CN115385867A - Cyclization reaction and ring opening method of amino acid and analogue thereof - Google Patents
Cyclization reaction and ring opening method of amino acid and analogue thereof Download PDFInfo
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
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- C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms
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- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
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Abstract
The invention relates to the field of pharmaceutical chemicals, and mainly relates to a cyclization reaction of amino acid and analogues thereof, which is carried out according to the following reaction formula,
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, and mainly relates to a cyclization reaction and ring opening method of amino acid and analogues thereof.
Background
Modification of proteins or polypeptides is a phenomenon naturally occurring in organisms, mainly the modification of residues constituting polypeptides or amino acids by some groups, and then the regulation of a series of vital activities in organisms, and amino acid modification is a common mode of protein modification. N-methyl-amino acids are important fragments of most biologically active peptidic natural products.
N-methylation of amino acids was a long proposition, and in 1915 Fischer first published a synthetic route for N-methylation of alpha-amino acids, which protected a primary alpha-amino group temporarily with a suitable group, thereby leaving a single N-H group, and then followed by α N-methylation to N-CH 3 Substitution of the N-H group by a group, subsequent removal of the protecting group by reaction to give the secondary α N-methyl amino acids. The key steps of the preparation method are still the majority α N-methylation chemistry. However, the reagents used in the Fischer steps are relatively strong and are not highly suitable for amide bonds, and therefore, it is necessary to develop milder reaction conditions.
In Proceedings of the 5 published by Quitt th The EUropen Peptide Symposium Oxford is improved so that the reaction conditions are milder and the partial conversion into the functional group is stereochemically pure α N-methyl amino acids. The preparation method is carried out by catalytic hydrogenation when the protective group is removed, but the amino acid has poor solubility under the hydrogenation condition, and simultaneously, the sulfur-containing amino acid can poison a hydrogenation catalyst to influence the reaction, so that the reaction yield is not ideal.
N-methylation of primary amines was more difficult to accomplish, in 1970, olsen et al chose Ag for use 2 O/CH 3 The process of I gives N-methylated products of some amino acids in yields of 52 to 99%, but the reagents used in the process are highly toxic compounds. Prashad et al, improved in 2003 by selecting a strong base, naH, to hydrogen abstraction followed by methylation, to provide N-methylated products of some amino acids in 90% yield. However, the problems of more reaction steps, great toxicity of reagents, large dosage, high cost, easy chiral turnover and the like still exist at present, and the method is not beneficial to industrial mass production.
Most of the reactions are performed by ring opening after ring formation by using polyformaldehyde, and the polyformaldehyde is easy to degrade at a high temperature to generate a large amount of irritant gases of formaldehyde. The high effective Assembly of Branched polymeric from (Cyclic Peptide) -Polymer Conjugates published by Koh et al used 6.7 times the equivalent of the amino acids involved in the reaction in the cyclization step of the methylation, while they also used a Dean-Stark apparatus for removing the water of reaction at reflux temperature.
Therefore, it is highly desirable to develop a safe, harmless and easy-to-operate industrial preparation method of N methylation, which can improve the reaction yield and the product purity.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a cyclization reaction and ring opening method of amino acid and analogues thereof.
