H),3.70(m 1H),3.81(dd,1H),5.05(s,1H),5.41-5.46(m,
2H)。
The preparation of 5. structure formula (X) of embodiment
Dess-Martin reagent oxidation method: compound shown in Formula IX (2.0g, 0.00326mol) is dissolved in methylene chloride
(30ml) is added with stirring 1,1,1- triacetyl -1, -1- dihydro -1,2- benzenesulfonyl -3- (1H) -one in 10~20 DEG C
(Dess-Martin reagent) (1.66g, 0.00391mol), reaction to TLC detect fully reacting.Reaction solution pours Na2S2O3/
NaHCO3In the aqueous solution (50mL) of (12g/4.5g), layering, water layer is extracted with methylene chloride, merges dichloromethane layer, anhydrous
Magnesium sulfate dries, filters, and filtrate is concentrated to give compound shown in Formula X: 1.40g (yield 70%).
TEMPO/TCCA oxidizing process: by compound shown in Formula IX (2.0g, 3.26mmol), NaOAc (0.79g,
9.67mmol), TEMPO (5.06mg, 0.0326mmol) is added in methylene chloride (20ml), is cooled to 5 DEG C, TCCA is added portionwise
(purity 90%, 0.290g, 1.124mmol), is then warmed to room temperature stirring 30min, and filtering is washed with methylene chloride (15ml)
Filter cake, methylene chloride (45ml) dilution is added in filtrate after merging, through being saturated Na2CO3Aqueous solution (25ml), saturated salt solution (20ml
× 2) it washs, anhydrous MgSO4Dry filter, filtrate are concentrated to give compound shown in Formula X: 1.0g (yield 50%).
SWEN oxidizing process: nitrogen protection, oxalyl chloride (0.623g, 0.00491mol) are dissolved in methylene chloride (12ml), will
Temperature is down to -78 DEG C, stirs lower methylene chloride (5ml) solution that DMSO (0.637g, 0.00815mol) is added dropwise, and drop finishes, continues
Keep the temperature 10min.Methylene chloride (8ml) solution of compound (2.0g, 0.00326mol) shown in Formula IX is added dropwise, about 10min is dripped off,
Continue to keep the temperature 1h, be added triethylamine (1.484g, 0.0147mol), is warmed to room temperature stirring 3h naturally after keeping the temperature 1h, reaction solution is fallen
Enter washing in 10% dilute hydrochloric acid (15ml), separate organic layer, water layer is extracted with methylene chloride (15ml × 3), and organic layer merges
By saturation NaHCO3Aqueous solution (10ml), saturated salt solution (10ml) washing, anhydrous MgSO4Dry, concentration, silica gel column chromatography
Obtain compound shown in Formula X: 0.89g (yield 45%).
Oxidant selects Dess-Martin reagent best.
The preparation of 6. structure formula (X) of embodiment
4 reaction flasks are taken, it is each that compound (2.0g, 0.00326mol) shown in Formula IX is added, methylene chloride is respectively added
(30ml), temperature control is in 10~20 DEG C.Be separately added under stirring Dess-Martin reagent 1.38g (0.00326mol, 1:1),
1.66g (0.00391mol, 1:1.2), 2.07g (0.00489mol, 1:1.5), 2.77g (0.00652mol, 1:2), reaction is extremely
TLC detects fully reacting.Reaction solution respectively pours Na2S2O3/NaHCO3In the aqueous solution (100mL) of (24g/9g), layering, water layer
(15ml × 4) are extracted with methylene chloride, merge dichloromethane layer, anhydrous magnesium sulfate dries, filters, and filtrate is concentrated to give shown in Formula X
Compound is respectively as follows: 1.21g (yield 62%), 1.41g (yield 71%), 1.51g (yield 76%), 1.35g (yield 68%).
Reaction feed ratio is that 1:1.5 (Formula IX compound: Dess-Martin reagent molar ratio) is most preferable.
