CN112110828A - Synthesis method of pipadiric acid and intermediate thereof - Google Patents
Synthesis method of pipadiric acid and intermediate thereof Download PDFInfo
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Abstract
The invention discloses a new intermediate compound 6 and a new intermediate compound 7 of pipadiric acid, and also discloses a synthesis method of the pipadiric acid, wherein the method shortens the route steps, provides the yield, reduces the process cost, improves the structure of the pipadiric acid intermediate, improves the crystallization performance of the pipadiric acid intermediate, is beneficial to improving the purity of the final product, and is suitable for large-scale production. The structural formulas of compound 6 and compound 7 are shown below:
wherein, -N (R)2)2Represented by N, N-dimethylamino, cyclohexylamino, morpholinyl or amino;
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a chemical synthesis method of a novel oral lipid-lowering drug, namely, bipedac acid.
Background
Bempedific acid (code ETC-1002) is a non-statin, once-a-day, oral drug for LDL-C reduction developed by Esperio thermal, USA. Within 2 months of 2020, the united states Food and Drug Administration (FDA) approved the use of biperidic acid in heterozygous patients with familial hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD), providing an important new and complementary oral drug option that is less expensive and convenient for use in ASCVD patients or high risk groups, particularly those intolerant to statins, who need additional LDL-C reduction.
The chemical name of beipai di is: 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedioic acid. The structural formula is as follows:
the existing synthetic route is as reported in WO2004067489, ethyl isobutyrate is used as a starting material, is subjected to hydrogen removal action by LDA and then is in butt joint with 1, 5-dibromopentane to obtain 7-bromo-2, 2-dimethylheptanoic acid ethyl ester, is subjected to 2+1 condensation with p-toluenesulfonylmethyl isonitrile under the action of sodium hydride under the catalysis of TBAI, is subjected to acidolysis to obtain 2,2,14, 14-tetramethyl-8-oxopentadecanedioic acid diethyl ester, is subjected to alkaline hydrolysis and acidification to obtain 2,2,14, 14-tetramethyl-8-oxopentadecanedioic acid, and is finally reduced by sodium borohydride to obtain the product of the betimeric acid.
The synthetic route is as follows:
the synthetic method has a long route, the yield of the alkylation reaction of the ethyl isopropoxide and the dibromopentane which are used as starting materials is low, 2+1 condensation is easy to occur, and the obtained dicarboxylic ester by-product is not easy to remove in subsequent reactions, so that the purity of the final product is influenced; the price of the raw material of the p-toluenesulfonyl methylisonitrile is high, sodium hydride is required for the condensation reaction, the process is dangerous to amplify and operate, and the yield is low; the intermediate generated by p-toluenesulfonylmethyl isonitrile needs strong acid to hydrolyze, the atom economy is poor and more waste is generated; the carbonyl reduction reaction needs a large amount of sodium borohydride, the reduction yield is low, the process and the post-treatment operation are complicated, and the danger coefficient is large. Generally speaking, the route has too many steps, low total yield, complex process operation, higher production cost of products and more three wastes, and is not suitable for large-scale production.
The synthetic route reported in indian Lupin pharmaceutical patent WO2020141419 is: the intermediate is obtained by 1+2 condensation of diethyl 1, 3-acetonedicarboxylate and ethyl 6-bromo-2, 2-dimethylhexanoate under the action of magnesium diethoxide, the intermediate can be subjected to alkaline hydrolysis under the condition of heating or not heating to obtain a ketone intermediate corresponding to the budesonide acid or ester, and finally the carbonyl is reduced by sodium borohydride to obtain the budesonide acid, the yields of alkylation and complete alkaline hydrolysis are not disclosed, but the total yield is not too high from the result of partial hydrolysis to ethyl ester (the yield is only 42.2%).
The synthetic route is as follows:
chinese patent CN111170855A also reports a similar synthetic method: the method is basically consistent with that of Indian company, but changes the condensation conditions, obtains the betadienoic acid ketone intermediate by heating and alkaline hydrolysis in one step, and finally obtains the target product by reducing with sodium borohydride.
Although these two methods greatly simplify the synthesis route of the bipartite acid, these routes still have certain drawbacks for scale-up production: the ester group of the 6-bromo-2, 2-dimethyl ethyl hexanoate has certain reactivity, and can easily generate acylation reaction with 1, 3-diethyl acetonedicarboxylate, and the side reaction of the double alkylation reaction is more; the total yield of alkylation and alkaline hydrolysis reaction is lower, and the amplification production cost is higher; the intermediate obtained by alkylation has poor crystallization performance and is difficult to purify and separate, and some viscous byproducts cannot be removed from the system in time, so that the purification difficulty of the final product is high; the carbonyl reduction reaction needs to use sodium borohydride with larger equivalent, the post-treatment has certain danger and more three wastes, and a low-cost and high-efficiency green synthetic route of the bipartite acid still needs to be researched.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a synthesis method of pipadiric acid, which has the advantages of simple process route, low cost and suitability for industrial production.
