CN105968038A - Hydrochlorides of dipeptide compounds and preparation method thereof - Google Patents
Hydrochlorides of dipeptide compounds and preparation method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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Abstract
The invention provides hydrochlorides of dipeptide compounds and a preparation method thereof. The method comprises the following steps: a first organic solvent is used for dissolving a compound shown in a formula 2; dissolving liquid of the compound shown in the formula 2 and a second organic solvent of hydrogen chloride are contacted, so that a first crude product of a compound shown in a formula 1 is obtained. The hydrochlorides of dipeptide compounds are precipitated from the solution by the method, and the product has the advantages of high purity, good properties and stability, and transport and long-time storage convenience.
Description
Technical field
The present invention relates to the field of chemical synthesis, specifically, the present invention relates to hydrochlorate and the preparation thereof of a kind of dipeptide compounds
Method.
Background technology
In recent years, dipeptides and the like is more and more applied in medicine and biological industry, and its demand becomes the most year by year
Greatly, but current preparation-obtained product purity is low, and character is not especially good, it is easy to the moisture absorption, unstable.For just
In placing for a long time and being readily transported, technical staff is generally selected and makes hydrochlorate, but major part hydrochloride compound surface is easy
Adsorb more hydrochloric acid, cause the isoelectric point, IP of dipeptides or polypeptide amino acid to change, thus cannot be normal from reactant liquor
Separate out, therefore in prior art and have not seen the dipeptide compounds hydrochlorate product of solid-state.This technical problem is difficult to obtain the most always
Solve.
Therefore, the method for the hydrochlorate preparing dipeptide compounds at present is further improved.
Summary of the invention
It is contemplated that one of technical problem solved the most to a certain extent in correlation technique or provide at a kind of useful business
Industry selects.To this end, it is an object of the present invention to propose hydrochlorate and the preparation side thereof of dipeptide compounds shown in a kind of formula 1
Method, products obtained therefrom purity is high, and preparation method is simple, low cost, is suitable for industrialized large-scaled production.
In the first aspect of the invention, the invention provides dipeptide compounds hydrochlorate shown in a kind of formula 1.According to the present invention
Embodiment, described compound is following structure.
Inventor has surprisingly found that, obtained dipeptide compounds hydrochlorate is easy to be formed from solution force out, and products obtained therefrom is pure
Degree height, character and stability are the most fine, it is simple to transport is placed with long-time.
In a second aspect of the present invention, the present invention proposes a kind of method of compound shown in formula 1, and described method includes:
(1) utilize the first organic solvent that compound shown in formula 2 is dissolved；
(2) by the second organic solvent exposure of the solution of compound shown in formula 2 Yu hydrogen chloride, in order to obtain of compound shown in formula 1
One crude product.
The term used in this article " contacts " and should be interpreted broadly, and it can be any at least two reactant to be made to occur
The mode of chemical reaction, such as, can be to be mixed under suitable condition by two kinds of reactants.In this article, " compound N "
Being otherwise referred to as in this article " compound shown in formula N ", N is the arbitrary integer of 1-2 in this article, such as " compound 2 "
It is referred to as " compound shown in formula 2 " in this article.
In describing the invention, it is to be understood that term " first ", " second " are only used for describing purpose, and are not understood that
For indicating or imply relative importance or the implicit quantity indicating indicated technical characteristic.Thus, define " first ", "
Two " feature can express or implicitly include one or more this feature.In describing the invention, the containing of " multiple "
Justice is two or more, unless otherwise expressly limited specifically.
The synthetic method of compound shown in formula 1 according to embodiments of the present invention, it is also possible to there is following additional technical feature:
According to embodiments of the invention, in step (2), under subzero 2 degrees Celsius-12 degrees Celsius, by compound and chlorine shown in formula 2
Change the second organic solvent exposure of hydrogen, be preferably under 5 degrees Celsius-10 degrees Celsius；Temperature is too low, and extent of reaction is very slow, raw material
Remain excessive；Temperature is too high, and reaction becomes miscellaneous, has impurity to generate, is particularly that the hydroxyl on compound 2 structural formula can be taken off.
