CN111039901B - Process for producing 1, 3-dicarbonyl compound and intermediate thereof - Google Patents
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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Abstract
The invention discloses a preparation method of a 1, 3-dicarbonyl compound and an intermediate thereof, and particularly discloses a preparation method of a compound shown as a formula I, which comprises the following steps: in a solvent, carrying out elimination reaction shown as the following on a compound shown as a formula II to obtain a compound shown as a formula I; wherein R is tert-butoxy, methoxy, ethoxy or methyl. The preparation method of the invention has lower cost and is beneficial to industrial production.
Description
Technical Field
The present invention relates to a process for producing a 1, 3-dicarbonyl compound and an intermediate thereof.
Background
Diabetes is a metabolic disease characterized by hyperglycemia accompanied by metabolic disorders of proteins, sugars, and fats, which occur due to altered insulin secretion, resulting in insulin deficiency and diminished action, or decreased insulin activity, or both. The degree of harm of diabetes and complications thereof to human health is the third place after cardiovascular diseases and tumors, and becomes an important disease harming human health. The international diabetes association predicts that by 2030, the total population will exceed 4.35 million people. However, china has become one of the countries with the fastest increase rate of the prevalence rate of diabetes in the world, about 4000 million diabetics currently live, and the number of the diabetics is second to Indian and second in the world. Of the four types of diabetes, type II diabetes accounts for over 90% of all the elderly over the age of 30 years, and the cause of the disease is mainly due to the body's insensitivity to insulin. In the medicines for clinically treating the type II diabetes mellitus, sitagliptin phosphate (Sitagliptin phosphate) is the first dipeptidyl enzyme-IV (DPP-4) inhibitor approved by FDA to be on the market in 2006, is used for treating the type II diabetes mellitus, has obvious blood sugar reducing effect when being used singly or used together with metformin and pioglitazone, and is safe to take, good in tolerance and less in adverse reaction. The trade name of the product is Jienovin (Januvia), the product is approved to be used in more than 60 countries in the world at present, the sales amount reaches $ 40.86 hundred million in 2012, and the sales amount is increased by 23 percent on year-by-year basis. Thus, sitagliptin phosphate is an internationally up-to-date and extremely value-added "heavy pound bomb".
Boc- (R) -3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid is an important intermediate for the preparation of sitagliptin,
U.S. Pat. No. 6,6699871 discloses a synthesis of Boc- (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid using chiral source to induce chiral alpha-amino acid, followed by diazotization to generate beta-amino acid to construct the desired chiral center. The raw material used in the route is chiral raw material, and dangerous diazomethane is needed to be used, so that the method is not suitable for industrial mass production.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of a 1, 3-dicarbonyl compound and an intermediate thereof, in particular to a preparation method of a compound shown as a formula I. The preparation method of the invention has lower cost and is beneficial to industrial production.
The invention provides a preparation method of a compound shown as a formula I, which comprises the following steps: in a solvent, carrying out elimination reaction shown as the following on a compound shown as a formula II to obtain a compound shown as a formula I;
wherein R is tert-butoxy, methoxy, ethoxy or methyl;
when R is tert-butoxy or methyl, the elimination reaction is carried out in the presence of an acid;
when R is methoxy or ethoxy, the elimination reaction is carried out in the presence of a base.
In some embodiments of the invention, R is tert-butoxy or methyl. In some embodiments of the invention, R is methyl. In some embodiments of the invention, R is tert-butoxy.
The conditions for the elimination reaction may be those conventional in the art for such reactions. Specifically, when R is t-butoxy, methoxy or ethoxy, the elimination reaction is decarboxylation. When R is methyl, the elimination reaction is deacylation. The following conditions are preferred in the present invention.