One of the purposes of the invention is to provide a synthesis method of a pipadiric acid intermediate compound 5, which adopts the following scheme:
a synthesis method of a betulic acid intermediate compound 5 comprises the following steps:
(1) carrying out condensation reaction on the compound 1 and the compound 2 under the action of alkali to obtain a compound 3;
(2) carrying out condensation reaction on the obtained compound 3 and the compound 4 under the action of alkali to obtain an intermediate compound 5;
in the chemical formula, EWG is N, N-dimethylaminoacyl, cyclohexylamino acyl, morpholinyl acyl or cyano; x is chlorine, bromine, iodine, methylsulfonyloxy or p-toluenesulfonyloxy; r1Is methyl, ethyl, tert-butyl or benzyl.
Further, the base in the condensation reaction of the step (1) is selected from n-butyl lithium, LDA, sodium tert-butoxide, potassium tert-butoxide or LiHMDS; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran; the reaction temperature is-78-50 ℃.
Further, the base in the condensation reaction of step (2) is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine; no catalyst is added or sodium iodide, potassium iodide, TBAB, TBAI or benzyltriethylammonium chloride is added as a catalyst; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene; the reaction temperature is-20 to 150 ℃.
The invention also aims to provide a pipadiric acid intermediate compound 6, which has the following structural formula:
wherein, -N (R)2)2Represented by N, N-dimethylamino, cyclohexylamino, morpholinyl or amino.
The invention also aims to provide a synthesis method of the intermediate compound 6 of the piparidic acid, which adopts the following technical scheme:
a synthesis method of a betulic acid intermediate compound 6 comprises the steps of carrying out acidolysis on an intermediate compound 5 under the action of acid to obtain the intermediate compound 6;
in the chemical formula, EWG represents N, N-dimethylaminoacyl, cyclohexylamino acyl, morpholinyl acyl or cyano; r1Is methyl, ethyl, tert-butyl or benzyl; -N (R)2)2Represented by N, N-dimethylamino, cyclohexylamino, morpholinyl or amino.
Further, the acidolysis reaction acid in the step is selected from methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid or hydrochloric acid; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, acetic acid, tetrahydrofuran, methanol, ethanol, isopropanol, 1, 4-dioxane or water; the reaction temperature is 0-80 ℃.
The fourth purpose of the invention is to provide a pipadiric acid intermediate 7, which has the following structural formula:
wherein, M is inorganic base or organic base including sodium, potassium, calcium, cyclohexanediamine or morpholine.
The fifth purpose of the invention is to provide a synthesis method of a pipadiric acid intermediate compound 7, which adopts the following technical scheme:
the method comprises the following steps:
a synthesis method of a betulic acid intermediate compound 7 comprises the steps of heating, carrying out acidolysis and salifying an intermediate compound 5 under the action of acid to obtain the intermediate compound 7;
in the chemical formula, EWG represents N, N-dimethylaminoacyl, cyclohexylamino acyl, morpholinyl acyl or cyano; r1Is methyl, ethyl, tert-butyl or benzyl.
Further, the acidolysis reaction acid in the step is selected from phosphoric acid, sulfuric acid or hydrochloric acid; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, acetic acid, ethanol, isopropanol, 1, 4-dioxane or water; the reaction temperature is 70-130 ℃; the salt-forming base is selected from sodium hydroxide, potassium hydroxide, calcium chloride, dicyclohexylamine or morpholine; the salifying temperature is-20 to 60 ℃.
The second method comprises the following steps:
a synthesis method of a betulic acid intermediate compound 7 comprises the steps of heating, carrying out acidolysis and salifying an intermediate compound 6 under the action of acid to obtain the intermediate compound 7;
in the formula, -N (R)2)2Represented by N, N-dimethylamino, cyclohexylamino, morpholinyl or amino.
Further, the acidolysis reaction acid in the step is selected from phosphoric acid, sulfuric acid or hydrochloric acid; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, acetic acid, ethanol, isopropanol, 1, 4-dioxane or water; the reaction temperature is 70-130 ℃; the salt-forming base is selected from sodium hydroxide, potassium hydroxide, calcium chloride, dicyclohexylamine or morpholine; the salifying temperature is-20 to 60 ℃.
The invention aims at providing a method for preparing the bipedal acid by an enzyme catalytic reduction method, which adopts the following technical scheme:
a method for preparing the betimeric acid by an enzyme catalytic reduction method comprises the following steps of reacting an intermediate compound 7 with carbonyl reductase and a reducing agent to obtain a betimeric acid product 9:
in the chemical formula, M is represented by inorganic base or organic base, and comprises sodium, potassium, calcium, cyclohexanediamine or morpholine.
Further, the carbonyl reductase is selected from horse liver alcohol dehydrogenase, iditol dehydrogenase and pig liver alcohol dehydrogenase; the coenzyme is NADP or NADPH; the reducing agent reagent is selected from ethanol, isopropanol or glucose; the selected reaction system is DMSO, acetone, ethanol, isopropanol or water and the mixed solution thereof; the selected buffer is potassium phosphate, monopotassium phosphate, dipotassium phosphate, sodium phosphate, monosodium phosphate, disodium phosphate or Tris-HCl; the reaction temperature is 20-40 ℃.
The seventh purpose of the invention is to provide another synthesis method of the pipidilic acid, which adopts the following technical scheme:
a synthesis method of pipadiric acid comprises the following steps:
(1) reducing carbonyl of the intermediate compound 6 under the action of a reducing agent to obtain a compound 8;
(2) acidolyzing the compound 8 under the action of acid to obtain a beipai acid product 9;
in the formula, N (R)2)2Represented by N, N-dimethylamino, cyclohexylamino, morpholinyl or amino.