According to a particular embodiment of the invention, the time of the contact in step (2) is 3-4 hour.From aerodynamic point analysis,
Extent of reaction has relation with the concentration of time and reaction substrate, and time of contact is less than 3 hours, and raw material residual is excessive, overlong time,
The efficiency of impact reaction, finds to contact 3-4 hour by test of many times inventor best.
According to a particular embodiment of the invention, in step (2), by compound shown in HPLC monitoring formula 2, control it and be less than
During 2.0 weight %, stopped reaction.The residual of compound shown in formula 2 is excessive, and reaction yield can be caused on the low side, and cannot react completely
Compound shown in formula 2 belongs to a known impurities in the product, is difficult to remove.
According to embodiments of the invention, described first organic solvent is selected from dichloromethane, dioxane, oxolane and 2-first
At least one in base oxolane, preferably dichloromethane.First organic solvent is primarily used to reaction dissolvent, and compound
2 dissolubility in dichloromethane are best, and beneficially product is fully contacted with hydrogen chloride, thus is conducive to adding fast response.
According to embodiments of the invention, compound shown in described formula 2 is 1:4-1:10 with the weight ratio of described first organic solvent,
It is preferably 1:4；Thus, after beneficially raw materials of compound shown in formula 2 fully dissolves, accelerate raw material and contact with hydrogen chloride, make product
Product fully become salt, and then are conducive to obtaining the hydrochlorate product of dipeptide compounds rather than the free state of product.
According to embodiments of the invention, described second organic solution is that methanol is molten selected from dioxane solution, ethyl acetate solution
At least one in liquid and aqueous isopropanol, preferably dioxane solution.Thus be conducive to obtaining the product that the good yield of purity is high.
According to embodiments of the invention, compound shown in described formula 2 is 1 with the mol ratio of the second organic solvent of described hydrogen chloride:
5-1:20, preferably 1:6；Thus, after beneficially raw materials of compound shown in formula 2 fully dissolves, accelerate raw material and connect with hydrogen chloride
Touch, make product fully become salt, and then be conducive to obtaining the hydrochlorate product of dipeptide compounds rather than the free state of product.
According to embodiments of the invention, the concentration of the second organic solvent of described hydrogen chloride is 2-4 mol/L, preferably 4 moles/
Rise.Thus being conducive to coming off of Boc in compound shown in formula 2, because acid concentration is the biggest, protection group the most easily comes off, instead
Should be the fastest.
According to embodiments of the invention, shown in the formula 1 of above-described embodiment, the method for compound farther includes: (3) are by institute
State the first crude product and the 3rd organic solvent exposure, make the first crude product separate out with the form of grease；(4) by described grease and
One mixed solvent contact, cooling stirring, and isolated the second crude product.
According to embodiments of the invention, described 3rd organic solvent is selected from methyl tertiary butyl ether(MTBE), heptane, at least in hexane
Kind, preferably methyl tertiary butyl ether(MTBE).Thus be easier to make hydrochloric acid salts substances force out from solution.
According to embodiments of the invention, compound shown in described formula 2 is 1:15-1:25 with the weight ratio of described 3rd organic solvent,
It is preferably 1:20.Thus, beneficially product fully separates out from solution with grease form, thus improves chemical combination shown in formula 1
The yield of the second crude product of thing.
According to a particular embodiment of the invention, in step (4), the temperature of described cooling stirring is 0-10 degree Celsius, is preferably
0-5 degree Celsius.Owing to crude product herein is grease, temperature is too low, is unfavorable for that grease is converted into solid；Temperature is too high, produces
Product dissolve in a solvent, can reduce the yield of crude product.According to a particular embodiment of the invention, the method for described separation is sucking filtration.