In the elimination reaction, the solvent may be an alcohol solvent, a mixed solvent of an alcohol solvent and water, or a chlorinated hydrocarbon solvent. When the elimination reaction is carried out in the presence of a base, the solvent may be an alcohol solvent, or a "mixed solvent of an alcohol solvent and water". The alcohol solvent in the alcohol solvent, the mixed solvent of the alcohol solvent and the water can be independently methanol and/or ethanol. The chlorinated hydrocarbon solvent may be dichloromethane. The amount of the solvent to be used may not be particularly limited as long as the reaction proceeds.
In the elimination reaction, the acid may be a protic acid (e.g., an inorganic protic acid such as HCl or H or an organic protic acid 2 SO 4 Organic protic acids, for example trifluoroacetic acid) or Lewis acids (for example nickel chloride, magnesium chloride, aluminum chloride, zinc chloride or iron chloride, again for example nickel chloride or magnesium chloride).
In some embodiments of the invention, when R is tert-butoxy in the elimination reaction, the acid is a protic acid (e.g., an inorganic protic acid such as HCl or H or an organic protic acid 2 SO 4 Organic protic acids such as trifluoroacetic acid).
In some embodiments of the invention, when R is methyl, the acid is a protic acid (e.g., an inorganic protic acid such as HCl or H or an organic protic acid) in the elimination reaction 2 SO 4 Organic protic acids such as trisFluoroacetic acid) or a Lewis acid (e.g., nickel chloride, magnesium chloride, aluminum chloride, zinc chloride, or ferric chloride, again such as nickel chloride or magnesium chloride).
In the elimination reaction, the molar ratio of the acid to the compound represented by formula II may be 1 to 60, for example 1 to 20. When the acid is a protic acid, the molar ratio of the protic acid to the compound of formula II may be from 1 to 60, for example from 1 to 20, and further from 3 to 4. When the acid is an organic protic acid, the molar ratio of the organic protic acid to the compound of formula II may be 1 to 60, for example 1 to 20, for example 40 to 50. When the acid is an inorganic protic acid, the molar ratio of the inorganic protic acid to the compound of formula II may be from 1 to 60, for example from 1 to 20.
In the elimination reaction, when the acid is a Lewis acid, the molar ratio of the Lewis acid to the compound represented by formula II may be 1 to 5, for example 1 to 2.
In the elimination reaction, the base may be an alkali metal hydroxide, such as sodium hydroxide.
In the elimination reaction, the molar ratio of the base to the compound represented by formula II may be 1 to 20, for example 2 to 3.
The reaction temperature for the elimination reaction may be a temperature conventional in the art for the same type of reaction (which may be adjusted by those skilled in the art depending on the reaction reagents), for example, 10 to 80 ℃. In some embodiments, when the elimination reaction is performed in the presence of a base, the reaction temperature of the elimination reaction may be the boiling temperature of the solvent (e.g., the boiling temperature of a "mixed solvent of an alcohol solvent and water").
The progress of the elimination reaction can be monitored by conventional assays in the art (e.g., TLC), and the end point is typically determined as the point at which the compound of formula II is no longer reacted. The reaction time of the elimination reaction can be 4 to 24 hours.
In some embodiments of the invention, in the elimination reaction, the R is tert-butoxy and the acid is an organic protic acid. In some embodiments of the invention, in the elimination reaction, R is t-butoxy, the acid is an organic protic acid, and the solvent is a chlorinated hydrocarbon solvent. In some embodiments of the invention, in the elimination reaction, the R is tert-butoxy, the acid is trifluoroacetic acid, and the solvent is dichloromethane. In some embodiments of the invention, in the elimination reaction, R is tert-butoxy, the acid is trifluoroacetic acid, the molar ratio of trifluoroacetic acid to the compound of formula II is 40 to 50, and the solvent is dichloromethane.
In some embodiments of the invention, in the elimination reaction, the R is methyl and the acid is an inorganic protic acid. In some embodiments of the present invention, in the elimination reaction, R is methyl, the acid is an inorganic protonic acid, and the solvent is a "mixed solvent of an alcohol solvent and water". In some embodiments of the present invention, in the elimination reaction, R is methyl, the acid is HCl, and the solvent is a "mixed solvent of an alcohol solvent and water". In some embodiments of the present invention, in the elimination reaction, R is methyl, the acid is HCl, the molar ratio of the acid to the compound represented by formula II is 3 to 4.