The invention provides a cyclization reaction of amino acid and analogues thereof, wherein a compound shown in a formula 1 and polyaldehyde react under the action of a catalyst to obtain a cyclic compound shown in a formula 2, and the reaction formula is shown as the following formula:
wherein, X 1 Is an alkyl chain- (CH) with a substituent 2 ) n-, n is 1-2, wherein X 1 The hydrogen on the methylene group may be substituted by a substituent C 1 -C 6 Alkyl, halogen, or C 1 -C 2 An alkoxy group; k is hydrogen, or methyl; r is 1 The amino protecting group is selected from carbobenzoxy (Cbz), fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), allyloxycarbonyl (Alloc), trimethylsiloxycarbonyl (Teoc), trichloroethoxycarbonyl (Troc), methylcarbonyl (Meoc), ethylcarbonyl (Etoc), trifluoroacetyl (Tfa), phthaloyl (Pht), p-toluenesulfonyl (tosyl)The structure of the compound is shown in the specification, wherein the compound is selected from the group consisting of a base (Tos), an o-nitrobenzenesulfonyl (oNbs), a p-nitrobenzenesulfonyl (pNbs), a 2-trimethylsilylethylsulfonyl (SES), an allyl (Al), a benzyl (Bn), ethyl dimethylbenzoate (Dmb), a p-methoxybenzyl (Pmb) and a trityl (Trt), and the specific structure is as follows:
specifically, C 1 -C 6 The alkyl group may be: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, or tert-butyl; c 1 -C 2 The alkoxy group may be-OCH 3 or-OCH 2 CH 3 。
Preferably, the reaction is represented by the formula:
wherein R is 1 K is as defined above; r group is selected from hydrogen atom, C 1 -C 6 Alkyl radical, C 1 -C 2 An alkoxy group; specifically, C 1 -C 6 The alkyl group may be: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, or tert-butyl; c 1 -C 2 The alkoxy group may be-OCH 3 or-OCH 2 CH 3 。
Further preferably, the reaction is represented by the following formula:
wherein R is 1 R is as defined above.
More preferably, the reaction is represented by the formula:
wherein R is 1 R is as defined above, the carbon marked by the symbol is a chiral carbon atom, and the chirality is consistent before and after the reaction.
Specifically, the reaction is represented by the following formula:
wherein R is 1 The definition of (a) is the same as above, the carbon marked by the letter is a chiral carbon atom, and the chirality is kept consistent before and after the reaction.
Preferably, the molar equivalent ratio of formula 1 to polyaldehyde is 1: (0.2-8), more preferably 1: (0.5-6), more preferably 1: (0.8-4), most preferably 1: (1-2).
Preferably, the catalyst is selected from p-toluenesulfonic acid, trifluoroacetic acid, dilute sulfuric acid, methanesulfonic acid, dodecylbenzenesulfonic acid, camphorsulfonic acid, magnesium sulfate, or potassium chloride, and more preferably, p-toluenesulfonic acid, camphorsulfonic acid, or magnesium sulfate.
Preferably, the reaction solvent is one or a mixture of more of dichloromethane, N-dimethylformamide, toluene, acetonitrile, benzene, dimethyl sulfoxide, carbon tetrachloride, 1,3-dimethyl-2-imidazolidinone, N-hexane and chloroform.
Preferably, the reaction temperature is 30 to 90 ℃, more preferably 50 to 70 ℃.
The reaction time is preferably 2 to 10 hours, more preferably 4 to 8 hours.
Further, the technical scheme also comprises a purification operation after the reaction in the step is finished.
Adding inorganic alkali liquor into the obtained reaction liquid for washing, separating after washing, removing the solvent by vacuum distillation of the obtained organic phase, adding benign solvent for dissolving again, continuing vacuum distillation, adding the organic solvent for pulping, and centrifuging to obtain the target product.
The benign solvent herein means a solvent having good solubility in the substance obtained by the first vacuum distillation.
Preferably, the benign solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, N-hexane, N-heptane, pentane, octane, benzene, toluene, xylene, chlorobenzene, dichloromethane, methyl tert-butyl ether, diethyl ether, petroleum ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, or cyclohexane, and more preferably N, N-dimethylformamide, N-hexane, N-heptane, or toluene.
Preferably, the inorganic alkali solution is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, or sodium bicarbonate, and more preferably sodium carbonate, potassium carbonate, or cesium carbonate.
Preferably, the concentration of the inorganic alkali liquor is 0.5% -10%, and more preferably 2% -6%.
Preferably, the organic solvent added is selected from methyl tert-butyl ether, diethyl ether, petroleum ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, propylene oxide, or ethylene oxide, and more preferably methyl tert-butyl ether, tetrahydrofuran, or ethylene oxide.
Further, the invention also provides a ring opening method of a cyclic compound, the compound of formula 2 is subjected to a ring opening reaction under the action of a catalyst to prepare a compound of formula 10, and the reaction formula is shown as the following formula:
wherein R is 1 、X 1 And K is as defined above.
Preferably, the reaction is represented by the formula:
wherein R is 1 K, R are as defined above.