According to embodiments of the invention, described first mixed solvent is the mixed solvent of dioxane and methyl tertiary butyl ether(MTBE)；Thus
The hydrogen chloride that grease product surface adsorbs fully can be dissolved in dioxane, be so conducive to making product and hydrogen chloride 1:1
In conjunction with, then by methyl tertiary butyl ether(MTBE), product is disperseed in the solution with solid forms, thus the formation of beneficially product solid,
And product is not easy the moisture absorption.
According to embodiments of the invention, compound shown in described formula 2 is 1:24 with the weight ratio of described first mixed solvent.
According to embodiments of the invention, in described first mixed solvent, dioxane is 1:1 with the weight ratio of methyl tertiary butyl ether(MTBE).
Methyl tertiary butyl ether(MTBE) is ether solvent, and beneficially hydrochloric acid salts substances changes into solid, and the effect of dioxane is to remove product
The hydrogen chloride on surface, if dioxane ratio reduces, is unfavorable for removing the hydrogen chloride that product surface is unnecessary, identical, if
Methyl tertiary butyl ether(MTBE) is too low, is unfavorable for that product separates out in solid form.
According to embodiments of the invention, shown in the formula 1 of above-described embodiment, the method for compound farther includes: (5) are by institute
State the second crude product and the contact of the second mixed solvent, making beating stirring, the solid pure product of compound shown in isolated formula 1.
According to embodiments of the invention, described second mixed solvent is the mixed solvent of oxolane and heptane.Thus can be favourable
Remove impurity in purification, obtain the purity product more than 99.5%.
According to embodiments of the invention, compound shown in described formula 2 is 1:16 with the weight ratio of described second mixed solvent.
According to embodiments of the invention, in described second mixed solvent, oxolane is 3:1 with the weight ratio of heptane；Oxolane
For polar solvent, being conducive to removing the impurity that polarity is big, and heptane belongs to low polar solvent and is anti-phase solvent, Main Function is to allow
More product separates out from solvent, same reason, if the ratio of oxolane is too low, may not have fully remove miscellaneous
The effect of matter, the ratio of heptane is too low, and the yield of product can reduce.
According to embodiments of the invention, by described second crude product and the second mixed solvent way of contact it is: by described second crude product
It is initially charged oxolane, stirs 30-60 minute, preferably 30-40 minute, add heptane, pull an oar under room temperature.
According to embodiments of the invention, after described second crude product and the contact of the second mixed solvent, room temperature is pulled an oar, sucking filtration, after drying
Obtain the solid pure product of compound shown in formula 1.Thus be conducive to the product obtaining purity more than 99.5%.
Shown in formula 1 according to the specific embodiment of the invention, the method for compound includes:
(1), at 0～10 DEG C, after being dissolved in dichloromethane by compound shown in formula 2 completely, temperature is controlled at 0～10 DEG C
The dioxane solution of lower dropping hydrogen chloride, after being added dropwise to complete, beginning insulation reaction 3～4 hours, shown in HPLC monitor-type 2
It is qualified that compounds content is reaction less than 2.0%, after question response is qualified, obtains the first crude product solution of compound shown in formula 1.
(2) adding methyl tertiary butyl ether(MTBE) in the first crude product solution, product separates out from solution with grease form, pours out upper strata
Clear liquid, adds dioxane and methyl tert-butyl ether solvent, is cooled to 0～10 DEG C, and stirring obtains white solid, sucking filtration, obtains
The second crude product to compound shown in formula 1.
(3) in described second crude product, add oxolane, stir 30～60 minutes under room temperature, be subsequently adding heptane solvent,
After stirring 30 minutes, sucking filtration is also dried, in order to obtain the solid pure product of compound shown in formula 1.
According to a particular embodiment of the invention, shown in synthesis type 1 of the present invention, the method for compound comprises the following steps:
(1) synthesis of formula 1 crude product: at 0～10 DEG C, compound 2 is dissolved in a solvent, raw material molten clear after, start to drip chlorine
Changing hydrogen solution, after being added dropwise to complete, stirring reaction 3～4 hours, it is qualified that HPLC monitoring raw material is less than 2%, reacts qualified
After, add methyl tertiary butyl ether(MTBE), stir 30 minutes, the supernatant is removed, add dioxane and t-butyl methyl ether solution,
Stirring, sucking filtration obtains crude product.