In some embodiments of the invention, in the elimination reaction, the R is methyl and the acid is a Lewis acid. In some embodiments of the invention, in the elimination reaction, the R is methyl, the acid is a Lewis acid, and the solvent is an alcoholic solvent. In some embodiments of the invention, in the elimination reaction, the R is methyl, the acid is magnesium chloride or nickel chloride, and the solvent is an alcoholic solvent. In some embodiments of the present invention, in the elimination reaction, R is methyl, the acid is magnesium chloride or nickel chloride, the molar ratio of the acid to the compound represented by formula II is 1 to 2.
The preparation method of the compound shown in the formula I can also comprise the following steps: in an organic solvent, carrying out substitution reaction shown as the following on a compound shown as a formula III and a compound shown as a formula IV in the presence of an organic base and a chelating agent to obtain a compound shown as a formula II;
wherein R is as defined above.
The conditions of the substitution reaction may be those conventional in the art for such reactions. The following conditions are preferred in the present invention.
In the substitution reaction, the organic solvent can be a chlorinated hydrocarbon solvent (such as dichloromethane) and/or a nitrile solvent (such as acetonitrile). The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the substitution reaction, the molar ratio of the compound shown in formula III to the compound shown in formula IV may be 1.
In the substitution reaction, the organic base may be a tertiary amine, such as triethylamine. The molar ratio of said organic base to said compound of formula IV may be from 1 to 3, for example from 1.2 to 2.
In the substitution reaction, the chelating agent can be one or more of magnesium chloride, calcium chloride and barium chloride. The molar ratio of the chelating agent to the compound of formula IV may be 1-2, for example 1.1-1.3.
In some embodiments of the invention, the chelating agent is magnesium chloride.
The reaction temperature of the substitution reaction may be 0 to 40 deg.C, for example 10 to 30 deg.C.
The progress of the substitution reaction can be monitored by conventional assays in the art (e.g., TLC), typically with the end point being that the compound of formula III is no longer reacted. The reaction time of the substitution reaction can be 10-24h.
In one embodiment of the present invention, in the substitution reaction, R is tert-butoxy, and the organic solvent is a nitrile solvent.
In one embodiment of the present invention, in the substitution reaction, R is methyl, and the organic solvent is a chlorinated hydrocarbon solvent.
In one embodiment of the present invention, in the substitution reaction, R is methoxy or ethoxy, and the organic solvent is a nitrile solvent.
The preparation method of the compound shown in the formula I can also comprise the following steps: in an organic solvent, carrying out an acyl chlorination reaction on a compound shown as a formula V and an acyl chlorination reagent as shown in the specification to obtain a compound shown as a formula III;
the reaction conditions for the acid chlorination reaction may be those conventional in the art for such reactions.
In the acyl chlorination reaction, the organic solvent can be a chlorinated hydrocarbon solvent, such as dichloromethane. The amount of the organic solvent may not be particularly limited as long as the reaction is not affected.
The acid chloride reagent may be thionyl chloride. The mole ratio of the acyl chlorination reagent to the compound of formula V may be 1.1-2.
The acyl chlorination reaction can also be added with a catalyst, and the catalyst can be DMF.
The reaction temperature of the acyl chlorination reaction can be 20-50 ℃.
The progress of the acid chlorination reaction may be monitored by conventional testing procedures (e.g., TLC) known in the art, and is generally determined by the end point of the reaction when the compound of formula IV is no longer reacted. The reaction time of the acyl chlorination reaction can be 4-10h.
The invention also provides a compound shown as a formula II or a tautomer thereof:
wherein R is tert-butoxy, methoxy, ethoxy or methyl.
The invention also provides a preparation method of the compound shown in the formula II, which comprises the following steps: in an organic solvent, carrying out substitution reaction shown as the following on a compound shown as a formula III and a compound shown as a formula IV in the presence of an organic base and a chelating agent to obtain a compound shown as a formula II;
wherein R is as defined above.