Further, the reducing reaction reducing agent in the step (1) is selected from lithium borohydride, sodium borohydride or potassium borohydride; the reaction solvent is selected from dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate or toluene; the reaction temperature is-20 to 80 ℃.
Further, the acidolysis reaction acid in the step (2) is selected from phosphoric acid, sulfuric acid or hydrochloric acid; n, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, acetic acid, ethanol, isopropanol, 1, 4-dioxane, or water; the reaction temperature is 70-130 ℃.
The eighth purpose of the invention is to provide a synthesis method of pipadiric acid, which adopts the following technical scheme:
a synthesis method of pimelic acid comprises the steps that a compound 1 is used as a starting material and condensed with a compound 2 to obtain a compound 3, then the compound 3 and a compound 4 are efficiently condensed to obtain a double-alkylated intermediate compound 5 through 2+1, the intermediate compound 5 is subjected to complete acidolysis under a heating condition, and then a crude product is subjected to alkalization salt formation and purification to obtain a compound 7; or the intermediate compound 5 is partially hydrolyzed and decarboxylated under mild heating condition to obtain a compound 6, and the compound 6 is continuously subjected to acidolysis and salification to obtain a compound 7; finally, the compound 7 is subjected to enzyme-catalyzed carbonyl reduction reaction to obtain a compound 9 of the product of the pimelic acid;
or the compound 6 is reduced by carbonyl to obtain a compound 8, and finally, the compound is subjected to acid hydrolysis to obtain a betimeric acid product 9.
The route is as follows:
the synthesis method comprises the following steps: the compound 3 obtained by alkylating the compound 1 has higher reaction yield, the amide or cyano group stability is better than that of an ester group, the alkali selection range is wider, the double-alkylation by-products of the compound 2 are fewer, the double-alkylation by-products can be removed by treating with a dilute alkali solution, and in addition, the deep cooling reaction condition can be avoided for part of substrates, so that the amplification production and the cost reduction are facilitated; the intermediate compound 3 takes part in 2+1 condensation by replacing ester with amide, so that the generation of acetylated by-products of the compound 4 is reduced, and the product purity is improved; the intermediate compound 5, the compound 6, the compound 7 and the compound 8 have better crystallization performance, are easy to crystallize and separate out in various solvents, and are beneficial to separation and purification; the water-soluble salt compound 7 is used for participating in the catalytic carbonyl reduction reaction, so that the method is efficient and green, and has less three wastes. In general, the method shortens the route steps, improves the route yield, reduces the process cost, improves the structure of the intermediate of the pipa acid, improves the crystallization performance of the intermediate, is favorable for improving the purity of the final product, is suitable for scale-up production, provides various selectable intermediates for the synthesis of the pipa acid by selective acidolysis of the compound 5, and provides more choices for industrial production.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
Adding the compound 1a (11.52g,100mmol) and 57mL of tetrahydrofuran into a three-neck flask, stirring and dissolving, cooling to the internal temperature of about-70 to-65 ℃ at low temperature, slowly dropping n-butyllithium solution (1M,105mL,105mmol), keeping the temperature and stirring for 0.5 hour after dropping, then dropping 2a of tetrahydrofuran solution (21.59g,100mmol, dissolved in 57mL of tetrahydrofuran), stirring uniformly, and naturally heating to 20-30 ℃ for reaction for 2-3 hours. After the reaction, dilute hydrochloric acid (5%, 115mL) was added, ethyl acetate (115mL) was added and extracted 3 times, and the combined organic phases were washed with brine 2 times, dried, filtered, concentrated, and distilled under reduced pressure to give compound 3a (19.64g, 78.6%). MS (ESI) M/z 250.1[ M + H ]]+
In example 1 tetrahydrofuran may be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile or 2-methyltetrahydrofuran; the n-butyllithium may be replaced by LDA, sodium tert-butoxide, potassium tert-butoxide or LiHMDS.
By the method of example 1, when the compound 2a is 1.4 dichlorobutane 2e, the compound 3e is obtained
When compound 2a is 1.4 diiodobutane 2f to give compound 3f
When the compound 2a is
When 2g is obtained, 3g of the compound is obtained
When the compound 2a is
2b, compound 3h is obtained
Example 2
Adding the compound 1b (15.72g,100mmol) and 78mL of tetrahydrofuran into a three-neck flask, stirring and dissolving, cooling to the internal temperature of about-70 to-65 ℃ at low temperature, slowly dropping LDA solution (1M,105mL,105mmol), keeping the temperature and stirring for 0.5 hour after dropping, then dropping 2a of tetrahydrofuran solution (21.59g,100mmol, dissolved in 77mL of tetrahydrofuran), stirring uniformly, and naturally heating to 20-30 ℃ for reaction for 2-3 hours. After the reaction, dilute hydrochloric acid (5%, 156mL) was added, ethyl acetate (156mL) was added and extracted 3 times, and the combined organic phases were washed with brine 2 times, dried, filtered, concentrated, and distilled under reduced pressure to give compound 3b (23.00g, 78.7%). MS (ESI) 292.0[ M + H ] M/z]+
In example 2 tetrahydrofuran can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile or 2-methyltetrahydrofuran; LDA can be replaced by n-butyl lithium, sodium tert-butoxide, potassium tert-butoxide or LiHMDS.
