CN112266356A - Asymmetric synthesis method of (S) -chloroquine phosphate - Google Patents

Asymmetric synthesis method of (S) -chloroquine phosphate Download PDF

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CN112266356A
CN112266356A CN202011020169.5A CN202011020169A CN112266356A CN 112266356 A CN112266356 A CN 112266356A CN 202011020169 A CN202011020169 A CN 202011020169A CN 112266356 A CN112266356 A CN 112266356A
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chloroquine
diethylamino
pentylamine
reaction
asymmetric synthesis
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陈旭桓
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Jiangsu Baiaoxinkang Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention provides a novel asymmetric synthesis method of (S) -chloroquine. The method comprises the steps of adopting 5- (N-diethylamino) -2-pentanone and (S) -alpha-methylbenzylamine as raw materials, carrying out asymmetric reductive amination reaction in the presence of Lewis acid to obtain (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine, carrying out catalytic hydrogenation to remove benzyl to obtain a chloroquine-synthesized side chain (S) -5- (N-diethylamino) -2-pentylamine, carrying out condensation with 4, 7-dichloroquinoline to obtain (S) -chloroquine, and finally carrying out salt formation and recrystallization with phosphoric acid to obtain the (S) -chloroquine phosphate, wherein the ee value of the chloroquine phosphate is more than 99%, and the total yield of the four-step reaction is more than 70%. The preparation method is stable, reliable, economical, efficient and easy to industrialize.

Description

Asymmetric synthesis method of (S) -chloroquine phosphate
Technical Field
The invention relates to an asymmetric synthesis method of (S) -chloroquine phosphate, belonging to the field of drug synthesis.
Background
The inventors investigated the relevant data for chloroquine phosphate. Chloroquine is a traditional old medicine for treating malaria, and is also applied to treating autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and the like, but has serious toxic and side effects in clinical use, and is fatal to the toxicity of heart in particular. The entry content of chloroquine phosphate in the encyclopedic shows that the saturated carbon atom connected with the 4-amino group of the quinoline ring in the chloroquine molecule is a carbon atom with a chiral center, while the clinically used chloroquine phosphate is a racemate. In a training course of the Olympic Games in high school chemistry, in which the inventors are participating in learning, the lecturer and the reference books of the related games teach in more detail knowledge about chiral molecules and chiral drugs. For enantiomers of chiral molecules, their physical and chemical properties in an achiral environment are essentially the same, but in a chiral environment, their properties are not the same. Enzymes and proteins in the body are chiral, and thus the physiological activities of enantiomers are often greatly different. For example, levorotatory nicotine is much more toxic than dextrorotatory nicotine; levo-chloramphenicol is therapeutic, while dextro-chloramphenicol is not; the aroma of levocarvone and the aroma of dextroisomer are not the same. Historically, the "reaction stop" event was most typical because of tragedies caused by chiral drugs. In 1953, thalidomide, a drug that can treat vomiting in pregnant women, was marketed in Federal Germany. After two years, more than 1 ten thousand and 2 thousand abnormal infants are discovered in European region. The research result shows that the R configuration of thalidomide has the effects of calming and stopping vomiting, while the S configuration isomer is the chief culprit of teratogenicity. In 1984, the netherlands pharmacologist ari strongly advocated the marketing of chiral drugs as single enantiomers, as well as the pharmacological research and marketing as racemates. In 1992, the U.S. drug administration stipulated that the efficacy and toxicity of the chiral enantiomers, respectively, must be studied before new chiral drugs can be marketed, or else they are not allowed to be marketed. In 2006, the drug administration in China also came out of corresponding policy and regulation.
By searching literature data, we have obtained that several studies have recommended toxicity comparison studies on chiral isomers of chloroquine and hydroxychloroquine to identify the chiral isomer with relatively low toxicity for clinical treatment of the novel coronavirus (molecules, 2020,25, 1834; Drug Discovery Today,2020,25, 1121) 1123; bioRxiv, doi: https:// doi.org/10.1101/2020.05.26.114033). According to the available research data, these documents also recommend that chloroquine in S configuration may be a relatively more preferred chiral isomer, and may have lower cardiac and retinal toxicity (Drug Discovery Today,2020,25,1121,1123; bioRxiv, doi: https:// doi. org/10.1101/2020.05.26.114033.). Thus, we set out studies on the synthesis of (S) -chloroquine phosphate.