In the preparation method of the compound shown in the formula II, the reaction conditions of the substitution reaction can be as described above.
The term "tautomer" refers to the movement of an atom (e.g., proton) of a molecule from an original position to another position on the same molecule, a typical example being enol-keto tautomers (e.g., acetone and propen-2-ol).
The above preferred conditions may be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: a process for the preparation of 1, 3-dicarbonyl compounds and intermediates therefor are provided. The preparation method has low cost and is beneficial to industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1: preparation of Compound 2
Dissolving 2,4, 5-trifluorophenylacetic acid (10g, 52.60mmol) in dichloromethane (100 mL), adding thionyl chloride (8.7g, 63.12mmol) and N, N-dimethylformamide (0.1 mL), stirring at 40 ℃ for 6h under the protection of nitrogen; TLC showed the starting material disappeared and the reaction was complete. The reaction mixture was concentrated under reduced pressure, and toluene (10 mL) was added to remove residual thionyl chloride, followed by concentration again to obtain a pale yellow oil (10.97 g, yield 100%).
Example 2: preparation of Compound 4-1
Dissolving compound 3-1 (0.5g, 2.18mmol) in anhydrous acetonitrile (6 mL), adding magnesium chloride (0.25g, 2.62mmol) at 40 ℃ under the protection of nitrogen, and magnetically stirring at the temperature for 1h; the reaction was then cooled to 15 deg.C and TEA (0.44g, 4.36mmol) was slowly added dropwise; after the addition, the temperature is raised to 25 ℃, and the stirring is continued for 1 hour; then the reaction solution was cooled to 0 ℃ and 2,4, 5-trifluorophenylacetyl chloride (0.46g, 2.18mmol) was slowly added dropwise to the reaction solution; the temperature naturally increased to 25 ℃ after the addition was complete, the mixture was stirred for 169h and the reaction was complete on TLC plate. Then cooling the reaction solution to 0 ℃, adding saturated saline (20 mL) to quench the reaction, and adjusting the pH value to 3-4 by using 1N HCl; then adding ethyl acetate (10 mL multiplied by 3) to extract a product; combining and drying the organic phases; concentration under reduced pressure and separation by column chromatography (PE: EA = 2). HNMR (400MHz, CDCl) 3 )δ7.125-7.020(m,1H),6.933-6.869(m,1H),3.612-3.454(m,8H),3.389-3.262(m,2H),1.5(s,9H)。
Example 3: preparation of Compound 4-2
To dichloromethane (200 mL) was added N-acetylacetonatomorpholine (10.4g, 60.5mmol); cooled to 10 ℃ under nitrogen, triethylamine (7.44g, 73.6 mmol) was added followed by magnesium chloride (6.24g, 65.8mmol); heating to 25 ℃ after the addition, and stirring for 3 hours; then the temperature was lowered to-3 ℃ and a solution of 2,4, 5-trifluorophenylacetyl chloride (5.49g, 26.3 mmol) in dichloromethane (50 mL) was slowly added dropwise; stirring for 0.5h at 0 ℃; then heating to room temperature and stirring for 16h; TLC plates showed the disappearance of starting material. Cooling the reaction solution to 0 ℃, dropwise adding 1N HCl (80 mL) to quench the reaction, stirring, and then carrying out static liquid separation; dichloromethane (30 mL × 2) was added and extracted twice; organic phase combined with anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave a yellow oil (8.2 g, yield 90.6%). HNMR (400MHz, CDCl) 3 )δ7.147-7.082(m,1H),6.951-6.887(m,1H),3.724-3.465(m,8H),3.441-3.341(m,2H),2.086(s,3H)。
EXAMPLE 4 preparation of Compounds 4-3
