CN112142703A - Carprostenol tromethamine related impurity L-butyl 15-ketone and preparation method thereof - Google Patents
Carprostenol tromethamine related impurity L-butyl 15-ketone and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a carboprost tromethamine related impurity levo-butyl 15-ketone and a preparation method thereof, belonging to the technical field of compounds and preparation thereof, wherein the method comprises the following steps: (1) in the presence of a fifth organic solvent, carrying out dehydrogenation reaction on methyl triphenyl phosphonium halide by using strong base, adding ethyl butyrate after reacting for a certain time, and continuing to react for a certain time to obtain 1-triphenylphosphine-2-pentanone; (2) and (2) carrying out wittig reaction on the 1-triphenylphosphine-2-pentanone obtained in the step (1) and a second organic solvent solution of benzoyl colactone aldehyde to obtain butyl 15-ketone. The method has the characteristics of simple and convenient operation, high safety, high product yield and high purity under the optimal conditions, and can meet the requirements of impurity research.
Description
Technical Field
The invention relates to a carboprost tromethamine related impurity levo-butyl 15-ketone and a preparation method thereof in the field of compound preparation.
Background
Carboprost tromethamine is a tromethamine salt containing a (15S) -15 methyl derivative of the natural prostaglandin F2 α, with the chemical name 7- {3 α,5 α -dihydroxy-2 β [ (3S) -3-hydroxy-3-methyl-trans-1-octene ] -1 α -cyclopentyl } -cis-5-heptenoic acid compound 2-amino-2- (hydroxymethyl) -1,3-propanediol, english name:
7-(3α,5α-dihydroxy-2β-[(3S)-3-hydroxy-3-methyl-trans-1-octenyl]-1α-cyclopentyl]-cis-5-heptenoic acid compound with
2-amino-2- (hydroxymethy) -1, 3-propanediol. The molecular formula is as follows: c25H47NO8Molecular weight 489.64.
Early postpartum hemorrhage is the leading cause of perinatal complications and increased mortality, and is one of the serious complications of obstetrics. When puerperae is complicated with factors such as advanced age, multiple gestation, giant child, uterine contraction and hypodynamia, bleeding is easy to occur during production, and prostaglandin is bioactive substance with wide physiological action and has multiple important physiological regulation functions, wherein prostaglandin F2αHas effects of contracting smooth muscle, and can effectively prevent puerperal hemorrhage. The carboprost tromethamine injection has the effects of conveniently, safely and efficiently preventing postpartum hemorrhage, can avoid emergency operation, has important significance for reducing the incidence rate of postpartum hemorrhage and reducing the fatality rate of high-risk pregnant and lying-in women, and is a product which can not be replaced in current clinical medication.
At present, according to the requirements of the drug evaluation center and the ICH guiding principle of the State drug administration, the starting materials, intermediates and finished products used for preparing the drugs must be fully researched for impurities, and the research work of the impurities of the drugs becomes the central importance of drug development.
The levo-15-ketone is a key material for completely synthesizing the carboprost tromethamine, and is also a key material for preparing medicaments such as dinoprost, abaprost, alprostadil and the like, researchers unexpectedly find the levo-butyl 15-ketone related to the levo-15-ketone during impurity research, and the impurity research inevitably needs to use a high-purity impurity reference substance. The L-butyl 15-ketone belongs to a key impurity in the L-butyl 15-ketone, and the impurities and a synthesis method thereof are not searched at present, so that the research and development of a preparation method of the L-butyl 15-ketone is a new problem to be solved at present.
Disclosure of Invention
The invention aims to provide a carboprost tromethamine related impurity, namely, levobutyl 15-ketone and a preparation method thereof, wherein the preparation method of the levobutyl 15-ketone is simple and convenient to operate and high in safety, and under the optimal conditions, the obtained product is high in yield and purity and can meet the requirements for impurity research.
