CN110099893B - Preparation method of droxidopa and intermediate thereof - Google Patents
Preparation method of droxidopa and intermediate thereof Download PDFInfo
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- CN110099893B CN110099893B CN201780066794.3A CN201780066794A CN110099893B CN 110099893 B CN110099893 B CN 110099893B CN 201780066794 A CN201780066794 A CN 201780066794A CN 110099893 B CN110099893 B CN 110099893B
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Abstract
The invention relates to a preparation method of a novel droxidopa intermediate (2S,3R) -3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-hydroxypropionate, which comprises the step of carrying out asymmetric hydrogenation reaction on 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate in an organic solvent in the presence of a hydrogen donor reagent and an organic base under the catalysis of a ruthenium catalyst. The reaction of the invention introduces two chiral centers of the droxidopa with high yield and high stereoselectivity in one step, and furthermore, the invention designs a brand-new preparation method of the droxidopa based on the reaction, and the method has a short route and can stereoselectively synthesize the droxidopa.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to improved droxidopa and a preparation method of a novel droxidopa intermediate.
Background
Droxidopa, also known as L-threo-3- (3, 4-dihydroxyphenyl) serine, a compound represented by formula (VIII), is a synthetic amino acid, and can restore abnormally reduced noradrenaline concentration in the brain to a normal level, thereby improving various symptoms caused by noradrenaline deficiency, such as dizziness, dizziness and weakness caused by orthostatic hypotension, stiff gait of parkinson's disease patients, and the like,
patent US3920728 (route one) discloses for the first time the reaction of 3, 4-dibenzyloxybenzaldehyde and glycine as starting materials to give racemic threo/erythro-3- (3, 4-dibenzyloxyphenyl) -N-benzyloxycarbonylserine, the resolution of dicyclohexylamine to give racemic threo-3- (3, 4-dibenzyloxyphenyl) -N-benzyloxycarbonylserine, the substance is further resolved by ephedrine or threo-3-p-nitrophenyl-2-amino-1, 3-propanediol to obtain threo-3- (3, 4-dibenzyloxyphenyl) -N-benzyloxycarbonyl serine, and finally hydrogenated to remove the protecting group to obtain L-threo-3- (3, 4-dihydroxyphenyl) serine.
EP0024210a1, EP0084928a1 improve the sequence of chiral resolving agents, protecting groups and deprotecting groups on the basis of this route. The method has the biggest defects that the droxidopa can be obtained only by two times of resolution, the total yield is low, and the cost is high.
WO2013142093A1 adopts L-ephedrine as resolving agent, and the serine derivative can be resolved in one step to obtain L-threo serine derivative, but the theoretical yield is still very low because no configuration transformation occurs in the resolution, and ephedrine belongs to controlled medicine and is difficult to obtain.
JPH01228946 discloses a novel method for synthesizing droxidopa (route II), which takes (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid as a starting material, and the oxazoline derivative with 4-substituted acetoxymethyl is formed through the steps of esterification, reduction, acetylation, oxidation and the like, and the compound is subjected to ring opening, oxidation and deprotection to obtain the droxidopa. Although the method can stereoselectively obtain the droxidopa, the route is too long, the operation is complicated, the starting material contains a chiral center, and the cost is high.
Although GB2300858 (route III) improves the route II, oxazoline derivatives substituted by ester groups at the 4-position can be formed by reacting N-carbonyl derivatives with halogen radical initiator or tetravalent cerium salt in one step, and the product droxidopa can be directly obtained by ring opening and deprotection, the defects that the raw materials are expensive and column chromatography is needed for post-treatment still exist.
WO2005085178 uses protected 3, 4-dihydroxybenzaldehyde as a starting material (route IV), a chiral center is constructed by a chiral metal coordination compound, and droxidopa is obtained by deprotection. Chiral selectivity is not reported in the patent, but heavy metals such as excessive metal nickel, copper or zinc are used, so that a large amount of heavy metal ion wastewater is generated, and the environmental pollution is serious.
Sang-Ho Baik [ Biotechnology Letters (2010), 32(1), 143-. The enzyme is used for catalyzing the reaction, and has the advantages of short route, mild reaction and low cost. However, strict conditions are required for the enzyme reaction, and no report on the realization of industrial production of droxidopa by enzyme catalysis is yet made at present, and most of the reports are in the laboratory research stage. In addition, in the reaction process of the enzyme, the chiral selectivity is not high, and a part of impurity isomers still exist (route five).
The reaction steps of the route (route six) reported by JPH09249626 are short, the yield of each step of chemical reaction is high, and a chiral center is directly constructed in the reaction process without resolution. However, the reaction involved in the process uses highly toxic and explosive sodium azide, and has potential safety hazards, so the method is not suitable for industrial production.
WO2016147133a1 discloses a method for the synthesis of droxidopa with chiral sulfinamide as chiral auxiliary (route seven), which is expensive, unstable in the form of a three-membered ring intermediate and low in reaction yield.
Disclosure of Invention
Summary of The Invention
In a first aspect, the present invention provides a process for preparing (2S,3R) -3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-hydroxypropionate represented by the formula (V),
wherein R is 1 Is C 1-4 Alkyl or benzyl;
the method comprises the step of carrying out asymmetric hydrogenation reaction on 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxo propionate in an organic solvent in the presence of a hydrogen donor reagent and an organic base under the catalysis of a ruthenium catalyst.
In a second aspect, the invention provides a method for preparing droxidopa by using the method as a key step, and the two methods have the advantages of high yield, high stereoselectivity, easily available raw materials, simple process, economy, environmental friendliness and the like, and are suitable for industrial production.