More preferably, the reaction is represented by the formula:
wherein R is 1 K, R are as defined above, the carbon marked by a is a chiral carbon atom, and the chirality remains the same before and after the reaction.
Specifically, the reaction is represented by the following formula:
wherein R is 1 R is as defined above, the carbon marked by the symbol is a chiral carbon atom, and the chirality is consistent before and after the reaction.
Preferably, the reactive agent is selected from triethylsilane, trimethyliodosilane, hexamethyldisilazane, tert-butyldimethylchlorosilane, or hydroxyethyltrimethylsilane.
Preferably, the catalyst is selected from trifluoroacetic acid, dilute hydrochloric acid, dilute sulfuric acid, p-toluenesulfonic acid, zinc bromide, aluminum chloride, ferric chloride, or ferrous chloride, and more preferably trifluoroacetic acid, dilute hydrochloric acid, dilute sulfuric acid, or p-toluenesulfonic acid.
Preferably, the reaction solvent is selected from dichloromethane, chloroform, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethylene oxide, ethyl acetate, methyl acetate, dimethyl carbonate, or propylene glycol methyl ether acetate, and more preferably dichloromethane, chloroform, acetonitrile, N-dimethylformamide, ethylene oxide, or ethyl acetate.
Preferably, the reaction temperature is 10 to 80 ℃, more preferably 20 to 45 ℃.
The reaction time is preferably 5 to 40 hours, more preferably 15 to 30 hours.
Further, the method also comprises a purification operation after the reaction in the step is finished.
And (3) distilling the reaction liquid obtained by the reaction under reduced pressure to remove the solvent, adding a benign solvent to dissolve again, continuing distilling under reduced pressure, adding an organic solvent to pulp again, and finally centrifuging to obtain the target product.
The benign solvent herein means a solvent having good solubility in the substance obtained by the first vacuum distillation.
Preferably, the benign solvent is selected from dichloromethane, chloroform, acetonitrile, N-dimethylformamide, ethyl acetate, toluene, benzene, chlorobenzene, octane, N-hexane, N-heptane, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, or petroleum ether, and further preferably dichloromethane, N-dimethylformamide, toluene, or methyl tert-butyl ether.
Preferably, the organic solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, toluene, xylene, or chlorobenzene, and more preferably N, N-dimethylformamide, dichloromethane, acetonitrile, or toluene.
Advantageous effects
The invention provides a cyclization reaction and ring-opening method of amino acid and analogues thereof, and the technical scheme of the invention can reasonably control the equivalent ratio of reactants in the cyclization step, reduce the amount of volatile aldehyde substances and simultaneously obtain a target product with high purity and high yield by using a simpler reaction device. The subsequent purification steps are simple to operate, and the steps are simplified and are more suitable for industrial production.
Detailed Description
For better understanding of the technical solutions of the present invention, the technical solutions of the present invention are further described below with reference to specific examples, which are only for assisting understanding of the present invention and should not be construed as specifically limiting the present invention.
EXAMPLE 1 preparation and purification of tert-butyl-4-methoxy-5-oxooxazolidine-3-carboxylate
The reaction steps are as follows: at room temperature, adding 200mL of acetonitrile into a 500mL reaction kettle, starting stirring, adding 150g of the compound of the formula a-1, 43.84g of paraformaldehyde and 40mL of dilute sulfuric acid, raising the internal temperature to 50-70 ℃, preserving the temperature and stirring for 4-8h.
A purification step: and (3) at the temperature, adding a 5% potassium carbonate aqueous solution into the reaction kettle for washing, adding tap water into an organic layer obtained by standing and separating liquid, washing again, adding n-hexane into the organic layer after removing the water phase, distilling under reduced pressure, separating out a solid, adding methyl tert-butyl ether, stirring for 2 hours at the temperature, pulping, centrifuging, collecting a white solid wet product, and drying under reduced pressure in vacuum for 24 hours. The finished product 141.52g is prepared, the yield is 89.13 percent, and the purity is 97.69 percent.