The preparation of (S) -chloroquine phosphate or (S) -chloroquine was first reported as a resolution method (Journal of the American Chemical Society,1949,71, 1129-.
Gideon Blauer et al reported the preparation of (S) or (R) -chloroquine phosphate (Chirality,1998,10,556-563) by a 10-step reaction using (S) or (R) -pyroglutamic acid as chiral source material. The synthetic route is as follows:
Figure RE-GDA0002841893910000021
manish Sinha et al reported the preparation of (S) -chloroquine via 12 steps of reactions using (S) -alanine as the chiral source (Bioorganic & Medicinal Chemistry,2014,22, 5950-. The synthetic route is as follows:
Figure RE-GDA0002841893910000022
cymerman Craig et al, using L-glutamic acid diethyl ester as a chiral source, through 10 steps of reactions, synthesize (R) -5-diethylamino-2-pentylamine, then condense with 4, 7-dichloroquinoline to obtain (R) -chloroquine (Journal of Organic Chemistry,1988, 53, 1167-1170). If D-diethyl glutamate is taken as a chiral source, the same route is adopted, and then the (S) -chloroquine can be obtained.
The method for synthesizing and preparing (S) -chloroquine/chloroquine phosphate by adopting different chiral sources as starting materials obviously has long synthetic route and high cost, and is not suitable for large-scale industrial production.
Chenfuxin and the like take 4-amino-7-chloroquinoline and 5-diethylamino-2-pentanone as raw materials, and the (S) -chloroquine is obtained through asymmetric reductive amination reaction under the catalysis of a chiral acid catalyst. The synthetic route is as follows:
Figure RE-GDA0002841893910000023
although the synthesis route of the above asymmetric catalytic synthesis method is simple, the yield of (S) -chloroquine provided by the method is low (36.5% -68%) because the amino group on the 4-amino-7-quinoline is aromatic amine and the nucleophilic attack capability is poor, the asymmetric catalytic chiral selectivity is not very ideal, and the ee value of the product (S) -chloroquine is 68% -92%.
Disclosure of Invention
The invention aims to provide a novel asymmetric synthesis method of (S) -chloroquine phosphate, aiming at overcoming the defects in the preparation method.
The industrial production process of chloroquine phosphate includes nucleophilic substitution reaction of 4, 7-dichloroquinoline as mother nucleus and 5- (N-diethylamino) -2-pentylamine as side chain at high temperature to obtain chloroquine, and salifying with phosphoric acid to obtain chloroquine phosphate. The synthesis of the mother nucleus 4, 7-dichloroquinoline takes 3-chloroaniline and diethyl butanone diacid as raw materials, and is prepared by condensation, cyclization, hydrolysis, decarboxylation and chlorination. The synthesis of the side chain 5- (N-diethylamino) -2-pentylamine is carried out by taking acetoacetic ester and 2-diethylaminochloroethane as raw materials, nucleophilic substitution, hydrolysis decarboxylation and reductive amination reaction. The synthetic route is as follows:
Figure RE-GDA0002841893910000031
in combination with the above synthetic route and method of chloroquine, the inventors considered that if the side chain of S configuration, i.e. (S) -5- (N-diethylamino) -2-pentylamine, can be conveniently synthesized and prepared, the chloroquine of S configuration can be conveniently prepared by the original synthetic route method.
Through searching documents, the inventor finds that the chiral auxiliary reagent (R)/(S) -alpha-methylbenzylamine) is widely applied to asymmetric Synthesis of chiral amine, and the method is stable and reliable and has high chiral selectivity (Shanghai university bulletin (Nature science edition), 2008,14, 80-84; Synthesis,2013,45, 153-166). The (R)/(S) -alpha-methylbenzylamine is a pharmaceutical and chemical intermediate which is very easy to obtain in the market, has low price and is very suitable for industrially preparing chiral amine. In this method, Lewis acid catalysis is usually employed, and (R)/(S) - α -methylbenzylamine can be obtained with certainty as (R)/(S) -amine (Journal of Organic Chemistry,2008,73, 1297-; Organic Letters,2005,7, 4967-.