Definition of terms
The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of elements, and the 75 th version of the handbook of chemistry and Physics, 1994. The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6 alkyl" refers specifically to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl", as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl radical may be optionally substituted with one or more substituents described herein.
The invention provides a preparation method of a novel droxidopa intermediate (2S,3R) -3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-hydroxypropionate, wherein the structure of the intermediate is shown as a formula (V):
the preparation method comprises the following steps of preparing 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate (IV) in an organic solvent
In a catalytic amount of ruthenium catalyst (VII)
Or a catalytic amount of ruthenium catalyst (VIII)
Carrying out asymmetric hydrogenation reaction under the catalysis of (1);
the asymmetric hydrogenation reaction is carried out in the presence of a hydrogen donor reagent and an organic base.
Wherein, the first and the second end of the pipe are connected with each other,
R 1 is represented by C 1-4 Alkyl or benzyl; in some embodiments, R 1 Is methyl, ethyl, tert-butyl or benzyl.
R 2 Is represented by C 1-6 Alkyl, optionally substituted C 1-6 Alkyl, phenyl or optionally substituted phenyl; in some embodiments, R 2 Is methyl, p-methylphenyl, p-trifluoromethylphenyl, pentafluorophenyl, trifluoromethyl or perfluorobutyl.
R 3 、R 4 Each represents phenyl or substituted phenyl, or R 3 、R 4 Together represent butylene; in some embodiments, R 3 、R 4 Are all phenyl groups.
Ar represents benzene, optionally substituted benzene, cyclopentadiene, optionally substituted cyclopentadiene; in some embodiments, Ar is benzene or, isopropyltoluene or cyclopentadiene.
P represents oxygen, a chemical bond or CH 2 。
Q represents hydrogen or alkyl; in some embodiments, Q is hydrogen or methyl.
The ruthenium catalyst (VII) or the ruthenium catalyst (VIII) may be any ruthenium catalyst satisfying the above definition; for example, the ruthenium catalyst (VII) or the ruthenium catalyst (VIII) may be a ruthenium catalyst of the following structure:
in some embodiments, ruthenium catalyst (VII) is catalyst VII-A, catalyst VII-B, catalyst VII-E, or catalyst VII-G; in some embodiments, the ruthenium catalyst (VIII) is catalyst VIII-a.
The asymmetric hydrogenation reaction may be carried out in any suitable organic solvent; for example, the organic solvent may be dichloromethane, toluene, N-dimethylformamide, tetrahydrofuran, or a combination thereof; in some embodiments, the organic solvent is dichloromethane, toluene, N-dimethylformamide, or tetrahydrofuran.
The hydrogen donor agent may be any suitable hydrogen donor agent; in some embodiments, the hydrogen donor agent is formic acid.
The organic base may be any suitable organic base; in some embodiments, the organic base is diethylamine, diisopropylamine, dicyclohexylamine, triethylamine, N-diisopropylethylamine, or a combination thereof.
The amount of the ruthenium catalyst (VII) or the ruthenium catalyst (VIII) may be any suitable amount of the catalyst; for example, the ruthenium catalyst (VII) or the ruthenium catalyst (VIII) may be used in an amount of 0.001 to 0.1 mole relative to 1 mole of 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate; in some embodiments, the ruthenium catalyst (VII) or the ruthenium catalyst (VIII) is used in an amount of 0.015 mol with respect to 1mol of 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate.
The amount of the organic base can be any suitable amount; for example, the organic base may be used in an amount of 1 to 10 moles with respect to 1 mole of 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropanoate; in some embodiments, the organic base is used in an amount of 7 moles with respect to 1 mole of 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropanoate.
The asymmetric hydrogenation reaction may be carried out at any suitable temperature; for example, the reaction is carried out at about 0 degrees celsius or below 100 degrees celsius; in some embodiments, the reaction is performed at about 40, 60, or 80 degrees celsius.
The reaction of the present invention is carried out by monitoring the end point of the reaction by High Performance Liquid Chromatography (HPLC), and the reaction is considered to be completed when the HPLC purity of the compound of formula (IV), 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate, is less than or equal to 5%, and the reaction time is usually 15 to 80 hours depending on the substrate and the catalyst.
After the reaction is finished, the reaction solution is washed by water, and the solvent is removed by reduced pressure distillation, thus obtaining the product (2S,3R) -3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-hydroxy propionate (V).
The invention also provides a synthetic method of the droxidopa by taking the asymmetric hydrogenation reaction as a key step. The method comprises the following steps:
(a) in an organic solvent, 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate represented by formula (IV)
In the presence of a catalytic amount of a ruthenium catalyst (VII)
Or catalytic amount of ruthenium catalyst (VIII)
In the presence of a hydrogen donor reagent and an organic base,
wherein, the first and the second end of the pipe are connected with each other,
R 1 is represented by C 1-4 Alkyl or benzyl;
R 2 is represented by C 1-6 Alkyl, optionally substituted C 1-6 Alkyl, phenyl, or optionally substituted phenyl;
R 3 、R 4 each independently represents phenyl or substituted phenyl, or R 3 、R 4 Together represent butylene;
ar is a ligand selected from the group consisting of benzene, optionally substituted benzene, cyclopentadiene, optionally substituted cyclopentadiene;
p represents oxygen, a chemical bond or CH 2 ；
Q represents hydrogen or alkyl.