Following the method of example 2, when compound 2a is 1.4 dichlorobutane 2e, compound 3e 'is obtained'
When the compound 2a is 1.4 diiodobutane 2f, the compound 3f 'is obtained'
When the compound 2a is
When 2g are obtained, the compound is obtained in an amount of 3 g'
When the compound 2a is
2b to obtain a compound of 3 h'
Example 3
Adding the compound 1c (15.52g,100mmol) and 77mL of tetrahydrofuran into a three-neck flask, stirring and dissolving, cooling to the internal temperature of about-15 to-10 ℃ at low temperature, slowly adding LiHMDS (1M toluene solution, 105mL), keeping the temperature and stirring for 0.5 hour after the addition is finished, then dropwise adding 2a of tetrahydrofuran solution (21.59g,100mmol, dissolved in 77mL of tetrahydrofuran), stirring uniformly, and naturally heating to 0-5 ℃ for reaction for 2-3 hours. After the reaction, dilute hydrochloric acid (5%, 155mL) was added, ethyl acetate (154mL) was added and extracted 3 times, and the combined organic phases were washed with brine 2 times, dried, filtered, concentrated, and distilled under reduced pressure to give compound 3c (23.02g, 79.3%).
MS(ESI)m/z＝290.0[M+H]+
In example 3 tetrahydrofuran can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile or 2-methyltetrahydrofuran; LiHMDS can be replaced by n-butyl lithium, LDA, sodium tert-butoxide, or potassium tert-butoxide.
According to implementationThe procedure of example 3, when Compound 2a is 1.4 dichlorobutane 2e, gives compound 3e "
When the compound 2a is 1.4 diiodobutane 2f, the compound 3f is obtained "
When the compound 2a is
At 2g, 3g of the compound is obtained "
When the compound 2a is
2b, give the compound 3h "
Example 4
Adding the compound 1d (6.91g,100mmol) and 69mL of tetrahydrofuran into a three-neck flask, stirring for dissolving, cooling to an internal temperature of about-15 to-10 ℃ at a low temperature, slowly adding LiHMDS (1M toluene solution, 105mL), keeping the temperature and stirring for 0.5 hour after the addition is finished, then dropwise adding 2b of tetrahydrofuran solution (39.85g,100mmol, dissolved in 69mL of tetrahydrofuran), stirring uniformly, and naturally heating to 0-5 ℃ for reacting for 2-3 hours. After the reaction, dilute hydrochloric acid (5%, 140mL) was added, ethyl acetate (140mL) was added for extraction 3 times, the organic phases were combined, washed with brine 2 times, dried, filtered, concentrated, heated to 50-55 ℃, n-heptane (140mL) was added, slowly cooled to 0-5 ℃, filtered, and dried to obtain compound 3d (22.51g, 76.2%).
MS(ESI)m/z＝318.1[M+Na]+
Example 4 tetrahydrofuran can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile or 2-methyltetrahydrofuran; LiHMDS can be replaced by n-butyl lithium, LDA, sodium tert-butoxide, or potassium tert-butoxide.
Following the method of example 4, when compound 2b is 1.4 dichlorobutane 2e, compound 3 e'
When the compound 2b is 1.4 diiodobutane 2f, the compound 3 f'
When the compound 2b is
At 2g, 3g 'of a compound is obtained'
When the compound 2b is
2a to obtain a compound of 3 h'
Example 5
A three-necked flask was charged with compound 3a (50.04g,200mmol), compound 4a (17.42g,100mmol) and acetonitrile (174mL), stirred to dissolve, then added with TBAB (3.22g,10mmol) and cesium carbonate (65.17g,200mmol), stirred well and heated to 55-60 ℃ for reaction overnight. After the reaction, water (300mL) was added, ethyl acetate (174mL) was added for extraction 2 times, the organic phases were combined, washed with brine for 2 times, concentrated, added with methanol (85mL) and water (340mL), heated to 50-55 ℃ and slowly cooled for crystallization, and a large amount of solid was precipitated, filtered and dried to obtain compound 5a (38.50g, 75.1%).
MS(ESI)m/z＝535.2[M+Na]+
In example 5, the cesium carbonate can be replaced by potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine; the solvent acetonitrile can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene; sodium iodide, potassium iodide, TBAB, TBAI or benzyltriethylammonium chloride can be added as catalyst during the reaction.
By the method of example 5, compound 3a can be replaced with 3e, 3f, 3g and 3h, and the methyl group in compound 4a can be replaced with ethyl, tert-butyl or benzyl, to give the corresponding compound
Wherein R is ethyl, tert-butyl or benzyl respectively.
Example 6
A three-neck flask was charged with compound 3b (58.44g,200mmol), compound 4b (20.22g,100mmol) and N-methylpyrrolidone (150mL), stirred to dissolve, added with TBAB (3.22g,10mmol) and sodium carbonate (31.80g,300mmol), stirred well and heated to 55-60 ℃ for reaction overnight. After the reaction, water (300mL) was added, ethyl acetate (150mL) was added for extraction 3 times, the organic phases were combined, washed with saturated brine 2 times, dried, filtered, concentrated, added with petroleum ether (400mL), cooled and crystallized, and a large amount of solid was precipitated, filtered and dried to obtain compound 5b (49.48g, 79.2%).