N 2 Under protection, compound 3-3 (11.32g, 52.57mmol) was dissolved in anhydrous ACN (63.5 mL); at 40 ℃ MgCl was added 2 (6.01g, 63.12mmol) was stirred for 1h; cooling to 15 ℃; triethylamine (10.63g, 105mmol) was slowly added dropwise; naturally heating to 25 ℃ after the addition, and stirring for 1h; then the temperature is reduced to 0 ℃, and the compound 2 (5.49g, 26.3mmol) is slowly dropped; after the addition, naturally heating to 25 ℃ and stirring for 16h; TLC spot plate shows disappearance of raw material, cooling reaction solution to 5 deg.C, adding H 2 Quenching reaction by using oxygen; adjusting the pH to 3 with 1N HCl; extract the product with EA (60ml x 3); combining and drying the organic phases; concentration under reduced pressure and purification by column chromatography gave 13.7g (yield 70%) of the desired product. HNMR (400MHz, CDCl) 3 )δ7.26-7.06(m,1H),6.94-6.88(m,1H),4.20-4.18(m,2H),3.71-3.46(m,10H),1.30-1.28(t,3H)。
Example 5: preparation of Compound 5
Dissolve Compound 4-1 (50mg, 0.125mmol) in DCM (0.5 mL); trifluoroacetic acid TFA (0.5 mL) was added at room temperature; the reflux reaction is continued for 4h, and a TCL board shows that the reaction is finished; then adding saturated saline (30 mL) to quench the reaction; the product was extracted twice by adding dichloromethane (15 mL. Times.2); combining and drying the organic phases; purification by preparative TCL plates (PE: EA = 1) gave compound 5 as a yellow oil (16 mg, 42.6% yield). 1 HNMR(400MHz,CDCl 3 )δ7.08-7.02(m,1H)，6.79-6.88(m,1H)，3.86(s,2H)，3.86-3.62(m,8H)，3.42-3.40(m,2H)。
Example 6: preparation of Compound 5
Compound 4-2 (10g, 29.1mmol) was dissolved in ethanol (50 mL), followed by addition of 1N HCl (100 mL), and stirring at room temperature for 16h; TLC showed the starting material disappeared and extracted three times with DCM (50 mL × 3); combined and anhydrous Na 2 SO 4 Drying the organic phase; concentration under reduced pressure gave compound 5 (8.8g, 90%) as a yellow semi-oily substance. The authentication data is as above.
Example 7: preparation of Compound 5
Dissolving compound 4-2 (1g, 1.0 eq) in methanol (10 mL), adding dropwise to a prepared solution of magnesium chloride (1.0 eq) and methanol (15 mL), and reacting at 30-40 deg.C for 16 hr; TLC showed disappearance of starting material and DCM (10 mL × 3) was extracted three times; combined and anhydrous Na 2 SO 4 Drying the organic phase; concentration under reduced pressure and purification by column chromatography gave compound 5 (0.7g, 80%). The authentication data is as above.
Example 8: preparation of Compound 5
Dissolving the compound 4-2 (1g, 1.0 eq) in methanol (10 mL), dropwise adding the mixture into a prepared solution of nickel chloride (1.0 eq) and methanol (15 mL), and reacting for 16 hours at the temperature of 30-40 ℃; TLC showed disappearance of starting material and DCM (10 mL × 3) was extracted three times; combined and anhydrous Na 2 SO 4 Drying the organic phase; concentration under reduced pressure and purification by column chromatography gave compound 5 (0.7g, 80%). The authentication data is as above.
Example 9: preparation of Compound 5
Dissolving NaOH (26.78mg, 0.7mmol) in H 2 O (2 mL) was pre-dosed as lye. Compound 4-3 (0.1g, 0.268mmol) was dissolved in CH 3 OH (2 mL), and then adding the prepared sodium hydroxide solution into the reaction solution; then heating to reflux for 16h; TLC plates showed the disappearance of starting material. Adjusting the pH value to weak acidity; extracting the product with EA; dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative TLC (DCM: CH) 3 OH = 20) to obtain the target compound 10mg (yield 12%). The authentication data is as above.