EXAMPLE 2 preparation and purification of tert-butyl-4-methoxy-2-methyl-5-oxooxazolidine-3-carboxylate
The reaction steps are as follows: at room temperature, adding 200mL of acetonitrile into a 500mL reaction kettle, starting stirring, adding 150g of the compound of the formula a-1, 192.94g of paraldehyde and 40mL of dilute sulfuric acid, raising the internal temperature to 50-70 ℃, keeping the temperature and stirring for 4-8h.
A purification step: and (3) at the temperature, adding a 5% potassium carbonate aqueous solution into the reaction kettle for washing, adding tap water into an organic layer obtained by standing and separating liquid, washing again, adding n-hexane into the organic layer after removing the water phase, distilling under reduced pressure, separating out a solid, adding methyl tert-butyl ether, stirring for 2 hours at the temperature, pulping, centrifuging, collecting a white solid wet product, and drying under reduced pressure in vacuum for 24 hours. The finished product 140.74g is prepared, the yield is 91.26 percent, and the purity is 98.44 percent.
EXAMPLE 3 preparation and purification of tert-butyl-4-methoxy-5-oxooxazolidine-3-carboxylate
Examples 3-19 were prepared according to the method of example 1, with the difference that the amount of paraformaldehyde used in the reaction step was varied, as specified in the following table:
| serial number | Amount of Paraformaldehyde | Yield of | Purity of |
| Example 3 | 4.38g | 26.82％ | 16.38％ |
| Example 4 | 9.76g | 33.62％ | 30.02％ |
| Example 5 | 10.96g | 52.79％ | 48.16％ |
| Example 6 | 13.14g | 60.35％ | 55.97％ |
| Example 7 | 17.54g | 65.83％ | 70.79％ |
| Example 8 | 21.92g | 85.71％ | 97.59％ |
| Example 9 | 26.30g | 86.67％ | 97.21％ |
| Example 10 | 30.61g | 8.58％ | 97.55％ |
| Example 11 | 35.07g | 8.23％ | 97.99％ |
| Example 12 | 39.46g | 8.98％ | 98.92％ |
| Example 13 | 65.76g | 86.23％ | 96.22％ |
| Example 14 | 87.68g | 87.17％ | 98.76％ |
| Example 15 | 109.1g | 85.99％ | 97.71％ |
| Example 16 | 131.52g | 87.23％ | 98.88％ |
| Example 17 | 153.44g | 86.36％ | 96.68％ |
| Example 18 | 173.36g | 85.01％ | 97.59％ |
| Example 19 | 197.28g | 86.30％ | 98.88％ |
EXAMPLE 20 preparation and purification of tert-butyl-4-methoxy-5-oxooxazolidine-3-carboxylate
Examples 20-26 were prepared according to example 1, except that the catalysts used in the reaction steps were different, as specified in the following table:
| serial number | Catalyst and process for preparing same | Yield of | Purity of |
| Example 20 | Para toluene sulfonic acid | 96.61％ | 98.26％ |
| Example 21 | Trifluoroacetic acid | 86.12％ | 93.63％ |
| Example 22 | Methanesulfonic acid | 89.89％ | 92.73％ |
| Example 23 | Dodecyl benzene sulfonic acid | 87.53％ | 94.25％ |
| Example 24 | Camphorsulfonic acid | 97.24％ | 99.78％ |
| Example 25 | Magnesium sulfate | 96.59％ | 98.22％ |
| Example 26 | Potassium chloride | 65.34％ | 91.13％ |
EXAMPLE 27-35 preparation and purification of tert-butyl-4-methoxy-5-oxooxazolidine-3-carboxylate
Examples 27-35 were prepared according to example 1, except that the reaction steps used different solvents, as specified in the following table:
| serial number | Reaction solvent | Yield of | Purity of |
| Example 27 | Methylene dichloride | 93.92％ | 97.13％ |
| Example 28 | N, N-dimethylformamide | 94.96％ | 96.38％ |
| Example 29 | Toluene | 91.56％ | 98.18％ |
| Example 30 | Benzene and its derivatives | 85.26％ | 92.48％ |
| Example 31 | Dimethyl sulfoxide | 82.91％ | 91.49％ |
| Example 32 | Carbon tetrachloride | 89.79％ | 90.62％ |
| Example 33 | 1,3-dimethyl-2-imidazolidinone | 74.52％ | 92.08％ |
| Example 34 | N-hexane | 73.33％ | 93.74％ |
| Example 35 | Chloroform | 71.72％ | 90.77％ |
EXAMPLE 36 preparation and purification of tert-butyl-4-methoxy-5-oxooxazolidine-3-carboxylate
The reaction steps are as follows: at room temperature, adding 100mL of acetonitrile and 100mL of toluene into a 500mL reaction kettle, starting stirring, adding 150g of the compound of the formula a-1, 43.84g of paraformaldehyde and 40mL of dilute sulfuric acid, raising the internal temperature to 50-70 ℃, and keeping the temperature and stirring for 4-8h.