As 5-diethylamino-2-pentanone and 4, 7-dichloroquinoline chemical intermediates are supplied on the market, the method adopts 5-dimethylamino-2-pentanone, (S) -alpha-methylbenzylamine and 4, 7-dichloroquinoline as raw materials, obtains (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine through asymmetric reductive amination reaction in the presence of Lewis acid, obtains (S) -5-diethylamino-2-pentylamine through catalytic hydrogenation debenzylation, then condenses with 4, 7-dichloroquinoline and forms salt with phosphoric acid to obtain (S) -chloroquine phosphate. The synthetic route is as follows:
Figure RE-GDA0002841893910000041
the invention provides an asymmetric synthesis preparation method of (S) -chloroquine phosphate, which comprises the following steps:
step 1: taking 5-dimethylamino-2-pentanone and (S) -alpha-methylbenzylamine as raw materials, and obtaining (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine through asymmetric reductive amination reaction in the presence of Lewis acid;
step 2: removing benzyl from (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine under the condition of catalytic hydrogenation to obtain (S) -5-diethylamino-2-pentylamine;
and step 3: condensing (S) -5-diethylamino-2-pentylamine and 4, 7-dichloroquinoline to obtain (S) -chloroquine;
and 4, step 4: salifying and recrystallizing (S) -chloroquine and phosphoric acid to obtain the (S) -chloroquine phosphate.
The Lewis acid in the step 1 can be one or more mixed reagents of isopropyl titanate, triisopropyl borate, aluminum isopropoxide, ytterbium acetate and cerium acetate.
The feeding molar ratio of the Lewis acid to the 5-diethylamino-2-pentanone in the step 1 is 0.5-1.5: 1.
The reducing agent used in the reductive amination reaction in step 1 may be one of catalytic hydrogenation, sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.
The invention provides an asymmetric synthesis preparation method of (S) -chloroquine phosphate, which is innovatively realized in the following points:
(1) 5-dimethylamino-2-pentanone, (S) -alpha-methylbenzylamine and 4, 7-dichloroquinoline which are easily available in the market are adopted as raw materials, and a target product can be obtained only through 4 steps of reaction, so that the reaction steps are few, and the chiral selectivity and the yield are high;
(2) the synthesis process has no special harsh reaction conditions, good process stability, high reliability, economy and high efficiency, and is very suitable for large-scale industrial production.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement or improvement of the present invention by those skilled in the art is within the technical scheme of the present invention.
Example 1: synthesis of (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine
The reaction formula is as follows:
Figure RE-GDA0002841893910000042
to a 500mL hydrogenation reactor was added methanol (150mL), stirring was turned on, and 5-diethylamino-2-pentanone (15.7g,0.1mol), (S) -methylbenzylamine (12.7g,0.105mol), and isopropyl titanate (14.2g,0.05mol) were added in that order. After stirring at room temperature for half an hour, wet Raney-Ni (25g) was added, and after three replacements with hydrogen, hydrogen was introduced to 1.0MPa, and the reaction was continued for 12 hours with stirring at room temperature. After the reaction was completed, the hydrogen gas in the reactor was discharged, the reactor was opened, and NaOH solution (1.0M, 100mL) was added thereto, followed by stirring at room temperature for 1 hour to obtain a reaction system in the form of a suspension. After filtration, the filtrate was evaporated to remove about half of the solvent by a rotary evaporator, and extracted three times with dichloromethane (60 mL. times.3). The dichloromethane organic phases were combined, dried over anhydrous sodium sulfate, filtered and the dichloromethane solvent was evaporated to give 22.1g (0.0842mol) of a colorless oily liquid in 84.2% yield.
Example 2: synthesis of (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine
The reaction formula is as follows:
Figure RE-GDA0002841893910000051
to a 500mL hydrogenation reactor was added methanol (150mL), stirring was turned on, and 5-diethylamino-2-pentanone (15.7g,0.1mol), (S) -methylbenzylamine (12.7g,0.105mol), and isopropyl titanate (28.4g,0.1mol) were added in that order. After stirring at room temperature for half an hour, wet Raney-Ni (25g) was added, and after three replacements with hydrogen, hydrogen was introduced to 1.0MPa, and the reaction was continued for 12 hours with stirring at room temperature. After the reaction was completed, the hydrogen gas in the reactor was discharged, the reactor was opened, and NaOH solution (1.0M, 100mL) was added thereto, followed by stirring at room temperature for 1 hour to obtain a reaction system in the form of a suspension. After filtration, the filtrate was evaporated to remove about half of the solvent by a rotary evaporator, and extracted three times with dichloromethane (60 mL. times.3). The dichloromethane organic phases were combined, dried over anhydrous sodium sulfate, filtered and the dichloromethane solvent was evaporated to give 25.2g (0.096mol) of a colorless oily liquid in a yield of 96%.