(b) Hydrolyzing the compound shown in the formula (V) in a mixed solvent of an organic solvent and water under the action of an inorganic base to prepare (2S,3R) -3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-hydroxypropionic acid shown in the formula (VI),
(c) the compound shown in the formula (VI) and hydrogen are subjected to hydrogenation reaction in a water-soluble organic solvent under the action of aqueous hydrochloric acid and Pd/C to prepare the droxidopa shown in the formula (IX),
wherein, the first and the second end of the pipe are connected with each other,
the organic solvent in step (b) may be any suitable organic solvent; in some embodiments, the organic solvent is tetrahydrofuran;
the inorganic base in step (b) may be any suitable inorganic base; for example, the inorganic base may be an alkali metal hydroxide or a hydrate thereof; in some embodiments, the inorganic base is sodium hydroxide;
the organic solvent in step (c) may be any suitable organic solvent; for example, the organic solvent can be methanol, ethanol, isopropanol, tetrahydrofuran, or a combination thereof; in some embodiments, the organic solvent is ethanol, isopropanol;
in step (c), the aqueous hydrochloric acid solution may be of any suitable concentration; for example, the concentration of the aqueous hydrochloric acid solution may be 0 to 12 mol/L; in some embodiments, the aqueous hydrochloric acid solution has a concentration of 3mol/L, 5 mol/L;
the hydrogen pressure in step (c) may be any suitable pressure; for example, the hydrogen pressure may be 1 to 50 atm; in some embodiments, the hydrogen pressure is 1atm, 30 atm.
In some embodiments, the 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate represented by formula (IV) described in step (a)
The preparation method comprises the following steps:
(a) preparation of intermediate 3- (3, 4-dibenzyloxyphenyl) -3-oxopropionate (II);
the intermediate 3- (3, 4-dibenzyloxyphenyl) -3-oxopropanoate (II) can be prepared by the following method in step (a1) or (a 2); (a1) the compound 3, 4-dibenzyloxybenzoic acid (I) generates an intermediate 3, 4-dibenzyloxybenzoyl chloride (I-a) under the action of thionyl chloride, the intermediate (I-a) reacts with Meldrum's acid under the action of alkali to generate an intermediate 5- (3, 4-dibenzyloxybenzoyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone (I-b), and the intermediate (I-b) and a structure R 1 Alcohol reaction of OH to prepare intermediate 3- (3, 4-dibenzyloxyphenyl) -3-oxopropionate (II) having the following reaction formula:
(a2) the compound 3, 4-dibenzyloxy benzoic acid (I) generates an intermediate 3, 4-dibenzyloxy benzoyl chloride (I-a) under the action of thionyl chloride, and the intermediate (I-a) reacts with potassium malonate monoester under the action of magnesium chloride and triethylamine to prepare an intermediate 3- (3, 4-dibenzyloxy phenyl) -3-oxopropionate (II), wherein the reaction formula is as follows:
(b) reaction of intermediate 3- (3, 4-dibenzyloxyphenyl) -3-oxopropionate (II) with a halogenating reagent to prepare intermediate 3- (3, 4-dibenzyloxyphenyl) -2-halo-3-oxopropionate (III) having the following structure
(c) The intermediate 3- (3, 4-dibenzyloxyphenyl) -2-halogeno-3-oxopropionate (III) reacts with dibenzylamine under the action of an acid-binding agent to prepare the intermediate 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate (IV) with the following structure
Wherein R is 1 As defined above; x is a halogen selected from chlorine, bromine or iodine.
Wherein the content of the first and second substances,
the halogenating agent in step (b) may be any suitable halogenating agent; for example, the halogenating agent may be sulfuryl chloride, N-chlorosuccinimide, N-bromosuccinimide, dibromohydantoin, bromine, or N-iodosuccinimide; in certain embodiments, the halogenating agent is sulfonyl chloride, N-bromosuccinimide, dibromohydantoin, N-iodosuccinimide;
the acid scavenger in step (c) may be any suitable organic or inorganic base; for example, the acid scavenger may be an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium acetate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, or combinations thereof, an organic base such as triethylamine, pyridine, N-diisopropylethylamine, N-methylmorpholine, or combinations thereof; in some embodiments, the acid-binding agent is potassium carbonate, sodium bicarbonate, triethylamine, pyridine, potassium acetate, diisopropylethylamine;
step (c) may be carried out at any suitable temperature; for example, the reaction temperature may be from 0 ℃ to 150 ℃; in some embodiments, the reaction temperature is room temperature, 58 ℃, 76 ℃, 100 ℃;
step (c) may be carried out in any suitable organic solvent; in some embodiments, the reaction solvent is N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, ethanol, or a combination thereof.
Compared with the prior art, the synthetic method of the droxidopa provided by the invention has the following advantages:
1. by using an asymmetric catalysis technology, two chiral centers of the droxidopa are introduced with high yield and high stereoselectivity in one step, so that the enantioselectivity (more than 98.5% ee) and the diastereoselectivity of a target product are both high (dr is more than 99: 1), and the theoretical yield is improved to 100% from 25% of the original resolution process;
2. the raw materials are cheap and easy to obtain, the reaction operation is simple, and the reaction under harsh conditions is avoided;
3. the protecting groups of phenolic hydroxyl and amino are unified into benzyl, so that not only can all the protecting groups be removed at one time, the operation is saved and the production efficiency is improved, but also the protecting mode is a key factor for ensuring high stereoselectivity, and if the benzyl of the amino protecting group is replaced, the asymmetric hydrogenation reaction cannot have high stereoselectivity. Therefore, the technology is more green and efficient and meets the requirement of industrial production.