Comparative example 1: acid hydrolysis compound 4-3
TsOH (46.15mg, 0.268mmol) was dissolved in H 2 O (2 mL) was pre-formulated into an acid solution. Compound 4-3 (0.1g, 0.268mmol) was dissolved in toluene (2 mL), and the prepared acid solution was added to the reaction solution; stirring at 120 ℃ for 169h and TLC spotting the plates showed disappearance of starting material. Extracting the product with EA; dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative TLC (PE: EA =2 1) to give the main product, trifluoro phenylacetic acid 30mg, without obtaining the target compound 5.
Application example 1 preparation of Boc- (R) -3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid
1mL of 0.2M TEA-HCl buffer, pH 8.0, 0.1mL of DMSO, 2mM of pyridoxal phosphate 0.1mL, 0.2mL of isopropylamine 4M, pH 8.0, 0.0 mg of Compound 5, 0.5mL of transaminase (the transaminase was made by itself, see example 1 in CN109234327A, protein concentration 20 mg/mL), and after 6 hours at 45 ℃ the reaction was stopped with acetonitrile. The conversion was determined to be 20% and the compound 6ee value to be 99%. 1 HNMR(400MHz,DMSO-d 6 )δ7.46-7.38(m，2H)，3.53-3.49(m，4H)，3.40-3.37(t，4H)，3.24-3.21(t，1H)，2.66-2.52(d，1H)，2.54-2.52(d，1H)，2.31-2.30(d，2H)，1.56(s，2H)。
Preparing lithium hydroxide aqueous solution (2-3 eq lithium hydroxide, 3 times water), adding the compound 6, heating to the external temperature of 95 ℃, and reacting for about 16h. TLC showed substantial completion of the reaction, cooled and extracted with dichloromethane to recover starting material. The pH value of the water phase is slowly adjusted to 5.5-5.8 (< 10 ℃) by concentrated hydrochloric acid under ice bath, and the light yellow solid (R) -3-amino-4- (2, 4, 5-trifluorophenyl) butyric acid is obtained after filtration, washing and drying.
(R) -3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid was dissolved in 20 times the amount of aqueous sodium hydroxide solution (10 eq NaOH), boc anhydride (3 eq) was added dropwise at a temperature of 25. + -. 3 ℃ and about (0.3 eq) was added continuously at 25 to 30 ℃ to complete the reaction of the starting material, and the HPLC tracking starting material was <0.5%. Extracting impurities twice with 5 times of dichloromethane, mixing dichloromethane, washing twice, mixing water phases, adjusting pH to 2.5-3.0 with 1N hydrochloric acid at 10-20 deg.C. Filtering, pulping with 50 times of water, detecting with HPLC that the single impurity is less than 0.1%, vacuum drying at 20-25 deg.C to obtain Boc- (R) -3-amino-4- (2, 4, 5-trifluorophenyl) butyric acid. After comparison with the standard, the product is determined.
Claims (9)
1. A method for preparing a compound shown as a formula I comprises the following steps: in a solvent, carrying out an elimination reaction shown as the following on a compound shown as a formula II to obtain a compound shown as a formula I;
wherein R is methyl;
when R is methyl, the elimination reaction is carried out in the presence of acid;
the solvent is an alcohol solvent or a mixed solvent of the alcohol solvent and water;
the acid is protonic acid or Lewis acid;
when the acid is protonic acid, the protonic acid is inorganic protonic acid;
when the acid is Lewis acid, the Lewis acid is nickel chloride, magnesium chloride, aluminum chloride, zinc chloride or ferric chloride.
2. The method of claim 1, wherein: the molar ratio of the acid to the compound shown in the formula II is 1-60;
and/or the reaction temperature of the elimination reaction is 10-80 ℃.
3. The method of claim 2, wherein: when the solvent is an alcohol solvent or a mixed solvent of the alcohol solvent and water, the alcohol solvent in the alcohol solvent or the mixed solvent of the alcohol solvent and water is methanol and/or ethanol;
and/or, when the acid is a Lewis acid, the Lewis acid is nickel chloride or magnesium chloride; and/or the molar ratio of the acid to the compound shown in the formula II is 1-20.