The purpose of the invention is realized as follows: a butyl 15-one of the formula I,
the butyl 15-ketone is selected from levo-butyl 15-ketone shown in a formula III,
a method for preparing butyl 15-ketone as shown in formula I, comprising the following steps:
(1) in the presence of a fifth organic solvent, carrying out dehydrogenation reaction on methyl triphenyl phosphonium halide by using strong base, adding ethyl butyrate after reacting for a certain time, and continuing to react for a certain time to obtain 1-triphenylphosphine-2-pentanone;
(2) carrying out wittig reaction on the 1-triphenylphosphine-2-pentanone obtained in the step (1) and a second organic solvent solution of benzoyl colactone aldehyde to obtain butyl 15-ketone;
the method further comprises step (3): pulping the butyl 15-ketone obtained in the step (2) in a fourth organic solvent, and filtering to obtain the butyl 15-ketone after solvent purification;
in step (1), the fifth organic solvent is selected from tetrahydrofuran; the methyl triphenyl phosphonium halide is selected from one or more of methyl triphenyl phosphonium chloride and methyl triphenyl phosphonium bromide; the strong base is selected from one or more of n-butyl lithium and potassium tert-butoxide; the temperature of the dehydrogenation reaction is-25 ℃ to 10 ℃, the preferable temperature of the dehydrogenation reaction is-25 ℃ to-5 ℃, and the more preferable temperature of the dehydrogenation reaction is-20 ℃ to-15 ℃; the temperature when the ethyl butyrate is added is-25 ℃ to 10 ℃, the preferable temperature when the ethyl butyrate is added is-25 ℃ to-5 ℃, and the more preferable temperature when the ethyl butyrate is added is-20 ℃ to-15 ℃; the temperature of the continuous reaction is-25 ℃ to 10 ℃, the preferable temperature of the continuous reaction is-25 ℃ to-5 ℃, and the more preferable temperature of the continuous reaction is-20 ℃ to-15 ℃; the continuous reaction time is 1-5 hours, the preferable reaction time is 2-4 hours, and the more preferable reaction time is 3 hours; in the step (1), after the reaction is continued for a certain time and before the 1-triphenylphosphine-2-pentanone is obtained, the method further comprises the steps of quenching reaction, extraction, concentration, solid precipitation, pulping by using a first organic solvent and filtration; the quenching reaction is to add water for quenching; the first organic solvent is selected from one or more of n-hexane, diethyl ether, isopropyl ether and methyl tert-butyl ether, and preferably isopropyl ether; the extraction is to extract the water layer by using a sixth organic solvent; the sixth organic solvent is selected from ethyl acetate; the dehydrogenation reaction is carried out under the protection of nitrogen; the adding mode of the strong base is slow adding, and the slow adding mode is selected from liquid dropwise adding or solid batch adding; the ethyl butyrate is added dropwise; the concentration is selected from reduced pressure concentration; the precipitated solid is a precipitated solid from an oily substance; the mass ratio of the methyl triphenyl phosphonium halide to the fifth organic solvent is as follows: 40-68:300, said units of mass are grams and said units of volume are milliliters; the molar ratio of the methyl triphenyl phosphonium halide to the strong base is 1: 1.0-1.6; the molar ratio of the methyl triphenyl phosphonium halide to the ethyl butyrate is 1: 0.9-1.6; the volume ratio of the mass of the methyl triphenyl phosphonium halide to the water used for quenching reaction is 60: 180-300, the unit of the mass is gram, and the unit of the volume is milliliter; the volume ratio of the mass of the methyl triphenyl phosphonium halide to the sixth organic solvent is 60: 300-600, the unit of the mass is gram, and the unit of the volume is milliliter; the volume ratio of the mass of the methyl triphenyl phosphonium halide to the first organic solvent for pulping is 60: 150-260, the unit of the mass is gram, and the unit of the volume is milliliter;
in the step (2), the second organic solvent is selected from one or more of dichloromethane or chloroform; the reaction time of the wittig reaction is 6-12 hours, and the preferable reaction time is 6-8 hours; the reaction temperature of the wittig reaction is 10-40 ℃, and the preferable reaction temperature is 20-25 ℃; in the step (2), after the wittig reaction and before butyl 15-ketone is obtained, a post-treatment step is further included; the post-treatment step is selected from the first method or the second method; the first method comprises (21a) a step of concentrating a reaction solution obtained after the wittig reaction, (21b) a step of performing first crystallization, filtration and washing on a residue obtained by the concentration