The preparation of 7. structure formula (X) of embodiment
4 reaction flasks are taken, it is each that compound (2.0g, 0.00326mol) shown in Formula IX is added, methylene chloride is respectively added
(30ml), each addition Dess-Martin reagent 2.07g (0.00489mol, 1:1.5) under stirring, respectively temperature control in 0~10 DEG C,
10-20 DEG C, 20~30 DEG C, 30~40 DEG C.It reacts to TLC and detects IX fully reacting.Reaction solution pours Na respectively2S2O3/NaHCO3
In the aqueous solution (100mL) of (24g/9g), layering, water layer extracts (15ml × 4) with methylene chloride, merges dichloromethane layer, nothing
Water magnesium sulfate dries, filters, and filtrate is concentrated to give compound shown in Formula X and is respectively as follows: 1.22g (yield 61%), 1.49g (yield
75%), 1.63g (yield 82%), 1.29g (yield 65%).
20~30 DEG C of reaction temperature best.
The preparation of 8. structure formula (X) of embodiment
Compound shown in Formula IX (61.2g, 0.1mol) is dissolved in methylene chloride (1000.0ml), (25 DEG C) of room temperature stirrings add
Enter Dess-Martin reagent (64.0g, 0.15mol), reaction to TLC detects fully reacting.Reaction solution pours Na2S2O3/
NaHCO3In the aqueous solution (1500L) of (350g/130g), layering, water layer is extracted with methylene chloride, merges dichloromethane layer, nothing
Water magnesium sulfate dries, filters, and filtrate is concentrated to give compound shown in Formula X: 50.6g (yield 83%).
The spectrum data of compound shown in Formula X is as follows:
MS(ES+):611(M+1)+。
1H-NMR(CDCl3): δ 0.02 (m, 12H), 0.84-0.90 (m, 24H), 1.05-1.59 (m, 18H), 2.02 (s,
3H),2.20-2.28(m,1H),2.39-2.43(t,2H),3.68(m 1H),3.78-3.82(m,1H),5.02(s,1H),
5.43-5.47(m,2H),9.74-9.75(s,1H)。
The preparation of 9. structural formula of embodiment (XI)
Compound shown in Formula X (50.4g, 0.0824mol) is dissolved in methylene chloride (1000.0ml), phosphinylidyne guanidine-acetic acid is added
Methyl esters diethylester (31.5g, 0.15mol) is cooled to 0 DEG C, is added dropwise 30% sodium hydroxide solution (16.0ml), and stirring to TLC is examined
Survey fully reacting.
Post-processing: 10% cooling aqueous citric acid solution is added into reaction solution and adjusts pH=3, stirring after twenty minutes, divides
Layer, water layer are extracted 2-3 times with methylene chloride, merge dichloromethane layer, and saturated salt washing is layered, and organic layer anhydrous magnesium sulfate is dry
Dry, filtering, filtrate decompression is concentrated to give grease.Target product is collected in silica gel column purification on grease, elution, is concentrated under reduced pressure to produce
Object: 44.0g (yield 80.0%).
The preparation of compound shown in 10. Formula XII of embodiment
Compound shown in Formula XI (67.0g, 0.1mol) is dissolved in dehydrated alcohol (670.0ml), stirring is cooled to 0 DEG C, drop
Add 2mol/L sodium hydroxide solution (250.0ml, 0.5mol), finish, is stirred at room temperature to TLC and detects fully reacting.It is cooled to 0
DEG C, pH=4-5 is adjusted with 1mol/L hydrochloric acid solution at 0 DEG C of control, methyl tertiary butyl ether is added and extracts 2 times, merges organic layer, successively
Washing, saturated salt washing, combining water layer, methyl tertiary butyl ether extract.Merge organic layer, anhydrous magnesium sulfate dries, filters, and filtrate subtracts
Pressure is concentrated to give compound shown in Formula XII, 43.0g (yield 70.5%).