MS(ESI)m/z＝625.2[M+H]+
In example 6, the sodium carbonate can be replaced by cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine; the solvent N-methylpyrrolidone can be replaced by acetonitrile, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene; sodium iodide, potassium iodide, TBAB, TBAI or benzyltriethylammonium chloride can be added as catalyst during the reaction.
By the method of example 6, compound 3b can be replaced by 3e ', 3 f', 3g 'and 3 h', and the ethyl group in compound 4b can be replaced by methyl, tert-butyl or benzyl, to give the corresponding compound
Wherein R is methyl, tert-butyl or benzyl respectively.
Example 7
A three-neck flask is added with compound 3c (58.04g,200mmol), compound 4c (25.83g,100mmol) and N, N-dimethylformamide (150mL), stirred to dissolve, added with TBAB (3.22g,10mmol) and potassium carbonate (41.46g,300mmol), stirred uniformly and heated to 55-60 ℃ for reaction overnight. After the reaction, water (300mL) was added, ethyl acetate (150mL) was added for extraction 3 times, the organic phases were combined, washed with brine 2 times, dried, filtered, concentrated, added with petroleum ether (400mL), cooled and crystallized, and a large amount of solid was precipitated, filtered and dried to obtain Compound 5c (57.95g, 85.6%).
MS(ESI)m/z＝677.4[M+H]+
In example 7, the potassium carbonate may be replaced by sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine; the solvent N, N-dimethylformamide can be replaced by N-methylpyrrolidone, acetonitrile, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene; TBAB may be omitted or replaced with sodium iodide, potassium iodide, TBAI or benzyltriethylammonium chloride.
By the method of example 7, compound 3c can be replaced by 3e ", 3 f", 3g "and 3 h", and the tert-butyl group in compound 4c can be replaced by ethyl, methyl or benzyl, to give the corresponding compound
Wherein R is each independentlyMethyl, ethyl or benzyl.
Example 8
A three-necked flask was charged with compound 3d (59.08g,200mmol), compound 4a (17.42g,100mmol) and N, N-dimethylformamide (180mL), and after stirring and dissolution, sodium iodide (3.22g,10mmol) and potassium carbonate (41.46g,300mmol) were added, and after stirring, the mixture was heated to 55 to 60 ℃ for reaction overnight. After the reaction, water (360mL) was added, ethyl acetate (180mL) was added for extraction 3 times, the organic phases were combined, washed with brine 2 times, dried, filtered, concentrated, added with petroleum ether (400mL), cooled and crystallized, and a large amount of solid was precipitated, filtered and dried to obtain compound 5d (34.19g, 81.3%).
MS(ESI)m/z＝443.2[M+Na]+
In example 8, the potassium carbonate may be replaced by sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine; the solvent N, N-dimethylformamide can be replaced by N-methylpyrrolidone, acetonitrile, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene; sodium iodide may be omitted or replaced by TBAB, potassium iodide, TBAI or benzyltriethylammonium chloride.
According to the method of example 8, compound 3d can be replaced by 3e '", 3 f'", 3g '"and 3 h'", and the methyl group in compound 4a can be replaced by ethyl, methyl tert-butyl or benzyl, to give the corresponding compound
Wherein R is tert-butyl, ethyl or benzyl respectively.
Example 9
Adding a compound 5a (51.27g,100mmol) and formic acid (255mL) into a three-neck flask, uniformly stirring, adding dilute sulfuric acid (20%, 255g), heating to 90-95 ℃ for reaction for 10-16 hours, concentrating to remove part of solvent after the reaction is finished, adding water (255mL), diluting and stirring, adding ethyl acetate (200mL), extracting for 3 times, combining organic phases, washing for 3 times, concentrating, adding ethanol (312mL), slowly adding a 20% sodium hydroxide solution (40mL,200mmol), heating to 50-55 ℃ after the addition is finished, slowly cooling to room temperature, pulping, filtering and drying to obtain a product 7a (31.11g, 80.5%).
In example 9, dilute sulfuric acid can be replaced by phosphoric acid or hydrochloric acid; formic acid can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetic acid, ethanol, isopropanol, 1, 4-dioxane or water; the sodium hydroxide can be replaced by potassium hydroxide, calcium chloride, dicyclohexylamine or morpholine.
Following the procedure of example 9, Compound 5a can be used
Wherein R is ethyl, tert-butyl or benzyl, and salified sodium hydroxide is replaced by sodium hydroxide, potassium hydroxide, calcium chloride, dicyclohexylamine or morpholine to obtain the compound
M is potassium, calcium, cyclohexanediamine or morpholine.
Example 10
Adding a compound 5b (62.48g,100mmol) and acetic acid (312mL) into a three-neck flask, uniformly stirring, adding concentrated hydrochloric acid (36%, 101g), heating to 85-90 ℃ for reacting for 8-10 hours, concentrating to remove part of solvent after the reaction is finished, adding water (312mL), stirring, adding ethyl acetate (200mL), extracting for 3 times, combining organic phases, washing for 3 times, concentrating to remove part of ethyl acetate, slowly adding dicyclohexylamine (36.26g,200mmol), heating to 50-55 ℃ after the addition is finished, slowly cooling to room temperature, pulping, filtering and drying to obtain a product 7b (62.54g, 88.7%).