by using a third organic solvent, (21c) a step of dissolving and concentrating a filter cake obtained after the first crystallization, filtration and washing by using a second organic solvent to obtain an oily substance, (21d) a step of adding the oily substance into the third organic solvent, performing second crystallization and filtration; in step (21b), the solvent used for the washing is selected from isopropyl ether; in the step (21b), the volume ratio of the mass of the 1-triphenylphosphine-2-pentanone to the third organic solvent is 16: 60-90, the unit of the mass is gram, and the unit of the volume is milliliter; in the step (21c), the volume ratio of the mass of the 1-triphenylphosphine-2-pentanone to the second organic solvent is 1: 0.8-1.2, the unit of the mass is gram, and the unit of the volume is milliliter; in the step (21d), the volume ratio of the mass of the 1-triphenylphosphine-2-pentanone to the third organic solvent is 1: 1.5-3, the unit of the mass is gram, and the unit of the volume is milliliter; the second method comprises (22a) a step of concentrating a reaction solution obtained after the wittig reaction, (22b) a step of purifying the oil obtained by the concentration with a silica gel column; the silica gel column is 100-500 mesh silica gel, and the preferred silica gel column is 200-300 mesh silica gel; the eluent of the silica gel column is selected from a mixed solvent of petroleum ether and alkyl ester; the alkyl ester is selected from ethyl acetate; the volume ratio of the petroleum ether to the alkyl ester is 1-3:1, and the preferred volume ratio of the petroleum ether to the alkyl ester is 2: 1;
in the step (3), the fourth organic solvent is selected from one or more of ethanol, isopropanol and isopropyl ether; the pulping temperature is 0-40 ℃, and the preferred temperature is 20-30 ℃; the pulping time is 2-6 hours, and the preferable pulping time is 4 hours; the volume ratio of the mass of the butyl 15-ketone crude product to the fourth organic solvent is 1-6: 17, the unit of the mass is gram, and the unit of the volume is milliliter;
in the step (2), the third organic solvent is an anhydrous organic solvent; the third organic solvent is selected from one or more of methanol, ethanol and isopropanol, preferably, the third organic solvent is selected from ethanol; the temperature of the first crystallization is-30 ℃ to 0 ℃, and the preferable temperature of the first crystallization is-25 ℃ to-10 ℃; the time for the first crystallization is 6-15 hours; the temperature of the second crystallization is-30 ℃ to 0 ℃, and the preferable temperature of the second crystallization is-25 ℃ to-10 ℃; the time of the second crystallization is 6-15 h;
the preparation method of the second organic solvent solution of the benzoyl colelactone aldehyde comprises the following steps: in the presence of the second organic solvent, adding the benzoyl colactonal, dimethyl sulfoxide and DCC into pyridine and trifluoroacetic acid under stirring, reacting, dropwise adding dilute hydrochloric acid, stirring, filtering, separating liquid, extracting a water layer with the second organic solvent, and combining organic layers to obtain a second organic solvent solution of the benzoyl colactonal; the benzoyl coriolide is selected from one of levo-benzoyl coriolide and mixed-benzoyl coriolide; the benzoyl coriolide aldehyde is selected from one of levo-benzoyl coriolide aldehyde and mixed-handed benzoyl coriolide aldehyde;
use of butyl 15-one of formula I as a control for impurities.
The key point of the invention is to provide the levo-butyl 15-ketone and the preparation method thereof, and the chemical principle is as follows: (a) by optimizing the kind of strong base in the step (1), the dehydrogenation reaction can obtain good effect, and the yield of the intermediate 1-triphenylphosphine-2-pentanone is obviously improved; (b) by optimizing the type of the first organic solvent, the obtained intermediate 1-triphenylphosphine-2-pentanone can obtain better purity; (c) by optimizing the third organic solvent, a good crystallization effect can be obtained, and the product is easier to separate out; (d) through the optimization of the fourth organic solvent, the removal of impurities can achieve good effect, and the obtained product has high purity; (e) by introducing a column chromatography purification means, the obtained L-butyl 15-ketone has high purity and meets the requirements of a reference substance.
Compared with the prior art, the preparation method of the related impurities of the carboprost tromethamine, namely the levorotation butyl 15-ketone, provides possible levorotation butyl 15-ketone impurities in the carboprost tromethamine product, and provides the preparation method of the levorotation butyl 15-ketone.