In reaction, starting compound 2 and hydrogen chloride solution mol ratio are 1:5-1:20, mainly enable product fully become salt,
React qualified after, starting compound 2 and methyl tertiary butyl ether(MTBE) weight ratio are 1:15-1:25, by product with grease form from molten
Liquid is sufficiently separated, improves crude yield.
Reaction controlling is at-2～12 degrees Celsius, and temperature is higher than 12 degrees Celsius, and impurity occurs in reaction, adds purification after product
Difficulty, reaction temperature is less than-2 degrees Celsius, and reaction carries out very slow, and the response time can lengthen, and starting material left is many, is unfavorable for fast
Speed obtains product.
(2) purification of compound 1 finished product: in formula 1 crude product, after adding oxolane dissolving clarification at room temperature, is slowly added to heptan
Alkane, stirs 30 minutes, sucking filtration, is dried to obtain the purity product more than 99.5%.
Starting compound 2 is 1:12:4 with the weight ratio of oxolane and heptane, and such product can be the most molten in oxolane
Clearly, adding heptane amount can not be many, and otherwise, product can become again grease after separating out, and is unfavorable for the sucking filtration of latter products.
Inventors be surprised to learn that, utilize the method can the dipeptide hydrochloride compound of structure shown in synthesis type 1 fast and effectively,
The method is by the understanding to product characteristics, and the easy moisture absorption of hydrochlorate, major part hydrochloride compound surface is easily adsorbed more
Hydrochloric acid, so that dipeptides or polypeptide amino acid isoelectric point, IP change, thus normally cannot separate out from reactant liquor.Inventor is led to
Cross and with low polar solvent, reactant is forced out from solution, then with the solvent of corresponding hydrogen chloride solution by the chlorination on grease surface
Hydrogen dissolves, so that hydrogen chloride is combined with product 1:1, separates out and obtain crude product in methyl tertiary butyl ether(MTBE), and crude product passes through recrystallization,
Obtain the purity product more than 99.5% after purification.
The additional aspect of the present invention and advantage will part be given in the following description, and part will become apparent from the description below,
Or recognized by the practice of the present invention.
Accompanying drawing explanation
Fig. 1 shows according to embodiments of the invention 1, the HPLC chromatogram of products obtained therefrom；
Fig. 2 shows according to embodiments of the invention 2, the HPLC chromatogram of products obtained therefrom；
Fig. 3 shows according to embodiments of the invention 3, the HPLC chromatogram of products obtained therefrom；And
Fig. 4 shows according to embodiments of the invention 3, the H-NMR figure of products obtained therefrom.
Detailed description of the invention
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining the present invention, and
It is not considered as limiting the invention.In embodiment, unreceipted concrete technology or condition, retouched according to the document in this area
The technology stated or condition or carry out according to product description.Agents useful for same or instrument unreceipted production firm person, be and can lead to
Cross city available from conventional products.
Conventional method
(1) synthesis of compound 1 crude product
At 0～10 DEG C, compound 2 is dissolved in dichloromethane, raw material molten clear after, start to drip hydrogen chloride dioxane
Solution, after being added dropwise to complete, stirring reaction 3～4 hours, HPLC monitoring raw material is less than 2%, and it is qualified to be, react qualified after,
In reactant liquor, add methyl tertiary butyl ether(MTBE), stir 30 minutes, the supernatant is outwelled from reaction bulb, then in reaction bulb
Adding dioxane and t-butyl methyl ether solution, stirring, sucking filtration obtains the crude product containing compound 1.
(2) purification of compound 1 finished product
By compound 1 crude product obtained above, after adding oxolane, it is stirred at room temperature and molten add and be slowly added to heptane clearly,
Reactant liquor becomes cloudy, and stirs 30 minutes, sucking filtration, dried to purity more than 99.5% product.