1H NMR(400MHz,CDCl3)2.81(s,4H),2.39(t,J＝7.2Hz,4H),1.99(s,8H),1.80(s,8H),1.72–1.58(m,8H),1.55–1.47(m,4H),1.38–1.21(m,26H),1.20–1.12(m,14H).
In example 10, concentrated hydrochloric acid may be replaced with dilute sulfuric acid or phosphoric acid; the solvent acetic acid can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, ethanol, isopropanol, 1, 4-dioxane or water; dicyclohexylamine may be replaced with sodium hydroxide, potassium hydroxide, calcium chloride, or morpholine.
Following the procedure of example 10, Compound 5b can be used
Wherein R is methyl, tert-butyl or benzyl respectively, salified dicyclohexylamine is replaced by sodium hydroxide, potassium hydroxide, calcium chloride or morpholine, and the compound can be obtained
M is sodium, potassium, calcium or morpholine.
Example 11
Adding a compound 5c (67.70g,100mmol) and acetic acid (312mL) into a three-neck flask, uniformly stirring, adding concentrated hydrochloric acid (36%, 101g), heating to 65-70 ℃, reacting for 8-10 hours, concentrating after the reaction is finished, removing part of solvent, adding water (312mL), stirring, adding ethyl acetate (200mL), extracting for 3 times, combining organic phases, concentrating, adding ethyl acetate (312mL), slowly adding morpholine (17.42g,200mmol), heating to 50-55 ℃, slowly cooling to 0 ℃, pulping, filtering and drying to obtain a product 7c (46.76g, 90.5%).
In example 11, concentrated hydrochloric acid may be replaced with dilute sulfuric acid or phosphoric acid; the solvent acetic acid can be replaced by tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, ethanol, isopropanol, 1, 4-dioxane or water; morpholine may be replaced by sodium hydroxide, potassium hydroxide, calcium chloride or dicyclohexylamine.
Following the procedure of example 11, Compound 5c can be used
Wherein R is methyl, ethyl or benzyl respectively, salified dicyclohexylamine is replaced by sodium hydroxide, potassium hydroxide, calcium chloride or morpholine, and the compound can be obtained
M is sodium, potassium, calcium or dicyclohexylamine.
Example 12
Adding a compound 5b (62.48g,100mmol) and tetrahydrofuran (312mL) into a three-neck flask, uniformly stirring, adding sulfuric acid (20%, 300g), heating to 40-45 ℃, reacting for 6-8 hours, concentrating to remove part of solvent after the reaction is finished, adding water (312mL), stirring, adding ethyl acetate (200mL), extracting for 3 times, combining organic phases, washing for 1 time, concentrating, heating to 55-60 ℃, adding n-heptane (312mL), slowly cooling, pulping, filtering and drying to obtain a product 6b (40.62g, 84.5%).
MS(ESI)m/z＝481.2[M+H]+
1HNMR(CD3Cl,400MHz)3.61-3.69(m,16H),2.38(t,J＝7.2Hz,4H),1.51-1.61(m,8H),1.24-1.32(m,8H),1.25(s,12H)。
In example 12, the sulfuric acid can be replaced by methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid or hydrochloric acid; tetrahydrofuran can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, acetic acid, methanol, ethanol, isopropanol, 1, 4-dioxane or water.
Following the procedure of example 12, Compound 5b can be used
Wherein R is methyl, tert-butyl or benzyl respectivelyInstead, compound 6b was prepared.
Example 13
Adding compound 5d (42.05g,100mmol) and ethanol (210mL) into a three-neck flask, uniformly stirring, adding concentrated hydrochloric acid (36%, 100g), heating to 40-45 ℃, reacting for 6-8 hours, concentrating to remove part of solvent after the reaction is finished, adding water (210mL), stirring, slowly cooling, pulping, filtering and drying to obtain product 6d (29.86g, 87.7%). MS (ESI) M/z 363.2[ M + Na ]]+
1HNMR(DMSO-d6,400MHz)6.97(br,2H),6.70(br,2H),2.36(t,J＝7.2Hz,4H),1.33-1.47(m,8H),1.08-1.22(m,8H),1.02(s,12H)；
In example 13, the hydrochloric acid can be replaced by methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid or sulfuric acid; the ethanol can be replaced by tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, acetic acid, methanol, isopropanol, 1, 4-dioxane or water.
Following the procedure of example 13, Compound 5d can be used
Wherein, R is tert-butyl, ethyl or benzyl respectively to prepare the compound 6 d.
Example 14
Adding a compound 6b (48.07g,100mmol) and ethyl acetate (240mL) into a three-neck flask, uniformly stirring, adding sodium borohydride (3.78g,100mmol), reacting at room temperature for 4-6 hours, slowly adding diluted hydrochloric acid to neutralize until no bubbles emerge after the reaction is finished, stirring, separating liquid, extracting the water phase for 2 times by using ethyl acetate (120mL), combining organic phases, washing for 1 time by using water, concentrating to a small volume, heating to 55-60 ℃, slowly adding petroleum ether (240mL), slowly cooling, pulping, filtering and drying to obtain a product 8b (44.64g, 92.5%).