Drawings
Figure 1 is a synthetic route to droxidopa.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means h, g means g, ml means ml, atm means standard atmospheric pressure, PE means petroleum ether, EA means ethyl acetate, DCM means dichloromethane, 1 h NMR refers to nuclear magnetic hydrogen spectrum, LCMS refers to liquid chromatography-mass spectrometry, HPLC refers to high performance liquid chromatography, CDCl 3 Refers to deuterated chloroform.
EXAMPLE 13 preparation of methyl (3, 4-dibenzyloxyphenyl) -3-oxopropanoate (II-A)
Adding 200g of compound 3, 4-dibenzyloxybenzoic acid (I) into a reaction bottle, dissolving with 1000mL of dichloromethane, and dropwise adding 120g of thionyl chloride at room temperature; stirring and refluxing at 40 ℃ to obtain a clear solution for later use. 87g N, N-dimethylaminopyridine and 76.3g of Meldrum's acid are added into another reaction bottle, the mixture is dissolved by 500mL of dichloromethane, the solution is dripped at 30 ℃ and reacts at 30 ℃ for 24 hours, the solution is washed by 2000mL of 1mol/L diluted hydrochloric acid after the reaction is finished, the dichloromethane is removed by organic phase decompression and concentration, 1000mL of methanol is added into the residue, and the temperature is raised to reflux reaction for 5 hours. After the reaction, the temperature is reduced to 0 ℃, solid is separated out, and 131g of white solid is obtained by suction filtration and washing, and the yield is 56%.
Example 23 preparation of ethyl (3, 4-bis (benzyloxy) phenyl) -3-oxopropanoate (II-B)
Adding 50g of compound 3, 4-dibenzyloxybenzoic acid (I) into a reaction bottle, dissolving with 300mL of tetrahydrofuran, and dropwise adding 40g of thionyl chloride at room temperature; stirring at 40 deg.C to obtain clear acyl chloride solution. In another flask were added 50g of potassium monoethyl malonate and 500mL of tetrahydrofuran. And adding 35g of anhydrous magnesium chloride and 40g of triethylamine, stirring for 2 hours at 30 ℃, dropwise adding the acyl chloride solution, reacting for 24 hours at 30 ℃ after the addition is finished, adding 500mL of 1mol/L diluted hydrochloric acid after the reaction is finished, extracting with 200mL of ethyl acetate, concentrating organic phase under reduced pressure to obtain a light yellow oily substance, and pulping with ethanol water to obtain 56.7g of a white solid with the yield of 93.6%.
Example 33 preparation of benzyl (3, 4-bis (benzyloxy) phenyl) -3-oxopropanoate (II-C)
Adding 10g of compound 3, 4-dibenzyloxybenzoic acid (I) into a reaction bottle, dissolving with 100mL of tetrahydrofuran, and dropwise adding 10g of thionyl chloride at room temperature; stirring at 40 deg.C to obtain clear acyl chloride solution. Another flask was charged with 15g of potassium monobenzyl malonate and 100mL of tetrahydrofuran. Then 7g of anhydrous magnesium chloride and 10g of triethylamine are added, the mixture is stirred for 2 hours at 30 ℃, the acyl chloride solution is dripped, the mixture reacts for 2 hours at 30 ℃ after the acyl chloride solution is added, 100mL of 1mol/L diluted hydrochloric acid is added after the reaction is finished, the mixture is extracted by 100mL of ethyl acetate, and the organic phase is concentrated under reduced pressure to obtain 11.2g of light yellow oily matter with the yield of 80.2%.
Example 43 preparation of tert-butyl (3, 4-bis (benzyloxy) phenyl) -3-oxopropanoate (II-D)
Adding 33g of compound I into a reaction bottle, dissolving with 120mL of tetrahydrofuran, and dropwise adding 20g of thionyl chloride at room temperature; stirring at 40 ℃ to give a clear acyl chloride solution, concentrating under reduced pressure to remove tetrahydrofuran, and dissolving the residue in 50mL of tetrahydrofuran. Another flask was charged with 23g of t-butyl acetate and 100mL of tetrahydrofuran. Dropping 120mL of lithium diisopropylamide tetrahydrofuran solution at the temperature of minus 20 ℃, stirring for 0.5 hour after the dropping, dropping the acyl chloride solution, heating to 30 ℃ after the dropping for reacting for 8 hours, adding 200mL of 1mol/L diluted hydrochloric acid after the reaction is finished, extracting with 200mL of ethyl acetate, and concentrating the organic phase under reduced pressure to obtain 42.1g of light yellow solid with the yield of 97.3 percent.
Example preparation of methyl 53- (3, 4-bis (benzyloxy) phenyl) -2-chloro-3-oxopropanoate (III-A)
80g of methyl 3- (3, 4-dibenzyloxyphenyl) -3-oxopropanoate (II-A) was added to a reaction flask, dissolved in 250mL dichloromethane, 29g of sulfonyl chloride was added at room temperature, and the reaction was stirred for 10 h. After the reaction, 200mL of a saturated aqueous solution of sodium bicarbonate was added, followed by liquid separation and organic phase concentration under reduced pressure to give 84g of foamy III-A with a yield of 99.0%.
Example preparation of ethyl 63- (3, 4-bis (benzyloxy) phenyl) -2-bromo-3-oxopropanoate (III-B)
57g of ethyl 3- (3, 4-bis (benzyloxy) phenyl) -3-oxopropanoate (II-B) was added to a reaction flask, dissolved in 150mL of dichloromethane, and 36g N-bromosuccinimide was added thereto at room temperature, followed by stirring and reacting for 24 hours. After the reaction, 500mL of a saturated aqueous solution of sodium bisulfite was added, and the mixture was separated, and the organic phase was concentrated under reduced pressure to obtain 63.1g of III-B, i.e., 93.1% yield.