The preparation of 11. limaprost of embodiment
Compound shown in Formula XII (61.0g, 0.1mol) is dissolved in methylene chloride (1000.0ml), stirring room temperature is added
Dess-Martin reagent (64.0g, 0.15mol), reaction to TLC detect fully reacting.Reaction solution pours Na2S2O3/NaHCO3
In the aqueous solution (1500L) of (350g/130g), layering, water layer is extracted with methylene chloride, merges dichloromethane layer, anhydrous slufuric acid
Magnesium dries, filters, and filtrate is concentrated to give compound shown in grease-Formula XIII.Grease is dissolved in acetonitrile (1200.0ml), is added
Pyridine (180.0ml) is cooled to 0 DEG C, is added dropwise 55%HF.Py (350.0ml), is stirred at room temperature to TLC and detects fully reacting.After
Reason: reaction solution is added to the water, methyl tertiary butyl ether(MTBE) extract, layering, organic layer washing, saturated salt washing, layering, organic layer without
Water magnesium sulfate dries, filters, and filtrate decompression is concentrated to give grease, silica gel column purification on grease, successively uses petroleum ether: acetic acid second
Ester=2:1, petroleum ether: ethyl acetate=1:1, ethyl acetate, elution collect target product, crude product, crude product second are concentrated under reduced pressure to obtain
Acetoacetic ester/petroleum ether recrystallizes to obtain finished product: 19.0g (yield 50.0%).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (11)
- The preparation method of compound below 1.,R1Selected from t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate or trimethyl silicon substrate；R2Selected from t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate or trimethyl silicon substrate；R4Selected from acetyl group, chloracetyl, Methoxyacetyl or benzoyl；WithR6For-CHO；It the described method comprises the following steps:(1) compound shown in Formula IV reacts to obtain compound shown in Formula VII with WITTIG reagent；With(2) compound shown in Formula VII obtains compound shown in Formula VIII through acylting agent protection hydroxylWith(3) compound shown in Formula VIII carries out selective double bond reduction and R using catalyst3The removing of protecting group obtains Formula IX institute Show compound, the method is as shown in following formulas:(4) compound shown in Formula IX obtains compound shown in Formula X after oxidising agent aoxidizes；In formula,R3Selected from benzyl；In step (4), the oxidant utilized that aoxidizes is Dess-Martin reagent；In the oxidation reaction, the molar ratio of compound and oxidant shown in Formula IX is 1:1.5；Reaction temperature is controlled at 20~30 DEG C.
- 2. the method as described in claim 1, which is characterized in that in step (3), the selectivity double bond reduction and R3Protection The removing of base is carried out using catalytic hydrogenation, and the catalyst of catalytic hydrogenation is 5%Pd/C or 10%Pd/C；And/orThe selectivity double bond reduction and R3The reaction temperature of the removing of protecting group is controlled at -40 DEG C~-20 DEG C；Reaction pressure control System is in 0.1~1atm H2；Reaction carries out in ethyl acetate.
- 3. method according to claim 2, which is characterized in that the catalyst of the catalytic hydrogenation is 10%Pd/C.
- 4. method according to claim 2, which is characterized in that the selectivity double bond reduction and R3The removing of protecting group it is anti- Answer temperature control at -30 DEG C；Reaction pressure is controlled in 1atm H2。
- 5. the method as described in claim 1, which is characterized in that in step (4), reaction temperature is controlled at 25 DEG C.
- 6. method as claimed in claim 5, which is characterized in thatR1For t-Butyldimethylsilyl；R2For t-Butyldimethylsilyl；R3Selected from benzyl；R4For acetyl group.