MS(ESI)m/z＝483.3[M+H]+
1HNMR(CD3Cl,400MHz)3.62-3.69(m,16H),3.52-3.60(m,1H),2.38(t,J＝7.2Hz,4H),1.53-1.61(m,4H),1.36-1.47(m,4H),1.24-1.47(m,10H),1.25(s,12H)；
In example 14, sodium borohydride can be replaced by lithium borohydride or potassium borohydride; the ethyl acetate can be replaced by dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate or toluene.
Example 13
Adding a compound 6d (34.05g,100mmol) and absolute ethyl alcohol (170mL) into a three-neck flask, uniformly stirring, adding sodium borohydride (3.78g,100mmol), reacting at room temperature for 4-6 hours, slowly adding diluted hydrochloric acid to neutralize until no bubbles emerge after the reaction is finished, stirring, separating liquid, extracting the water phase for 2 times by using ethyl acetate (100mL), combining the organic phase, washing for 1 time, concentrating to a small volume, heating to 55-60 ℃, slowly adding petroleum ether (200mL), slowly cooling, pulping, filtering and drying to obtain a product 8d (32.30g, 94.3%).
MS(ESI)m/z＝365.3[M+Na]+
1HNMR(DMSO-d6,400MHz)6.96(br,2H),6.70(br,2H),4.19(d,J＝5.2Hz,1H),1.09-1.43(m,20H),1.02(s,12H)；
In example 15, sodium borohydride can be replaced by lithium borohydride or potassium borohydride; the ethanol can be replaced by ethyl acetate, dichloromethane, methanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate or toluene.
Example 15
Adding a compound shown in formula 7a (38.64g,100mmol) into a three-neck flask under the protection of nitrogen, adding isopropanol (116mL) and water (386mL), stirring for full dissolution, adding Tris & HCl to adjust the pH value to 6.9-7.1, adding horse liver alcohol dehydrogenase (100mg) and NADH (0.6g) after the addition, and reacting for 16-24 hours at the temperature of 32 +/-0.5 ℃. And after the reaction is finished, adding ethyl acetate (116mL) for extraction, separating, collecting a water phase, adding 0.5M diluted hydrochloric acid to adjust the pH value to 3-4, separating out a solid, filtering and collecting a crude product, adding ethyl acetate (60mL), adding n-heptane (240mL), heating to 50-55 ℃, stirring, slowly cooling to 0-5 ℃, filtering and drying to obtain a product 6, collecting a solid, and drying to obtain a product 7(32.49g, 91.1% and 99.8% purity).
In example 15, horse liver alcohol dehydrogenase can be replaced by iditol dehydrogenase or pig liver alcohol dehydrogenase; the coenzyme NADP can be replaced by NADPH; the reducing agent reagent isopropanol can be replaced by ethanol or glucose; the isopropanol here also acts as a solvent, and the buffer Tris. HCl can be replaced by potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate or disodium hydrogen phosphate.
By the method of example 15, 7a useful compound
Where M is potassium, calcium, cyclohexanediamine or morpholine, to give compound 9.
Example 16
Adding a compound 8b (48.27g,100mmol) and absolute ethyl alcohol (240mL) into a three-neck flask, uniformly stirring, adding dilute sulfuric acid (20%, 240g), heating to 70-80 ℃, reacting for 16-20 hours, concentrating to remove most of solvent after the reaction is finished, slowly cooling and pulping, filtering to collect a crude product, adding absolute ethyl alcohol (60mL), adding water (300mL), heating to 50-55 ℃, stirring, slowly cooling to 0-5 ℃, filtering and drying to obtain a product 9(22.66g, 92.4%, 99.7% purity)
In example 16, sulfuric acid may be replaced with phosphoric acid, or hydrochloric acid; the reaction solvent ethanol can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, acetic acid, isopropanol, 1, 4-dioxane or water.
Following the procedure of example 16, Compound 8b can be used
In place of, wherein N (R)2)2Expressed as N, N-dimethylamino, cyclohexylamino or amino, to give compound 9.
Example 17
Adding a compound 8d (34.25,100mmol) and formic acid (170mL) into a three-neck flask, uniformly stirring, adding dilute sulfuric acid (20% and 170g), heating to 70-80 ℃ for reaction for 16-20 hours, concentrating after the reaction is finished to remove most of solvent, slowly cooling and pulping, filtering to collect a crude product, adding absolute ethyl alcohol (60mL), adding water (300mL), heating to 50-55 ℃, stirring, slowly cooling to 0-5 ℃, filtering and drying to obtain a product 9(32.27g, 93.5% and 99.8% in purity)
In example 17, sulfuric acid may be replaced with phosphoric acid, or hydrochloric acid; the reaction solvent formic acid can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, ethanol, isopropanol, 1, 4-dioxane or water.
Following the procedure of example 16, Compound 8d can be used
In place of, wherein N (R)2)2Represented by N, N-dimethylamino, cyclohexylamino or morpholinyl to give compound 9.
Claims (10)
1. A synthesis method of a pipadiric acid intermediate compound 5 is characterized by comprising the following steps:
(1) carrying out condensation reaction on the compound 1 and the compound 2 under the action of alkali to obtain a compound 3;
(2) carrying out condensation reaction on the obtained compound 3 and the compound 4 under the action of alkali to obtain an intermediate compound 5;
in the chemical formula, EWG is N, N-dimethylaminoacyl, cyclohexylamino acyl, morpholinyl acyl or cyano; x is chlorine, bromine, iodine, methylsulfonyloxy or p-toluenesulfonyloxy; r1Is methyl, ethyl, tert-butyl or benzyl.