Chemical equation:
Embodiment 1
A, the synthesis of compound 1 crude product solution
Compound 42.0g (0.1mol), dichloromethane 168.0g (2.0mol) shown in formula 2 is added in 2000mL reaction bulb,
Stirring at normal temperature is dissolved, and after question response liquid dissolves clarification, cools to 5～10 DEG C, starts to drip the hydrogen chloride dioxy six of 4 mol/L
Ring solution 150.0ml (0.6mol), control temperature 5～10 DEG C, stir 3.0 hours, HPLC monitors starting material left 0.07%,
It is qualified to react, and adds methyl tertiary butyl ether(MTBE) 840.0g (9.5mol), stir 10 minutes, the supernatant outwelled in reactant liquor,
At 0～5 DEG C, add dioxane 504.0g (5.7mol), stir 10 minutes, add methyl tertiary butyl ether(MTBE) 504.0g
(5.7mol), 0～5 DEG C is stirred 30 minutes, and sucking filtration obtains crude product 34.1g, crude product purity 98.8%, crude yield 95.7%.
B, the purification of formula 1 finished product
By crude product obtained above, add oxolane 504.0g (7.0mol), be stirred at room temperature molten clear after, be slowly added dropwise heptane 168.0g
(1.7mol), after being added dropwise to complete, stirring 30 minutes, sucking filtration is dried, and obtains product 30.3g, total recovery 85.1%, HPLC
Purity 99.8%, liquid chromatograph (HPLC) figure of products obtained therefrom is shown in Fig. 1.
Embodiment 2
The synthesis of crude compound solution shown in a, formula 1
Compound 42.0g (0.1mol), dichloromethane 420.0g (4.9mol) shown in formula 2 is added in 2000mL reaction bulb,
Stirring at normal temperature is dissolved, and after question response liquid dissolves clarification, cools to-2～5 DEG C, starts to drip the hydrogen chloride dioxane of 4 mol/L
Solution 125.0ml (0.5mol), control temperature 5～10 DEG C, stir 3.0 hours, HPLC monitors starting material left 1.8%, reaction
Qualified, in reactant liquor, add methyl tertiary butyl ether(MTBE) 840.0g (9.5mol), stir 10 minutes, the supernatant is outwelled, 0～
Add dioxane 504.0g (5.7mol) at 5 DEG C, stir 10 minutes, add methyl tertiary butyl ether(MTBE) 504.0g (5.7mol),
0～5 DEG C is stirred 30 minutes, and sucking filtration obtains crude product 30.1g, crude product purity 96.8%, crude yield 84.2%.
B, the purification of compound 1 finished product
By crude product obtained above, add oxolane 504.0g (7.0mol), be stirred at room temperature molten clear after, be slowly added dropwise heptane 168.0g
(1.7mol), after being added dropwise to complete, stirring 30 minutes, sucking filtration is dried, and obtains product 21.3g, total recovery 60.1%, HPLC
Purity 99.5%, liquid chromatograph (HPLC) figure of products obtained therefrom is shown in Fig. 2.
Embodiment 3
The synthesis of crude compound solution shown in a, formula 1
Compound 42.0g (0.1mol), dichloromethane 168.0g (2.0mol) shown in formula 2 is added in 2000mL reaction bulb,
Stirring at normal temperature is dissolved, and after question response liquid dissolves clarification, cools to 5～10 DEG C, starts to drip 2 mol/L hydrogen chloride dioxane
Solution 300.0ml (0.6mol), control temperature 5～10 DEG C, stir 3.0 hours, HPLC monitors starting material left 0.3%, reaction
Qualified, in reactant liquor, add methyl tertiary butyl ether(MTBE) 840.0g (9.5mol), stir 10 minutes, the supernatant is outwelled, 5～
Add dioxane 504.0g (5.7mol) at 10 DEG C, stir 10 minutes, add methyl tertiary butyl ether(MTBE) 504.0g (5.7mol),
5～10 DEG C are stirred 30 minutes, and sucking filtration obtains crude product 32.1g, crude product purity 98.0%, crude yield 90.1%.