A purification step: and (2) at the temperature, adding a 5% potassium carbonate aqueous solution into the reaction kettle, washing with water, adding tap water into the organic layer obtained by standing and liquid separation, washing with water again, removing the water phase, adding n-hexane into the organic layer, distilling under reduced pressure, separating out a solid, adding methyl tert-butyl ether, stirring at the temperature for 2 hours, pulping, centrifuging, collecting a white solid wet product, and drying under reduced pressure in vacuum for 24 hours. The finished product 146.92g is prepared, the yield is 96.88%, and the purity is 99.62%.
EXAMPLE 37 preparation and purification of tert-butyl-4-methoxy-5-oxooxazolidine-3-carboxylate
The reaction steps are as follows: at room temperature, 100mL of dichloromethane, 100mLN and N-dimethylformamide are added into a 500mL reaction kettle, stirring is started, 150g of the compound of the formula a-1, 5363 g of paraformaldehyde, 43.84g and 40mL of dilute sulfuric acid are added, the internal temperature is raised to 50-70 ℃, and stirring is carried out under the condition of heat preservation for 4-8 hours.
A purification step: and (3) at the temperature, adding a 5% potassium carbonate aqueous solution into the reaction kettle for washing, adding tap water into an organic layer obtained by standing and separating liquid, washing again, adding n-hexane into the organic layer after removing the water phase, distilling under reduced pressure, separating out a solid, adding methyl tert-butyl ether, stirring for 2 hours at the temperature, pulping, centrifuging, collecting a white solid wet product, and drying under reduced pressure in vacuum for 24 hours. The finished product 139.49g is prepared, the yield is 94.58 percent, and the purity is 96.92 percent.
EXAMPLE 38 preparation and purification of tert-butyl-4-methoxy-5-oxooxazolidine-3-carboxylate
The reaction steps are as follows: at room temperature, adding 100mL of chloroform and 100mL of n-hexane into a 500mL reaction kettle, starting stirring, adding 150g of the compound of the formula a-1, 43.84g of paraformaldehyde and 40mL of dilute sulfuric acid, raising the internal temperature to 50-70 ℃, and keeping the temperature and stirring for 4-8h.
A purification step: and (2) at the temperature, adding a 5% potassium carbonate aqueous solution into the reaction kettle, washing with water, adding tap water into the organic layer obtained by standing and liquid separation, washing with water again, removing the water phase, adding n-hexane into the organic layer, distilling under reduced pressure, separating out a solid, adding methyl tert-butyl ether, stirring at the temperature for 2 hours, pulping, centrifuging, collecting a white solid wet product, and drying under reduced pressure in vacuum for 24 hours. The finished product 140.79g is prepared, the yield is 95.46 percent, and the purity is 97.69 percent.