Example 73 preparation of benzyl- (3, 4-bis (benzyloxy) phenyl) -2-bromo-3-oxopropanoate (III-C)
To a reaction flask were added 75mL of toluene and 9.3g of benzyl 3- (3, 4-bis (benzyloxy) phenyl) -3-oxopropionate (II-C), and the mixture was dissolved by stirring, and 2.57g of dibromohydantoin was added at room temperature, followed by reaction for 16 hours under incubation. After the reaction, 100mL of a saturated aqueous solution of sodium bisulfite was added, followed by liquid separation and organic phase concentration under reduced pressure to obtain 10.6g of III-C with a yield of 97.2%.
Example 83 preparation of tert-butyl (3, 4-bis (benzyloxy) phenyl) -2-iodo-3-oxopropanoate (III-D)
120ml of toluene and 22g of tert-butyl 3- (3, 4-bis (benzyloxy) phenyl) -3-oxopropanoate (II-D) as a compound were put into a reaction flask, dissolved by stirring, and 11g N-iodosuccinimide was added thereto at room temperature, followed by incubation for 4 hours. After the reaction, 200mL of a saturated aqueous solution of sodium bisulfite was added, followed by liquid separation and organic phase concentration under reduced pressure to obtain 20.9g of III-D with a yield of 75%.
Example preparation of methyl 93- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate (IV-A)
To a reaction flask were added 500mL of N, N-dimethylformamide, 80g of 3- (3, 4-bis (benzyloxy) phenyl) -methyl 2-chloro-3-oxopropanoate (III-A), and 40g of dibenzylamine, followed by stirring to dissolve, addition of 28g of potassium carbonate at room temperature, and reaction with incubation for 48 hours. After the reaction was completed, 500mL of water was added, extraction was performed twice with 300mL of ethyl acetate, the combined organic phases were evaporated to dryness under reduced pressure, and the residue was recrystallized from methanol to give 76.4g of compound IV-A with a yield of 68.54%.
Example preparation of ethyl 103- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate (IV-B)
To a reaction flask were added 350mL of acetonitrile, 50g of ethyl 3- (3, 4-bis (benzyloxy) phenyl) -2-bromo-3-oxopropanoate (III-B) and 40mL of dibenzylamine, and after stirring and dissolution, 12.6g of sodium hydrogencarbonate was added at room temperature, and the mixture was refluxed for 24 hours. After the reaction is finished, the temperature is reduced to room temperature, 500mL of water is added, 250mL of ethyl acetate is used for extraction twice, organic phases are combined and evaporated to dryness under reduced pressure, and residues are recrystallized by normal hexane to obtain 50.2g of a compound IV-B with the yield of 81.1%.
EXAMPLE 113 preparation of (IV-B) of ethyl (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate
Adding 50mL of acetonitrile, 5g of 3- (3, 4-bis (benzyloxy) phenyl) -2-bromo-3-oxopropanoic acid ethyl ester (III-B) and 4mL of dibenzylamine into a reaction bottle, stirring to dissolve, adding 1mL of triethylamine at room temperature, and heating to reflux for 5 hours; after the reaction is finished, cooling to room temperature, adding 50mL of water, extracting twice with 25mL of ethyl acetate, combining organic phases, evaporating to dryness under reduced pressure, and recrystallizing residues with n-hexane to obtain 5.9g of a compound IV-B with the yield of 95%.
Example 123 preparation of benzyl (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate (IV-C)
To a reaction flask were added 50mL of DMSO, 4g of benzyl 3- (3, 4-bis (benzyloxy) phenyl) -2-bromo-3-oxopropanoate (III-C), and 2.4mL of dibenzylamine, and after stirring and dissolution, 3mL of pyridine was added at room temperature, and the mixture was heated to 100 ℃ to react for 5 hours. After the reaction is finished, the temperature is reduced to room temperature, 50mL of water is added, 25mL of ethyl acetate is used for extraction twice, organic phases are combined and evaporated to dryness under reduced pressure, and the residue is eluted by column chromatography with PE/EA/DCM (50: 1: 2.5) to obtain the yield of 3.5gIV-C of 74.8%.
1 H NMR(400MHz，CDCl 3 )δ7.52-7.18(m，23H)，7.18-7.08(m，4H)，6.83(d，J＝8.5Hz，1H)，5.36(d，J＝12.2Hz，1H)，5.22(s，2H)，5.19(d，J＝12.3Hz，1H)，5.05(q，J＝11.7Hz，2H)，4.94(s，1H)，3.89(q，J＝13.6Hz，4H).
Example 133 preparation of tert-butyl (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate (IV-D)
120mL of 95 ethanol, 20g of 3- (3, 4-bis (benzyloxy) phenyl) -2-iodo-3-oxopropanoic acid tert-butyl ester (III-D), and 15mL of dibenzylamine were added to a reaction flask, and after stirring and dissolving, 7.0g of potassium acetate was added thereto at room temperature, and the mixture was allowed to react at 78 ℃ for 2 hours. After the reaction is finished, cooling to room temperature, adding 120mL of water, precipitating a solid, performing suction filtration, and washing the obtained solid with 50mL of 1: 1 ethanol aqueous solution to obtain 17.5g of IV-D with the yield of 78%.