Drawings
FIG. 1 is a structural formula diagram of carboprost tromethamine
FIG. 2 is a structural formula diagram of L-butyl 15-ketone
FIG. 3 is a structural formula diagram of L-benzoylcolelactone alcohol
FIG. 4 is a structural formula diagram of L-benzoylcolelactone aldehyde
FIG. 5 is a synthetic scheme of the preparation of L-butyl 15-one
FIG. 6 is a mass spectrum of levo-butyl 15-ketone
FIG. 7 is a hydrogen spectrum of L-butyl 15-ketone
FIG. 8 is a carbon spectrum of L-butyl 15-one
Detailed Description
The following examples will help to understand the present invention, but they are only for illustrative purposes and the present invention is not limited to these contents.
Example one
Adding 57.0g of methyl triphenyl phosphonium bromide and 300ml of tetrahydrofuran into a 1L four-necked bottle, stirring and cooling to-20 ℃ to-15 ℃ under the protection of nitrogen, dropwise adding 76.8ml of 2.5M n-butyl lithium (dropwise adding is finished after 30 minutes), carrying out dehydrogenation reaction for 2h after the addition is finished, maintaining the temperature range of-20 ℃ to-15 ℃, dropwise adding 25.0g of ethyl butyrate, continuing reaction for 3h after the addition is finished, adding 240ml of water for quenching reaction, separating liquid, extracting a water layer by using 200ml of ethyl acetate for 2 times, combining organic layers, washing by using 200ml of saturated sodium chloride, drying by using anhydrous sodium sulfate, carrying out suction filtration, carrying out reduced pressure concentration on filtrate to obtain an oily substance, standing to separate out a solid, adding 200ml of isopropyl ether for pulping for 2h, carrying out suction filtration, washing a filter cake by using 50ml of isopropyl ether, and drying to obtain 45.6g of 1-triphenylphosphine-2-pentanone. The content is as follows: 97.8% (area normalized).
A500 ml single-mouth bottle is added with dichloromethane solution of levo-benzoyl colide aldehyde and 15.3g of 1-triphenylphosphine-2-pentanone, and subjected to wittig reaction at 20-25 ℃ for 8h to obtain reaction liquid, and the reaction liquid is decompressed, concentrated and evaporated to remove the solvent to obtain brown oily matter. Purifying with silica gel column (200-mesh silica gel 300 meshes, eluent petroleum ether and ethyl acetate at a volume ratio of 2:1) to obtain 4.6g of oily L-butyl 15-ketone with a content of 99.8% (area normalization). ESI-MS m/z: 365.1[ M + Na ]]+，m/z 380.9[M+K]+。1H-NMR(600MHz，CD3OD3)：7.984～7.970(d,J＝7.8Hz,2H),7.597～7.585(t,J＝7.2Hz,1H),7.471～7.445(t,J＝7.8Hz,2H),6.847～6.807(dd,J＝15.6Hz,7.8Hz 1H),6.286～6.260(d,J＝15.6Hz 1H),5.354～5.344(q,J＝4.8Hz 1H),5.171～5.160(m,1H),3.017～2.946(m,3H),2.638～2.513(m,4H),2.256～2.224(dd,J＝15.0Hz,3.6Hz 1H),1.609～1.572(m,2H),0.915～0.891(t,J＝7.2Hz,3H)。13C-NMR(150MHz，CD3OD3): 201.9,178.4,166.4,145.1,133.7,131.6,130.1,129.8,128.8,84.8,79.7,54.9,43.1,42.2,37.9,35.1,17.8,13.2. See fig. 6, 7, 8.
Example two
Adding 57.0g of methyl triphenyl phosphonium bromide and 300ml of tetrahydrofuran into a 1L four-necked bottle, stirring and cooling to-20 ℃ to-15 ℃ under the protection of nitrogen, dropwise adding 76.8ml of 2.5M n-butyl lithium (dropwise adding is finished after 30 minutes), carrying out dehydrogenation reaction for 2h after the addition is finished, maintaining the temperature range of-20 ℃ to-15 ℃, dropwise adding 25.0g of ethyl butyrate, continuing reaction for 3h after the addition is finished, adding 240ml of water for quenching reaction, separating liquid, extracting a water layer by using 200ml of ethyl acetate for 2 times, combining organic layers, washing by using 200ml of saturated sodium chloride, drying by using anhydrous sodium sulfate, carrying out suction filtration, carrying out reduced pressure concentration on filtrate to obtain an oily substance, standing to separate out a solid, adding 200ml of isopropyl ether for pulping for 2h, carrying out suction filtration, washing a filter cake by using 50ml of isopropyl ether, and drying to obtain 45.6g of 1-triphenylphosphine-2-pentanone.