EXAMPLE 39 preparation and purification of tert-butyl-4-methoxy-5-oxooxazolidine-3-carboxylate
Examples 39-44 were prepared according to example 1, except that the purification step used an inorganic base, as specified in the following table:
| serial number | Inorganic base | Yield of | Purity of |
| Example 39 | Sodium hydroxide | 85.69％ | 94.33％ |
| Example 40 | Potassium hydroxide | 88.15％ | 92.41％ |
| EXAMPLE 41 | Sodium carbonate | 94.48％ | 97.87％ |
| Example 42 | Cesium carbonate | 95.19％ | 98.13％ |
| Example 43 | Potassium bicarbonate | 89.99％ | 90.16％ |
| Example 44 | Sodium bicarbonate | 80.53％ | 93.77％ |
EXAMPLE 45-82 preparation and purification of tert-butyl-4-methoxy-5-oxooxazolidine-3-carboxylate
Examples 45-82 were prepared according to example 1, except that the purification step used benign solvents as opposed to organic solvents, as specified in the following table:
according to the preparation method of example 1 or example 2 of the present invention, the compounds shown in the following table were prepared by performing a cyclization reaction of reactants with paraformaldehyde or paraldehyde to obtain a product:
example 8978 preparation and purification of zxft 8978- ((tert-butoxycarbonyl) - (methyl) amino) -2-methoxyacetic acid
The reaction steps are as follows: at room temperature, 200mL of chloroform and 100g of the compound of the formula a-2 are added into a 500mL reaction kettle, stirring is started, 100mL of dilute sulfuric acid and 75g of triethylsilane are added, the internal temperature is raised to 20-45 ℃, and the temperature is kept for reaction for 18-30 hours.
A purification step: and (3) carrying out reduced pressure distillation on the reaction liquid to separate out a solid, adding dichloromethane to dissolve again, carrying out reduced pressure distillation again, adding toluene to the solid separated out, keeping the temperature and stirring for 2 hours, pulping, centrifuging to obtain a white wet product solid, and drying under reduced pressure in vacuum for 24 hours. The finished product 87.97g is prepared, the yield is 92.16%, and the purity is 98.45%.
Example 103-106,2- ((tert-butoxycarbonyl) - (methyl) amino) -2-methoxyacetic acid preparation and purification
Examples 103-106 were prepared according to example 102, except that the reagents were different, as specified in the following table:
| serial number | Reaction reagent | Yield of | Purity of |
| Example 103 | Trimethyliodisilane | 84.13％ | 92.66％ |
| Example 104 | Hexamethyldisilazane | 79.26％ | 90.38％ |
| Example 105 | Tert-butyldimethylsilyl chloride | 81.02％ | 93.03％ |
| Example 106 | Hydroxyethyl trimethylsilane | 76.59％ | 90.68％ |
Example 107-113,2- ((tert-butoxycarbonyl) - (methyl) amino) -2-methoxyacetic acid preparation and purification
Examples 107-113 were prepared by reference to example 102, except that the catalysts were different, as specified in the following table:
| serial number | Catalyst and process for preparing same | Yield of the product | Purity of |
| Example 107 | Trifluoroacetic acid | 93.23％ | 96.13％ |
| Example 108 | Dilute hydrochloric acid | 91.22％ | 95.25％ |
| Example 109 | P-toluenesulfonic acid | 93.96％ | 97.03％ |
| Example 110 | Zinc bromide | 84.66％ | 91.95％ |
| Example 111 | Aluminium chloride | 88.74％ | 92.56％ |
| Example 112 | Ferric chloride | 83.21％ | 94.15％ |
| Example 113 | Ferrous chloride | 85.93％ | 94.11％ |
Example 114-123,2- ((tert-butyloxycarbonyl) - (methyl) amino) -2-methoxyacetic acid preparation and purification
Examples 114-123 were prepared by reference to example 102, except that the reaction solvent was different, as specified in the following table:
| serial number | Reaction solvent | Yield of the product | Purity of |
| Example 114 | Methylene dichloride | 93.44％ | 96.34％ |
| Example 115 | Acetonitrile | 92.67％ | 97.32％ |
| Example 116 | N, N-dimethylformamide | 93.52％ | 97.16％ |
| Example 117 | Dimethyl sulfoxide | 89.25％ | 92.87％ |
| Example 118 | Tetrahydrofuran (THF) | 87.61％ | 93.67％ |
| Example 119 | Ethylene oxide | 95.78％ | 98.22％ |
| Example 120 | Ethyl acetate | 94.56％ | 99.10％ |
| Example 121 | Acetic acid methyl ester | 84.42％ | 91.09％ |
| Example 122 | Carbonic acid dimethyl ester | 81.68％ | 93.27％ |
| Example 123 | Propylene glycol methyl ether acetate | 86.28％ | 94.36％ |