Example 3: synthesis of (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine
The reaction formula is as follows:
Figure RE-GDA0002841893910000052
to a 500mL hydrogenation reactor was added methanol (150mL), stirring was turned on, and 5-diethylamino-2-pentanone (15.7g,0.1mol), (S) -methylbenzylamine (12.7g,0.105mol), and isopropyl titanate (42.6g,0.15mol) were added in that order. After stirring at room temperature for half an hour, wet Raney-Ni (25g) was added, and after three replacements with hydrogen, hydrogen was introduced to 1.0MPa, and the reaction was continued for 12 hours with stirring at room temperature. After the reaction was completed, the hydrogen gas in the reactor was discharged, the reactor was opened, and NaOH solution (1.0M, 100mL) was added thereto, followed by stirring at room temperature for 1 hour to obtain a reaction system in the form of a suspension. After filtration, the filtrate was evaporated to remove about half of the solvent by a rotary evaporator, and extracted three times with dichloromethane (60 mL. times.3). The dichloromethane organic phases were combined, dried over anhydrous sodium sulfate, filtered and the dichloromethane solvent was evaporated to give 25.6g (0.0976mol) of a colorless oily liquid with a yield of 97.6%.
Example 4: synthesis of (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine
The reaction formula is as follows:
Figure RE-GDA0002841893910000061
into a 500mL reaction flask was added methanol (150mL), stirring was turned on, and 5-diethylamino-2-pentanone (15.7g,0.1mol), (S) -methylbenzylamine (12.7g,0.105mol), and triisopropyl borate (22.5g,0.12mol) were added in this order. After stirring at room temperature for half an hour, sodium borohydride (3.8g,0.1mol) was added slowly in portions and the reaction was continued with stirring at room temperature for 12 hours. After the reaction is finished, saturated NH is added4Cl solution (100mL) was stirred at room temperature for 1 hour. After filtration, the filtrate was evaporated to remove about half of the solvent by a rotary evaporator, and extracted three times with dichloromethane (60 mL. times.3). The dichloromethane organic phases were combined, dried over anhydrous sodium sulfate, filtered and the dichloromethane solvent was evaporated to give 23.9g (0.0911mol) of a colorless oily liquid in 91.1% yield.
Example 5: synthesis of (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine
The reaction formula is as follows:
Figure RE-GDA0002841893910000062
methanol (150mL) was added to a 500mL reaction flask, stirring was turned on, and 5-diethylamino-2-pentanone (15.7g,0.1mol), (S) -methylbenzylamine (12.7g,0.105mol), and freshly dried ytterbium acetate anhydrous (28.0g,0.08mol) were added in that order. After stirring at room temperature for half an hour, sodium cyanoborohydride (12.5g,0.2mol) was added slowly in portions and the reaction was continued with stirring at room temperature for 12 hours. After the reaction is finished, saturated NH is added4Cl solution (100mL) was stirred at room temperature for 1 hour. After filtration, the filtrate was evaporated to remove about half of the solvent by a rotary evaporator, and extracted three times with dichloromethane (60 mL. times.3). The dichloromethane organic phases are combined and freed from anhydrous sulfurAfter the sodium salt was dried, it was filtered, and the methylene chloride solvent was distilled off to obtain 24.5g (0.0933mol) of a colorless oily liquid in a yield of 93.3%.
Example 6: synthesis of (S) -5- (N-diethylamino) -2-pentylamine
The reaction formula is as follows:
Figure RE-GDA0002841893910000063
to a 500mL hydrogenation reactor, 5% Pd/C (10g), the (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine (25.2g,0.096mol) obtained in example 2, and methanol (100mL) were added in this order, and after the mixture was replaced with hydrogen three times, hydrogen was introduced into the reactor to 0.5MPa, and the reaction was stirred at room temperature for 24 hours. After the reaction was completed, the hydrogen gas in the reactor was discharged, the reactor was opened, the reaction solution was filtered, and the methanol solvent was distilled off to obtain 15.1g (0.095mol) of a colorless oily liquid in a yield of 99%.