Adding a dichloromethane solution of the benzoyl colide aldehyde into a 500ml single-neck flask, carrying out wittig reaction for 8h at 20-25 ℃ to obtain a reaction solution, concentrating under reduced pressure to evaporate the solvent, adding 75ml of absolute ethyl alcohol into the residue, carrying out crystallization for 10h at-20 ℃ to separate out crystals, carrying out suction filtration, washing a filter cake with 24ml of isopropyl ether, dissolving with 15ml of dichloromethane, concentrating the dichloromethane solution to obtain an oily substance, adding 30ml of absolute ethyl alcohol, carrying out crystallization for 10h at-20 ℃, separating out the crystals, carrying out suction filtration, washing the filter cake with 12ml of isopropyl ether, and drying to obtain 15.3g of a crude product of the mixed butyl 15-ketone.
15.0g of crude product of the racemic butyl 15-ketone and 75ml of absolute ethyl alcohol are added into a 100ml single-mouth bottle, stirred and pulped for 4 hours at the temperature of 20-30 ℃, filtered, and a filter cake is dried to obtain 14.3g of the racemic butyl 15-ketone, the yield is 95.3%, and the content is 99.8% (area normalization).
EXAMPLE III
The dichloromethane solution of levo-benzoyl-colelactone aldehyde in the first embodiment of the invention is prepared by the following method:
adding 12.0g of levo-benzoyl-colelactone alcohol, 73ml of dimethyl sulfoxide, 30.0g of DCC (dicyclohexylcarbodiimide), 150ml of dichloromethane into a 1L four-mouth bottle, cooling to 10 ℃ under stirring, adding 3.4ml of pyridine and 1.7ml of trifluoroacetic acid, heating to 20-25 ℃ for reaction for 5 hours, cooling to 15 ℃, dropwise adding dilute hydrochloric acid (4.4ml of hydrochloric acid is prepared with 300ml of water), stirring for 20min after the addition is finished, performing suction filtration, separating liquid, extracting a water layer for 2 times by using 100ml of dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, and performing suction filtration to obtain a dichloromethane solution of levo-benzoyl-colelactone aldehyde.
Example four
The dichloromethane solution of the racemic benzoyl coriolide aldehyde in the second embodiment of the invention is prepared by the following method:
adding 12.0g of mixed benzoyl colilide alcohol, 73ml of dimethyl sulfoxide, 30.0g of DCC (dicyclohexylcarbodiimide), 150ml of dichloromethane into a 1L four-mouth bottle, cooling to 10 ℃ under stirring, adding 3.4ml of pyridine and 1.7ml of trifluoroacetic acid, heating to 20-25 ℃ for reaction for 5 hours, cooling to 15 ℃, dropwise adding diluted hydrochloric acid (4.4ml of hydrochloric acid is prepared with 300ml of water), stirring for 20min after the addition is finished, performing suction filtration, separating liquid, extracting a water layer for 2 times by using 100ml of dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, and performing suction filtration to obtain a dichloromethane solution of mixed benzoyl colilide aldehyde.
Claims (10)
1. A butyl 15-one of the formula I,
2. the butyl 15-ketone of formula I as claimed in claim 1, wherein said butyl 15-ketone is selected from the group consisting of L-butyl 15-ketone of formula III,
3. a process for the preparation of butyl 15-one of formula I according to claim 1, comprising the steps of:
(1) in the presence of a fifth organic solvent, carrying out dehydrogenation reaction on methyl triphenyl phosphonium halide by using strong base, adding ethyl butyrate after reacting for a certain time, and continuing to react for a certain time to obtain 1-triphenylphosphine-2-pentanone;
(2) and (2) carrying out wittig reaction on the 1-triphenylphosphine-2-pentanone obtained in the step (1) and a second organic solvent solution of benzoyl colactone aldehyde to obtain butyl 15-ketone.