Example 124-154,2- ((tert-butyloxycarbonyl) - (methyl) amino) -2-methoxyacetic acid preparation and purification
Examples 124-154 were prepared as described in example 102, except that the purification step used benign solvents as opposed to organic solvents, as specified in the following table:
according to the preparation method of example 102 of the present invention, the reactants were subjected to a ring-opening reaction to obtain products for preparing the compounds shown in the following table:
Claims (13)
1. a cyclization reaction of amino acid and analogues thereof is carried out by reacting compound of formula (1) with poly-aldehyde under the action of catalyst to obtain cyclic compound of formula (2), wherein the reaction formula is shown as follows:
wherein, X 1 Is an alkyl chain- (CH) with a substituent 2 ) n-, n is 1-2, wherein X 1 The hydrogen on the methylene group may be substituted by a substituent C 1 -C 6 Alkyl, halogen, or C 1 -C 2 An alkoxy group; k is hydrogen or methyl; r 1 The amino protecting group is selected from carbobenzoxy, fluorenylmethyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, trimethylsiloxyethyl, trichloroethoxycarbonyl, methylcarbonyl, ethylcarbonyl, trifluoroacetyl, phthaloyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, 2-trimethylsilylethylsulfonyl, allyl, benzyl, ethyldimethylbenzoate, p-methoxybenzyl and trityl.
2. The method of claim 1, wherein the reaction is of the formula:
wherein R is 1 K is as defined above; r group is selected from hydrogen atom, C 1 -C 6 Alkyl radical, C 1 -C 2 An alkoxy group; specifically, C 1 -C 6 The alkyl group may be: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, or tert-butylA group; c 1 -C 2 The alkoxy group may be-OCH 3 or-OCH 2 CH 3 。
3. The method of claim 1, wherein the reaction is of the formula:
wherein R is 1 R is as defined above.
4. The method of claim 1, wherein the reaction is of the formula:
wherein R is 1 R is as defined above, the carbon marked as the chiral carbon atom, and the chirality is consistent before and after the reaction.
5. The method of claim 1, wherein the reaction is of the formula:
wherein R is 1 The definition of (c) is the same as above, the carbon marked by x is a chiral carbon atom, and the chirality remains the same before and after the reaction.
6. The process of claim 1, the molar equivalent ratio of formula 1 to polyaldehyde is 1: (0.2-8), more preferably 1: (0.5-6), more preferably 1: (0.8-4), most preferably 1: (1-2); the catalyst is selected from p-toluenesulfonic acid, trifluoroacetic acid, dilute sulfuric acid, methanesulfonic acid, dodecylbenzenesulfonic acid, camphorsulfonic acid, magnesium sulfate or potassium chloride, and is further preferably p-toluenesulfonic acid, camphorsulfonic acid or magnesium sulfate; the reaction solvent is selected from one or more of dichloromethane, N-dimethylformamide, toluene, acetonitrile, benzene, dimethyl sulfoxide, carbon tetrachloride, 1,3-dimethyl-2-imidazolidinone, N-hexane and chloroform.
7. The method of claim 1, further comprising a purification operation after the reaction is completed: adding inorganic alkali liquor into the obtained reaction liquid for washing, separating after washing, removing the solvent by vacuum distillation of the obtained organic phase, adding a benign solvent for dissolving again, continuing vacuum distillation, adding an organic solvent for pulping, and centrifuging to obtain a target product; the benign solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, N-hexane, N-heptane, pentane, octane, benzene, toluene, xylene, chlorobenzene, dichloromethane, methyl tert-butyl ether, diethyl ether, petroleum ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, or cyclohexane, and further preferably N, N-dimethylformamide, N-hexane, N-heptane, or toluene; the inorganic alkali liquor is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate or sodium bicarbonate, and is further preferably sodium carbonate, potassium carbonate or cesium carbonate; the concentration of the inorganic alkali liquor is 0.5-10%, and the concentration is more preferably 2-6%; the organic solvent added is selected from methyl tert-butyl ether, diethyl ether, petroleum ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, propylene oxide, or ethylene oxide, and is further preferably methyl tert-butyl ether, tetrahydrofuran, or ethylene oxide.