4. The method of claim 3, wherein: when the protonic acid is inorganic protonic acid, the inorganic protonic acid is HCl or H 2 SO 4 ；
And/or, when the acid is a protonic acid, the molar ratio of the protonic acid to the compound shown in formula II is 3-4;
and/or, when the acid is a Lewis acid, the molar ratio of the Lewis acid to the compound shown in the formula II is 1-5.
5. The method of claim 4, wherein: when the acid is Lewis acid, the molar ratio of the Lewis acid to the compound shown in the formula II is 1-2.
6. The method of claim 1, wherein: when the R is methyl, the acid is HCl, the molar ratio of the acid to the compound shown as the formula II is 3-4; or the acid is magnesium chloride or nickel chloride, the molar ratio of the acid to the compound shown in the formula II is 1-2.
7. The method of claim 1, further comprising the steps of: in an organic solvent, carrying out substitution reaction shown as the following on a compound shown as a formula III and a compound shown as a formula IV in the presence of an organic base and a chelating agent to obtain a compound shown as a formula II;
8. the method of claim 7, wherein: in the substitution reaction, the organic solvent is a chlorohydrocarbon solvent and/or a nitrile solvent; and/or the molar ratio of the compound shown in the formula III to the compound shown in the formula IV is 1-6;
and/or, the organic base is tertiary amine;
and/or the molar ratio of the organic base to the compound shown in the formula IV is 1-3;
and/or the chelating agent is one or more of magnesium chloride, calcium chloride and barium chloride;
and/or the molar ratio of the chelating agent to the compound shown in the formula IV is 1-2;
and/or the reaction temperature of the substitution reaction is 0-40 ℃.
9. The method of claim 8, wherein: the chlorohydrocarbon solvent is dichloromethane, and the nitrile solvent is acetonitrile;
and/or the molar ratio of the compound shown as the formula III to the compound shown as the formula IV is 1-3;
and/or the organic base is triethylamine;
and/or the molar ratio of the organic base to the compound shown in the formula IV is 1.2-2;
and/or, the chelating agent is magnesium chloride;
and/or the molar ratio of the chelating agent to the compound shown in the formula IV is 1.1-1.3;
and/or the reaction temperature of the substitution reaction is 10-30 ℃.
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| JP2010122269A (en) * | 2008-11-17 | 2010-06-03 | Konica Minolta Business Technologies Inc | Electrophotographic toner and metal-containing compound |
| KR20110018959A (en) * | 2009-08-19 | 2011-02-25 | 장지환 | Novel liquid crystalline compounds and liquid crystalline composition comprising the same |
| CN108586346A (en) * | 2018-05-10 | 2018-09-28 | 中国国际医药卫生有限公司 | A kind of method that living things catalysis synthesizes sitagliptin and its intermediate |
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2019
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010122269A (en) * | 2008-11-17 | 2010-06-03 | Konica Minolta Business Technologies Inc | Electrophotographic toner and metal-containing compound |
| KR20110018959A (en) * | 2009-08-19 | 2011-02-25 | 장지환 | Novel liquid crystalline compounds and liquid crystalline composition comprising the same |
| CN108586346A (en) * | 2018-05-10 | 2018-09-28 | 中国国际医药卫生有限公司 | A kind of method that living things catalysis synthesizes sitagliptin and its intermediate |
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| "HYDROLYSIS OF 2-ACETYL-SUBSTITUTED FLUOROALKYL 3-KETOESTERS";V. M. Krokhalev等;《Plenum Publishing Corporation》;19870930;第9卷;第1963页Scheme1 * |
| "西他列汀中间体的合成研究";林艳艳;《中国优秀博硕士学位论文全文数据库（硕士） 工程科技I辑》;20100815(第08期);正文第13页2.4和正文第31页3.3.1.3 * |
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