4. The process for preparing butyl 15-one according to claim 3, further comprising the step (3): pulping the butyl 15-ketone obtained in the step (2) in a fourth organic solvent, and filtering to obtain the butyl 15-ketone purified by the solvent.
5. The process for preparing butyl 15-one according to claim 3, wherein in step (1), the fifth organic solvent is selected from tetrahydrofuran; the methyl triphenyl phosphonium halide is selected from one or more of methyl triphenyl phosphonium chloride and methyl triphenyl phosphonium bromide; the strong base is selected from one or more of n-butyl lithium and potassium tert-butoxide; the temperature of the dehydrogenation reaction is-25 ℃ to 10 ℃, the preferable temperature of the dehydrogenation reaction is-25 ℃ to-5 ℃, and the more preferable temperature of the dehydrogenation reaction is-20 ℃ to-15 ℃; the temperature when the ethyl butyrate is added is-25 ℃ to 10 ℃, the preferable temperature when the ethyl butyrate is added is-25 ℃ to-5 ℃, and the more preferable temperature when the ethyl butyrate is added is-20 ℃ to-15 ℃; the temperature of the continuous reaction is-25 ℃ to 10 ℃, the preferable temperature of the continuous reaction is-25 ℃ to-5 ℃, and the more preferable temperature of the continuous reaction is-20 ℃ to-15 ℃; the continuous reaction time is 1-5 hours, the preferable reaction time is 2-4 hours, and the more preferable reaction time is 3 hours; in the step (1), after the reaction is continued for a certain time and before the 1-triphenylphosphine-2-pentanone is obtained, the method further comprises the steps of quenching reaction, extraction, concentration, solid precipitation, pulping by using a first organic solvent and filtration; the quenching reaction is to add water for quenching; the first organic solvent is selected from one or more of n-hexane, diethyl ether, isopropyl ether and methyl tert-butyl ether, and preferably isopropyl ether; the extraction is to extract the water layer by using a sixth organic solvent; the sixth organic solvent is selected from ethyl acetate; the dehydrogenation reaction is carried out under the protection of nitrogen; the adding mode of the strong base is slow adding, and the slow adding mode is selected from liquid dropwise adding or solid batch adding; the ethyl butyrate is added dropwise; the concentration is selected from reduced pressure concentration; the precipitated solid is a precipitated solid from an oily substance; the mass ratio of the methyl triphenyl phosphonium halide to the fifth organic solvent is as follows: 40-68:300, said units of mass are grams and said units of volume are milliliters; the molar ratio of the methyl triphenyl phosphonium halide to the strong base is 1: 1.0-1.6; the molar ratio of the methyl triphenyl phosphonium halide to the ethyl butyrate is 1: 0.9-1.6; the volume ratio of the mass of the methyl triphenyl phosphonium halide to the water used for quenching reaction is 60: 180-300, the unit of the mass is gram, and the unit of the volume is milliliter; the volume ratio of the mass of the methyl triphenyl phosphonium halide to the sixth organic solvent is 60: 300-600, the unit of the mass is gram, and the unit of the volume is milliliter; the volume ratio of the mass of the methyl triphenyl phosphonium halide to the first organic solvent for pulping is 60: 150-260, the unit of the mass is gram, and the unit of the volume is milliliter.