Example 143 preparation of ethyl (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate (IV-B)
50mL of acetone, 10g of ethyl 3- (3, 4-bis (benzyloxy) phenyl) -2-bromo-3-oxopropanoate (III-B) and 6mL of dibenzylamine were added to a reaction flask, and after stirring and dissolving, 5mL of diisopropylethylamine was added thereto at room temperature, and the mixture was allowed to react at 56 ℃ for 8 hours. After the reaction, the temperature is reduced to room temperature, 100mL of water is added, solid is separated out and filtered, and the obtained solid is washed by water to obtain 8.9g of a compound IV-B with the yield of 74.2%.
Example 15 preparation of methyl (2S,3R) -3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-hydroxypropionate (V-A)
4-Methylpropylphenylruthenium dichloride [ RuCl ] was added in sequence to a Schlenk flask 2 (p-Cymene)] 2 (250mg), N- ((1R, 2R) -2-amino-1, 2-diphenyl ethyl) methanesulfonamide MsDPEN (270mg), 0.5mL triethylamine and 10mL isopropanol, wherein the whole reaction system is replaced by nitrogen for 3 times, the temperature is increased to 80 ℃ for reaction for 1 hour to obtain a catalyst VII-A solution, and the temperature is reduced to room temperature for later use.
22.5g of methyl 3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate (IV-A), 200mL of LPCM and 38mL of triethylamine were added to the reaction flask, the temperature was reduced to 0 ℃ and then 45mL of formic acid was added slowly, after which the reaction was started by warming to 40 ℃ under nitrogen. The reaction was carried out for about 60 hours with the sampling being controlled and the reaction was complete. Washing the reaction liquid twice with water, decompressing and distilling to eliminate solvent to obtain V-A product, and purifying the residue with column chromatography to obtain white solid with yield of 75%, diastereoselectivity of 98 to 2 and ee over 98%.
1 HNMR(400MHz，CDCl 3 )δ7.44-7.32(m，20H)，6.83(d，J＝8.0，1H)，6.75-6.72(m，2H)，5.10(s，2H)，5.02-4.95(m，2H)，4.92(d，J＝8.1，1H)，4.24(s，1H)，4.18(s，1H)，4.09-4.03(m，1H)，3.68(s，3H)，3.54(d，J＝11.9，2H)，3.42(d，J＝11.9，1H).
[M+H] + (LCMS)＝588.3
Example 16 preparation of ethyl (2S,3R) -3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-hydroxypropionate (V-B)
4-Methylpropylphenylruthenium dichloride [ RuCl ] was added in sequence to a Schlenk flask 2 (p-Cymene)] 2 (1.38g), N- ((1R, 2R) -2-amino-1, 2-diphenylethyl) trifluoromethanesulfonamide TfDPEN (1.55g), 3mL of triethylamine and 30mL of isopropanol, replacing the whole reaction system with nitrogen for 3 times, heating the reaction system to 80 ℃, reacting for 1 hour to obtain a catalyst VII-B solution, and cooling to room temperature for later use.
50g of ethyl 3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate (IV-B), 500mL of LPCM and 140mL of triethylamine were added to the reaction flask, the temperature was reduced to 0 ℃ and then 100mL of formic acid was added slowly, after which the reaction was started by heating to 40 ℃ under nitrogen. The reaction was carried out for about 35 hours with the sampling being controlled and the reaction was complete. The reaction solution is washed twice with water, and the solvent is removed by reduced pressure distillation to obtain brown solid V-B, the yield is 85%, the diastereoselectivity of the product V-B is 99: 1, and ee is more than 98.5%.
1 H-NMR(400MHz，CDCl 3 )δ7.45-7.31(m，20H)，6.83(d，J＝8.0，1H)，6.76-6.73(m，2H)，5.12(s，2H)，5.04-4.95(m，2H)，4.90(d，J＝8.0，1H)，4.24(s，1H)，4.21-4.14(m，3H)，4.09-4.03(m，1H)，3.52(d，J＝12.0，2H)，3.40(d，J＝12.0，1H)，1.21(t，J＝8.0，3H).
[M+H] + (LCMS)＝602.3
Example 17 preparation of ethyl (2S,3R) -3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-hydroxypropionate (V-B)
In a Schlenk flask, phenylruthenium dichloride [ RuCl ] was added in sequence 2 (benzene)] 2 (118mg), N- ((1R, 2R) -2-amino-1, 2-diphenylethyl) trifluoromethanesulfonamide TfDPEN (150mg), 0.5mL of diisopropylethylamine and 5mL of isopropanol, replacing the whole reaction system with nitrogen for 3 times, heating the reaction system to 80 ℃, reacting for 1 hour to obtain a catalyst VII-G solution, and cooling to room temperature for later use.
2.5g of ethyl 3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate (IV-B), 50mL of toluene and 8mL of diisopropylethylamine were added to the reaction flask, the temperature was reduced to 0 deg.C, 10mL of formic acid was added slowly, and after the addition was complete, the reaction was started by warming to 80 deg.C under nitrogen. The reaction was carried out for about 40 hours with the sampling being controlled and the reaction was complete. The reaction solution is washed twice with water, and the solvent is removed by reduced pressure distillation to obtain brown solid V-B with yield of 79 percent, diastereoselectivity of the product V-B is 95: 5, ee is between 90.5 percent.
Example 18 preparation of ethyl (2S,3R) -3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-hydroxypropionate (V-B)
10.0g of ethyl 3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate (IV-B), 552mg of catalyst VIII-A, 80mL of dichloromethane and 1.6g of diethylamine were added to a 250mL reaction flask, the temperature was reduced to 0 deg.C, 2.5g of formic acid was slowly added, and after the addition, the reaction was started by heating to 40 deg.C under nitrogen. The reaction was sampled and controlled in about 39 hours with 100% conversion. The reaction solution was washed twice with water, and the solvent was removed by distillation under reduced pressure to give V-B as a brown solid in 99% yield with a diastereoselectivity of 99: 1 for the product V-B of 99.1% ee.