- 7. a kind of method for synthesizing limaprost, the described method comprises the following steps:(1) compound shown in Formula IV reacts to obtain compound shown in Formula VII with WITTIG reagent；(2) compound shown in Formula VII obtains compound shown in Formula VIII through acylting agent protection hydroxyl；(3) compound shown in Formula VIII carries out selective double bond reduction and R using catalyst3The removing of protecting group obtains Formula IX institute Show compound；(4) compound shown in Formula IX obtains compound shown in Formula X after oxidising agent aoxidizes, compound and Wittig shown in Formula X Reagent reacts to obtain compound shown in Formula XI；(5) limaprost is finally prepared using compound shown in Formula XI；In formula, R1Selected from t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate or trimethyl silicon substrate；R2Selected from t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate or trimethyl silicon substrate；R3Selected from benzyl；R4Selected from acetyl group, chloracetyl, Methoxyacetyl or benzoyl；R5For C1-C4Linear or branched alkyl group；In step (4), the oxidant utilized that aoxidizes is Dess-Martin reagent；In the oxidation reaction, the molar ratio of compound and oxidant shown in Formula IX is 1:1.5；Reaction temperature is controlled at 20~30 DEG C.
- 8. the method for claim 7, which is characterized in that in step (3), the selectivity double bond reduction and R3Protection The removing of base is carried out using catalytic hydrogenation, and the catalyst of catalytic hydrogenation is 5%Pd/C or 10%Pd/C；And/orThe selectivity double bond reduction and R3The reaction temperature of the removing of protecting group is controlled at -40 DEG C~-20 DEG C；Reaction pressure control System is in 0.1~1atm H2；Reaction carries out in ethyl acetate.
- 9. method according to claim 8, which is characterized in that the catalyst of catalytic hydrogenation is 10%Pd/C.
- 10. method according to claim 8, which is characterized in that the selectivity double bond reduction and R3The removing of protecting group it is anti- Answer temperature control at -30 DEG C；Reaction pressure is controlled in 1atm H2。
- 11. the method for claim 7, which is characterized in that in step (4), reaction temperature is controlled at 25 DEG C.
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| US3931296A (en) * | 1972-12-29 | 1976-01-06 | Masaki Hayashi | Trans-Δ2 -prostaglandins |
| JPS5170754A (en) * | 1974-11-11 | 1976-06-18 | Ono Pharmaceutical Co | PUROSUTA GURANJINRUIJIKAGOBUTSU NO SEIZOHO |
| US4052512A (en) * | 1976-01-05 | 1977-10-04 | Ono Pharmaceutical Co., Ltd. | Prostaglandin analogues |
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| WO2014040457A1 (en) * | 2012-09-13 | 2014-03-20 | 上海源力生物技术有限公司 | Intermediate of limaprost, preparation method thereof and preparation method of limaprost therefrom |
| CN103787942A (en) * | 2012-11-02 | 2014-05-14 | 上海源力生物技术有限公司 | Intermediate for preparing lubiprostone, preparation method of intermediate and method for preparing lubiprostone through intermediate |
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| US3931296A (en) * | 1972-12-29 | 1976-01-06 | Masaki Hayashi | Trans-Δ2 -prostaglandins |
| JPS5170754A (en) * | 1974-11-11 | 1976-06-18 | Ono Pharmaceutical Co | PUROSUTA GURANJINRUIJIKAGOBUTSU NO SEIZOHO |
| US4052512A (en) * | 1976-01-05 | 1977-10-04 | Ono Pharmaceutical Co., Ltd. | Prostaglandin analogues |
| US4294849A (en) * | 1979-01-29 | 1981-10-13 | Warner-Lambert Company | Prostaglandin analogues |
| WO2014040457A1 (en) * | 2012-09-13 | 2014-03-20 | 上海源力生物技术有限公司 | Intermediate of limaprost, preparation method thereof and preparation method of limaprost therefrom |
| CN103787942A (en) * | 2012-11-02 | 2014-05-14 | 上海源力生物技术有限公司 | Intermediate for preparing lubiprostone, preparation method of intermediate and method for preparing lubiprostone through intermediate |
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