Example 7: synthesis of (S) -chloroquine
The reaction formula is as follows:
Figure RE-GDA0002841893910000071
phenol (100g) was added to a 250mL reaction flask, heated to 100 ℃ to melt the phenol, 4, 7-dichloroquinoline (18.8g,0.095mol) was added with stirring turned on, and after the solid dissolved to a homogeneous phase, (S) -5- (N-diethylamino) -2-pentylamine (15.1g,0.095mol) obtained in example 6 was added. The reaction mixture was heated to 135 ℃ and reacted for 3 hours. After completion of the reaction, most of the phenol was distilled off under reduced pressure and then cooled to room temperature, and the obtained solid was dissolved in methylene chloride (200mL), and then washed three times (100 mL. times.3) with 1.0M NaOH solution and twice (100 mL. times.2) with pure water. And drying the organic phase by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, cooling (at 0-4 ℃) and crystallizing to obtain a yellow (S) -chloroquine crude product. Recrystallizing the crude product with n-hexane to obtain light yellow (S) -chloroquine 26.1g (0.0816mol), with yield of 85.9%,
Figure RE-GDA0002841893910000074
the content analysis of the enantiomer of the obtained (S) -chloroquine adopts a high performance liquid chromatography, and the detection conditions are as follows: by using
Figure RE-GDA0002841893910000072
AY-H chiral column; the mobile phase was n-hexane/isopropanol/diethylamine 85:15:0.1 (v/v/v); the flow rate is 0.8 mL/min; the column temperature was 35 ℃; the detection wavelength was 254 nm. The analysis and detection result is as follows: (R) -chloroquine was not detected. Therefore, the ee values of (S) -chloroquine and (S) -chloroquine phosphate should be greater than 99%.
Example 8: synthesis of (S) -chloroquine phosphate
The reaction formula is as follows:
Figure RE-GDA0002841893910000073
methanol (100mL) and (S) -chloroquine from example 7 (25g,0.0782mol) were added to a 250mL reaction flask, heated to reflux, and 85% concentrated phosphoric acid (10.5g,0.091mol) was added dropwise. After the completion of the dropwise addition, stirring was continued for 1 hour under reflux. Slowly cooling to room temperature while keeping slowly stirring. After 12 hours, filtration was carried out, and the filter cake was recrystallized from pure water to obtain 36.3g (0.0704mol) of a white crystalline solid with a yield of 90%,
Figure RE-GDA0002841893910000075
1H NMR(D2O, 500MHz):δ(ppm)1.01～1.06(m,6H),1.18(d,3H),1.54～1.60(m,4H),2.92～2.99(m,6H), 3.80～3.84(m,1H),6.51(d,1H),7.03(dd,1H),7.13(s,1H),7.65(d,1H),7.94(d,1H)。13C NMR (D2O,125MHz):δ(ppm)8.00,8.06,18.55,20.16,31.70,46.99,47.07,49.41,51.03,98.49,114.39, 118.32,123.67,126.77,137.34,138.69,141.98,154.59。HRMS(ESI+):C18H27ClN3[M+H]+(m/z): theoretical value is 320.1888, found 320.1886.

Claims (4)

1. An asymmetric synthesis preparation method of (S) -chloroquine phosphate comprises the following steps:
step 1: taking 5-dimethylamino-2-pentanone and (S) -alpha-methylbenzylamine as raw materials, and obtaining (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine through asymmetric reductive amination reaction in the presence of Lewis acid;
step 2: removing benzyl from (S, S) -5- (N' -diethylamino) -N- ((1-phenyl) ethyl) -2-pentylamine under the condition of catalytic hydrogenation to obtain (S) -5-diethylamino-2-pentylamine;
and step 3: condensing (S) -5-diethylamino-2-pentylamine and 4, 7-dichloroquinoline to obtain (S) -chloroquine;
and 4, step 4: salifying and recrystallizing (S) -chloroquine and phosphoric acid to obtain the (S) -chloroquine phosphate.
2. The method for asymmetric synthesis of chloroquine (S) -phosphate according to claim 1, wherein the Lewis acid in step 1 is selected from one or more of isopropyl titanate, triisopropyl borate, aluminum isopropoxide, ytterbium acetate and cerium acetate.
3. The asymmetric synthesis method for preparing (S) -chloroquine phosphate according to claim 1, wherein the molar ratio of the Lewis acid and 5-diethylamino-2-pentanone in step 1 is 0.5-1.5: 1.
4. The asymmetric synthesis method of (S) -chloroquine phosphate according to claim 1, wherein the reductive amination reaction in step 1 employs one of catalytic hydrogenation, sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.
CN202011020169.5A 2020-09-25 2020-09-25 Asymmetric synthesis method of (S) -chloroquine phosphate Pending CN112266356A (en)

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