EXAMPLE 19 preparation of benzyl (2S,3R) -3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-hydroxypropionate (V-C)
4-Methylpropylphenylruthenium dichloride [ RuCl ] was added in sequence to a Schlenk flask 2 (p-Cymene)] 2 (2.5mg), N- ((1R, 2R) -2-amino-1, 2-diphenyl ethyl) -2, 3,4, 5, 6-pentafluorobenzene sulfonamide pentaF-DPEN (3.5mg), 0.1mL of triethylamine and 1mL of isopropanol, replacing the whole reaction system with nitrogen for 3 times, heating the reaction system to 80 ℃, reacting for 1 hour to obtain a catalyst VII-E solution, and cooling to room temperature for later use.
3g of benzyl 3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-oxopropanoate (IV-C), 20mL of LPCM and 7mL of triethylamine were added to the flask, the temperature was reduced to 0 ℃ and then 5mL of formic acid was added slowly, after which the reaction was started by heating to 40 ℃ under nitrogen. The reaction was sampled and controlled in about 80 hours with a conversion of 33%. Washing the reaction liquid twice with water, decompressing and distilling to eliminate solvent, column chromatographic separation to obtain brown solid V-C with diastereoselectivity over 99 to 1 and ee over 99%.
1 H NMR(400MHz，CDCl 3 )δ7.49-7.11(m，25H)，6.79-6.61(m，3H)，5.17-5.03(m，3H)，5.01-4.79(m，4H)，4.08(t，J＝11.4Hz，2H)，3.80(s，1H)，3.40(t，J＝11.4Hz，3H).
[M+H] + (LCMS)＝663.3
EXAMPLE 20 preparation of (2S,3R) -3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-hydroxypropionic acid (VI)
41g of ethyl (2S,3R) -3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-hydroxypropionate (V-B) was added to a reaction flask, and dissolved in 400mL of tetrahydrofuran, 54g of NaOH and 500mL of water were added, and the mixture was stirred at room temperature and reacted for 6 hours; after the reaction is finished, the pH value is adjusted to 6-7 by using dilute hydrochloric acid, the mixture is extracted for 2 times by using 300ml of dichloromethane, organic phases are combined, and the solvent is removed by evaporation under reduced pressure to obtain 35g of yellow solid VI with the yield of 91.4%.
1 H NMR(400MHz，CDCl3)δ7.41-7.15(m，20H)，6.73(t，J＝10.5Hz，3H)，5.00(s，3H)，4.89(dd，J＝22.6，11.8Hz，2H)，4.00(d，J＝13.1Hz，2H)，3.67(d，J＝13.2Hz，2H)，3.46(d，J＝8.4Hz，1H).
[M+H] + (LCMS)＝574.3
EXAMPLE 21 preparation of droxidopa (IX)
4.2g of (2S,3R) -3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-hydroxypropionic acid (VI), 50mL of ethanol and 3M HCl solution were added to a stainless steel autoclave, and the mixture was stirred at room temperature to clear the reaction solution, followed by addition of 1g of Pd/C, H 2 Displacing 3 times, reacting at 30atm H 2 Stirring at room temperature for 2 hr to react completely, filtering to remove palladium and carbon, and adding Et 3 And adjusting the pH value to about 6 by N, precipitating a solid, and filtering to obtain 1.5g of droxidopa with the yield of 96%.
1 H NMR(400MHz，DMSO)δ8.72(s，1H)，6.76(s，1H)，6.62(dd，J＝23.2，7.4Hz，2H)，4.86(d，J＝3.5Hz，1H)，3.23(d，J＝3.7Hz，1H).
[M+H] + (LCMS)＝214.1
EXAMPLE 22 preparation of droxidopa (IX)
20g of (2S,3R) -3- (3, 4-bis (benzyloxy) phenyl) -2-dibenzylamino-3-hydroxypropionic acid (VI), 200mL of isopropanol, and 5M HCl solution were added to a stainless steel autoclave, and the mixture was stirred at room temperature to clear the reaction solution, followed by addition of 5g of Pd/C, H 2 Replacement 3 times, reaction at 1atm H 2 Stirring and reacting for 12 hours at room temperature under the atmosphere; the reaction is completed, palladium carbon is removed by filtration, and Et is used 3 Adjusting the pH value to about 6 by N, separating out solid, and filtering to obtain 7.0g of droxidopa, wherein the yield is 94.2%.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (20)
1. A process for preparing (2S,3R) -3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-hydroxypropionate represented by the formula (V),
wherein R is 1 Is C 1-4 Alkyl or benzyl;
the method is characterized by comprising the following steps:
in an organic solvent, 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate represented by formula (IV)
Wherein R is 1 As defined above;
in a catalytic amount of ruthenium catalyst (VII)
Or a catalytic amount of ruthenium catalyst (VIII)
In the presence of a hydrogen donor reagent, which is formic acid, and an organic base, wherein,
R 1 as defined above;
R 2 is represented by C 1-6 Alkyl, fluorine optionally substituted C 1-6 Alkyl, phenyl, or phenyl optionally substituted with fluoro, trifluoromethyl or methyl;
R 3 、R 4 each independently represents phenyl, or R 3 、R 4 Together represent butylene;
ar is selected from benzene, isopropyl toluene or cyclopentadiene;
p represents oxygen, a chemical bond or CH 2 ；
Q represents hydrogen or alkyl.