2. The method for synthesizing the intermediate compound 5 of budesonide according to claim 1, wherein the base in the condensation reaction of step (1) is selected from n-butyllithium, LDA, sodium tert-butoxide, potassium tert-butoxide, or LiHMDS; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran; the base in the condensation reaction in the step (2) is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine and diisopropylethylamine; no catalyst is added or sodium iodide, potassium iodide, TBAB, TBAI or benzyltriethylammonium chloride is added as a catalyst; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene.
3. A pipadidic acid intermediate compound 6 and a synthesis method thereof, wherein the structural formula of the compound 6 is as follows:
wherein, -N (R)2)2Expressed as N, N-dimethylamino, cyclohexylaminoMorpholinyl or amino;
the synthesis method of the compound 6 comprises the steps of carrying out acidolysis on the intermediate compound 5 under the action of acid to obtain an intermediate compound 6;
in the chemical formula, EWG represents N, N-dimethylaminoacyl, cyclohexylamino acyl, morpholinyl acyl or cyano; r1Is methyl, ethyl, tert-butyl or benzyl; -N (R)2)2Represented by N, N-dimethylamino, cyclohexylamino, morpholinyl or amino.
4. The process for the synthesis of bethydric acid intermediate compound 6 as claimed in claim 3, wherein said step acidolysis reaction acid is selected from methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid or hydrochloric acid; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, acetic acid, tetrahydrofuran, methanol, ethanol, isopropanol, 1, 4-dioxane or water.
5. A betadiic acid intermediate 7 has the following structural formula:
wherein M is inorganic base or organic base, including sodium, potassium, calcium, cyclohexanediamine or morpholine.
6. A synthesis method of a betulic acid intermediate compound 7 is characterized in that the first method comprises the steps of heating, acidolysis and salifying an intermediate compound 5 under the action of acid to obtain the intermediate compound 7;
in the chemical formula, EWG is N, N-dimethylaminoacyl, cyclohexylamino acyl, morpholinyl acyl or cyano; r1Is methyl, ethyl, tert-butyl or benzyl; m is an inorganic or organic base, including sodium, potassium, calcium, cyclohexanediamine or morpholine;
or the second method comprises heating the intermediate compound 6 under the action of acid for acidolysis and salifying to obtain an intermediate compound 7;
in the formula, -N (R)2)2Represented by N, N-dimethylamino, cyclohexylamino, morpholinyl or amino.
7. The process for the synthesis of bethydric acid intermediate compound 7 as claimed in claim 6, wherein said first process acid hydrolysis reaction acid is selected from phosphoric acid, sulfuric acid or hydrochloric acid; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, acetic acid, ethanol, isopropanol, 1, 4-dioxane or water; the reaction temperature is 70-130 ℃; the salt-forming base is selected from sodium hydroxide, potassium hydroxide, calcium chloride, dicyclohexylamine or morpholine; the salifying temperature is-20-60 ℃; in the second method, the acid of the acidolysis reaction is selected from phosphoric acid, sulfuric acid or hydrochloric acid; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, formic acid, acetic acid, ethanol, isopropanol, 1, 4-dioxane or water; the reaction temperature is 70-130 ℃; the salt-forming base is selected from sodium hydroxide, potassium hydroxide, calcium chloride, dicyclohexylamine or morpholine; the salifying temperature is-20 to 60 ℃.
8. A method for preparing the pipadiric acid by an enzyme catalytic reduction method is characterized by comprising the following steps of reacting an intermediate compound 7 with carbonyl reductase and a reducing agent to obtain a pipadiric acid product 9:
in the chemical formula, M is represented by inorganic base or organic base and comprises sodium, potassium, calcium, cyclohexanediamine or morpholine.
9. A synthesis method of pipadiric acid is characterized by comprising the following steps:
(1) reducing carbonyl of the intermediate compound 6 under the action of a reducing agent to obtain a compound 8;
(2) acidolyzing the compound 8 under the action of acid to obtain a beipai acid product 9;
in the formula, -N (R)2)2Represented by N, N-dimethylamino, cyclohexylamino, morpholinyl or amino.
10. A synthesis method of pimelic acid is characterized in that a compound 1 is used as a starting material and condensed with a compound 2 to obtain a compound 3, then the compound 3 and a compound 4 are condensed with 2+1 at high efficiency to obtain a double-alkylated intermediate compound 5, the intermediate compound 5 is subjected to complete acidolysis under a heating condition, and then a crude product is subjected to alkalization salt-forming purification to obtain a compound 7; or the intermediate compound 5 is partially hydrolyzed and decarboxylated under mild heating condition to obtain a compound 6, and the compound 6 is continuously subjected to acidolysis and salification to obtain a compound 7; finally, the compound 7 is subjected to enzyme-catalyzed carbonyl reduction reaction to obtain a compound 9 of the product of the pimelic acid;
or the compound 6 is reduced by carbonyl to obtain a compound 8, and finally, the compound is subjected to acid hydrolysis to obtain a betulic acid product 9;
the route is as follows:
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