6. The method for preparing butyl 15-ketone according to claim 3, wherein in the step (2), the second organic solvent is one or more selected from dichloromethane and chloroform; the reaction time of the wittig reaction is 6-12 hours, and the preferable reaction time is 6-8 hours; the reaction temperature of the wittig reaction is 10-40 ℃, and the preferable reaction temperature is 20-25 ℃; in the step (2), after the wittig reaction and before butyl 15-ketone is obtained, a post-treatment step is further included; the post-treatment step is selected from the first method or the second method; the first method comprises (21a) a step of concentrating a reaction solution obtained after the wittig reaction, (21b) a step of performing first crystallization, filtration and washing on a residue obtained by the concentration by using a third organic solvent, (21c) a step of dissolving and concentrating a filter cake obtained after the first crystallization, filtration and washing by using a second organic solvent to obtain an oily substance, (21d) a step of adding the oily substance into the third organic solvent, performing second crystallization and filtration; in step (21b), the solvent used for the washing is selected from isopropyl ether; in the step (21b), the volume ratio of the mass of the 1-triphenylphosphine-2-pentanone to the third organic solvent is 16: 60-90, the unit of the mass is gram, and the unit of the volume is milliliter; in the step (21c), the volume ratio of the mass of the 1-triphenylphosphine-2-pentanone to the second organic solvent is 1: 0.8-1.2, the unit of the mass is gram, and the unit of the volume is milliliter; in the step (21d), the volume ratio of the mass of the 1-triphenylphosphine-2-pentanone to the third organic solvent is 1: 1.5-3, the unit of the mass is gram, and the unit of the volume is milliliter; the second method comprises (22a) a step of concentrating a reaction solution obtained after the wittig reaction, (22b) a step of purifying the oil obtained by the concentration with a silica gel column; the silica gel column is 100-500 mesh silica gel, and the preferred silica gel column is 200-300 mesh silica gel; the eluent of the silica gel column is selected from a mixed solvent of petroleum ether and alkyl ester; the alkyl ester is selected from ethyl acetate; the volume ratio of the petroleum ether to the alkyl ester is 1-3:1, and the preferred volume ratio of the petroleum ether to the alkyl ester is 2: 1.
7. The method for preparing butyl 15-ketone according to claim 4, wherein in the step (3), the fourth organic solvent is one or more selected from ethanol, isopropanol and isopropyl ether; the pulping temperature is 0-40 ℃, and the preferred temperature is 20-30 ℃; the pulping time is 2-6 hours, and the preferable pulping time is 4 hours; the volume ratio of the mass of the butyl 15-ketone crude product to the fourth organic solvent is 1-6: 17, the unit of the mass is gram, and the unit of the volume is milliliter.
8. The process for preparing butyl 15-one according to claim 6, wherein in step (2), the third organic solvent is an anhydrous organic solvent; the third organic solvent is selected from one or more of methanol, ethanol and isopropanol, preferably, the third organic solvent is selected from ethanol; the temperature of the first crystallization is-30 ℃ to 0 ℃, and the preferable temperature of the first crystallization is-25 ℃ to-10 ℃; the time for the first crystallization is 6-15 hours; the temperature of the second crystallization is-30 ℃ to 0 ℃, and the preferable temperature of the second crystallization is-25 ℃ to-10 ℃; and the time of the second crystallization is 6-15 h.
9. The method of claim 3, wherein the second organic solvent solution of benzoylcoriolide aldehyde is prepared by the steps of: in the presence of the second organic solvent, adding the benzoyl colactonal, dimethyl sulfoxide and DCC into pyridine and trifluoroacetic acid under stirring, reacting, dropwise adding dilute hydrochloric acid, stirring, filtering, separating liquid, extracting a water layer with the second organic solvent, and combining organic layers to obtain a second organic solvent solution of the benzoyl colactonal; the benzoyl coriolide is selected from one of levo-benzoyl coriolide and mixed-benzoyl coriolide; the benzoyl coriolide aldehyde is selected from one of levo-benzoyl coriolide aldehyde and mixed-handed benzoyl coriolide aldehyde.
10. Use of the butyl 15-one of formula I according to claim 1 as an impurity control.
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| CN202011056146.XA Pending CN112142703A (en) | 2020-09-30 | 2020-09-30 | Carprostenol tromethamine related impurity L-butyl 15-ketone and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5422368A (en) * | 1988-09-06 | 1995-06-06 | Kabi Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
| CN1533372A (en) * | 2001-07-17 | 2004-09-29 | �������Ŷ���Լ��������˾ | Process and intermediates to prepare latanoprost |
| CN105566266A (en) * | 2015-12-25 | 2016-05-11 | 东北制药集团股份有限公司 | 15-ketone preparation method |
-
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- 2020-09-30 CN CN202011056146.XA patent/CN112142703A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5422368A (en) * | 1988-09-06 | 1995-06-06 | Kabi Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
| CN1533372A (en) * | 2001-07-17 | 2004-09-29 | �������Ŷ���Լ��������˾ | Process and intermediates to prepare latanoprost |
| CN105566266A (en) * | 2015-12-25 | 2016-05-11 | 东北制药集团股份有限公司 | 15-ketone preparation method |
Non-Patent Citations (1)
| Title |
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| 无: "CAS：374674-53-0", 《STN REGISTRY》 * |
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