2. The method of claim 1, said R 1 Is methyl, ethyl, tert-butyl or benzyl.
3. The method of claim 1, said R 2 Is methyl, p-methylphenyl, p-trifluoromethylphenyl, pentafluorophenyl, trifluoromethyl or perfluorobutyl.
4. The method of claim 1, said R 3 、R 4 And is simultaneously phenyl.
5. The process of claim 1, wherein Ar is benzene or p-cymene.
6. The method of claim 1, wherein Q is hydrogen or methyl.
7. The process of claim 1, wherein the ruthenium catalyst has the structure of one of:
8. the method of claim 1, wherein the organic solvent is selected from the group consisting of dichloromethane, toluene, N-dimethylformamide, tetrahydrofuran, and combinations thereof.
9. The method of claim 1, wherein the organic base is diethylamine, diisopropylamine, dicyclohexylamine, triethylamine, N-diisopropylethylamine, or a combination thereof.
10. The process of claim 1, wherein the ruthenium catalyst is used in an amount of 0.1 to 0.001 mol with respect to 1mol of 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate (V).
11. The method of claim 1, wherein the organic base is used in an amount of 1 to 10 moles with respect to 1 mole of 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate (V).
12. A method of preparing droxidopa comprising the steps of:
(a) the preparation method of (2S,3R) -3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-hydroxypropionate shown in the formula (V) according to the claim 1
Wherein R is 1 Is C 1-4 Alkyl or benzyl;
(b) hydrolyzing the compound shown in the formula (V) in a mixed solvent of an organic solvent and water under the action of an inorganic base to prepare (2S,3R) -3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-hydroxypropionic acid shown in the formula (VI),
(c) the compound shown in the formula (VI) and hydrogen are subjected to hydrogenation reaction in a water-soluble organic solvent under the action of aqueous hydrochloric acid and Pd/C to prepare the droxidopa shown in the formula (IX)
13. The process of claim 12, wherein the organic solvent in step (b) is tetrahydrofuran.
14. The process of claim 12, wherein the inorganic base in step (b) is an alkali metal hydroxide or a hydrate thereof.
15. The process of claim 12, wherein the water-soluble organic solvent in step (c) is selected from methanol, ethanol, isopropanol, tetrahydrofuran, or a combination thereof.
16. A method of preparing droxidopa comprising the steps of:
(a) the compound 3, 4-dibenzyloxybenzoic acid (I) generates an intermediate 3, 4-dibenzyloxybenzoyl chloride (I-a) under the action of thionyl chloride, the intermediate (I-a) reacts with Meldrum's acid under the action of alkali to generate an intermediate 5- (3, 4-dibenzyloxybenzoyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone (I-b), and the intermediate (I-b) and a structure R 1 The intermediate 3- (3, 4-dibenzyloxyphenyl) -3-oxopropionate (II) is obtained by reacting OH with alcohol, and the reaction formula is as follows:
(b) the intermediate 3- (3, 4-dibenzyloxyphenyl) -3-oxo propionate (II) reacts with a halogenating reagent to prepare the intermediate 3- (3, 4-dibenzyloxyphenyl) -2-halogeno-3-oxo propionate (III),
(c) the intermediate 3- (3, 4-dibenzyloxyphenyl) -2-halogeno-3-oxo propionate (III) reacts with dibenzyl amine under the action of an acid-binding agent to prepare the intermediate 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxo propionate (IV),
(d) preparing droxidopa according to the process of claim 12 using intermediate 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate (IV) as substrate;
wherein X is chlorine, bromine or iodine; r 1 Is C 1-4 Alkyl or benzyl.
17. A method of preparing droxidopa comprising the steps of:
(a) the compound 3, 4-dibenzyloxy benzoic acid (I) generates an intermediate 3, 4-dibenzyloxy benzoyl chloride (I-a) under the action of thionyl chloride, the intermediate (I-a) reacts with malonic acid monoester potassium salt under the action of magnesium chloride and triethylamine to prepare an intermediate 3- (3, 4-dibenzyloxy phenyl) -3-oxo propionate (II), and the reaction formula is as follows:
(b) the intermediate 3- (3, 4-dibenzyloxyphenyl) -3-oxopropionate (II) reacts with a halogenating reagent to prepare an intermediate 3- (3, 4-dibenzyloxyphenyl) -2-halogeno-3-oxopropionate (III),
(c) the intermediate 3- (3, 4-dibenzyloxyphenyl) -2-halogeno-3-oxo propionate (III) reacts with dibenzylamine under the action of an acid-binding agent to prepare the intermediate 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxo propionate (IV),
(d) preparing droxidopa according to the process of claim 12, using as substrate the intermediate 3- (3, 4-dibenzyloxyphenyl) -2-dibenzylamino-3-oxopropionate (IV);
wherein X is chlorine, bromine or iodine; r is 1 Is C 1-4 Alkyl or benzyl.
18. The process of claim 16 or 17, wherein the halogenating agent in step (b) is selected from sulfonyl chloride, N-chlorosuccinimide, N-bromosuccinimide, dibromohydantoin, bromine, N-iodosuccinimide, or a combination thereof.
19. The process of claim 16 or 17, wherein the acid scavenger in step (c) is selected from an organic base or an inorganic base, wherein the inorganic base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium acetate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, or a combination thereof, and the organic base is selected from triethylamine, pyridine, N-diisopropylethylamine, N-methylmorpholine, or a combination thereof.
20. The process of claim 16 or 17, step (c) the reaction solvent is selected from N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, ethanol, or a combination thereof.
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