8. A ring opening method of a cyclic compound is characterized in that a compound of a formula (2) is subjected to a ring opening reaction under the action of a catalyst to prepare a compound of a formula (10), wherein the reaction formula is shown as the following formula:
wherein R is 1 、X 1 And K is as defined above.
9. The method of claim 8, wherein the reaction is of the formula:
wherein R is 1 K, R are as defined above.
10. The method of claim 8, wherein the reaction is of the formula:
wherein R is 1 K, R are as defined above, the carbon marked by a is a chiral carbon atom, and the chirality remains the same before and after the reaction.
11. The method of claim 8, wherein the reaction is of the formula:
wherein R is 1 R is as defined above, the carbon marked as the chiral carbon atom, and the chirality is consistent before and after the reaction.
12. The process of claim 8, wherein the reaction reagent is selected from triethylsilane, trimethyliodosilane, hexamethyldisilazane, tert-butyldimethylchlorosilane, or hydroxyethyltrimethylsilane; the catalyst is selected from trifluoroacetic acid, dilute hydrochloric acid, dilute sulfuric acid, p-toluenesulfonic acid, zinc bromide, aluminum chloride, ferric chloride or ferrous chloride, and is further preferably trifluoroacetic acid, dilute hydrochloric acid, dilute sulfuric acid or p-toluenesulfonic acid; the reaction solvent is selected from dichloromethane, chloroform, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethylene oxide, ethyl acetate, methyl acetate, dimethyl carbonate, or propylene glycol methyl ether acetate, and more preferably dichloromethane, chloroform, acetonitrile, N-dimethylformamide, ethylene oxide, or ethyl acetate.
13. The method according to claim 8, further comprising a purification operation after the end of the reaction of the step: distilling the reaction solution obtained by the reaction under reduced pressure to remove the solvent, adding a benign solvent to dissolve again, continuing distilling under reduced pressure, adding an organic solvent to pulp again, and finally centrifuging to obtain a target product; the benign solvent is selected from dichloromethane, chloroform, acetonitrile, N-dimethylformamide, ethyl acetate, toluene, benzene, chlorobenzene, octane, N-hexane, N-heptane, tetrahydrofuran, methyl tert-butyl ether, diethyl ether or petroleum ether, and is further preferably dichloromethane, N-dimethylformamide, toluene or methyl tert-butyl ether; the organic solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, toluene, xylene, or chlorobenzene, and is more preferably N, N-dimethylformamide, dichloromethane, acetonitrile, or toluene.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4535167A (en) * | 1981-12-14 | 1985-08-13 | Merck & Co. Inc. | Chiral, N-protected, N-substituted α-amino acids |
| CN114729006A (en) * | 2019-11-07 | 2022-07-08 | 中外制药株式会社 | Cyclic peptide compounds having Kras inhibitory activity |
| CN117279933A (en) * | 2021-05-07 | 2023-12-22 | 中外制药株式会社 | Cyclic compounds having selective KRAS inhibition relative to HRAS and NRAS |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4535167A (en) * | 1981-12-14 | 1985-08-13 | Merck & Co. Inc. | Chiral, N-protected, N-substituted α-amino acids |
| CN114729006A (en) * | 2019-11-07 | 2022-07-08 | 中外制药株式会社 | Cyclic peptide compounds having Kras inhibitory activity |
| CN117279933A (en) * | 2021-05-07 | 2023-12-22 | 中外制药株式会社 | Cyclic compounds having selective KRAS inhibition relative to HRAS and NRAS |
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| Title |
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| DR. SAIOA DIOSDADO等: ""Ureidopeptide-based Bronsted bases. Design, synthesis, and application to the catalytic enantioselective synthesis of β-amino nitriles from (arylsulfonyl)acetonitriles"", CHEMISTRY - A EUROPEAN JOURNAL, vol. 20, no. 21, 31 December 2014 (2014-12-31), pages 6526 - 6531 * |
| THIMMALAPURA M. VISHWANATHA等: ""Tubulysin synthesis featuring stereoselective catalysis and highly convergent multicomponent assembly"", ORGANIC LETTERS, vol. 22, no. 14, 31 December 2020 (2020-12-31), pages 5396 - 5400 * |
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