B, the purification of compound 1 finished product
By crude product obtained above, add oxolane 504.0g (7.0mol), be stirred at room temperature molten clear after, be slowly added dropwise heptane 168.0g
(1.7mol), after being added dropwise to complete, stirring 30 minutes, sucking filtration is dried, and obtains product 28.3g, total recovery 79.5%, HPLC
Purity 99.7%, liquid chromatograph (HPLC) figure of products obtained therefrom is shown in Fig. 3.
Embodiment 4
The synthesis of crude compound solution shown in a, formula 1
Compound 42.0g (0.1mol), dichloromethane 168.0g (2.0mol) shown in formula 2 is added in 2000mL reaction bulb,
Stirring at normal temperature is dissolved, and after question response liquid dissolves clarification, cools to 5～10 DEG C, starts to drip the hydrogen chloride dioxy six of 4 mol/L
Ring solution 500ml (2.0mol), control temperature 5～10 DEG C, stir 3.0 hours, HPLC monitors starting material left 0.0%, instead
Should be qualified, in reactant liquor, add methyl tertiary butyl ether(MTBE) 1050g (11.9mol), stir 10 minutes, the supernatant is outwelled,
At 0～5 DEG C, add dioxane 504.0g (5.7mol), stir 10 minutes, add methyl tertiary butyl ether(MTBE) 504.0g
(5.7mol), 0～5 DEG C is stirred 30 minutes, and sucking filtration obtains crude product 30.1g, crude product purity 98.3%, crude yield 84.5%.
B, the purification of compound 1 finished product
By crude product obtained above, add oxolane 504.0g (7.0mol), be stirred at room temperature molten clear after, be slowly added dropwise heptane 168.0g
(1.7mol), after being added dropwise to complete, stirring 30 minutes, sucking filtration is dried, and obtains product 27.6g, total recovery 77.5%, HPLC
Purity 99.8%.
Embodiment 5
The synthesis of crude compound solution shown in a, formula 1
Compound 42.0g (0.1mol), dichloromethane 168.0g (2.0mol) shown in formula 2 is added in 2000mL reaction bulb,
Stirring at normal temperature is dissolved, and after question response liquid dissolves clarification, cools to 5～10 DEG C, starts to drip the hydrogen chloride dioxy six of 4 mol/L
Ring solution 125.0ml (0.5mol), control temperature 5～10 DEG C, stir 3.0 hours, HPLC monitors starting material left 1.1%, instead
Should be qualified, in reactant liquor, add methyl tertiary butyl ether(MTBE) 840.0g (9.5mol), stir 10 minutes, the supernatant is outwelled,
At 0～5 DEG C, add dioxane 504.0g (5.7mol), stir 10 minutes, add methyl tertiary butyl ether(MTBE) 504.0g
(5.7mol), 0～5 DEG C is stirred 30 minutes, and sucking filtration obtains crude product 32.8g, crude product purity 97.8%, crude yield 92.1%.
B, the purification of compound 1 finished product
By crude product obtained above, add oxolane 504.0g (7.0mol), be stirred at room temperature molten clear after, be slowly added dropwise heptane 168.0g
(1.7mol), after being added dropwise to complete, stirring 30 minutes, sucking filtration is dried, and obtains product 29.3g, total recovery 82.3%, HPLC
Purity 99.6%.
Embodiment 6
The synthesis of crude compound solution shown in a, formula 1
Compound 42.0g (0.1mol), dichloromethane 168.0g (2.0mol) shown in formula 2 is added in 2000mL reaction bulb,
Stirring at normal temperature is dissolved, and after question response liquid dissolves clarification, cools to 5～10 DEG C, starts to drip the hydrogen chloride dioxy six of 4 mol/L
Ring solution 150.0ml (0.6mol), control temperature 5～10 DEG C, stir 3.0 hours, HPLC monitors starting material left 0.1%, instead
Should be qualified, in reactant liquor, add methyl tertiary butyl ether(MTBE) 840.0g (9.5mol), stir 10 minutes, the supernatant is outwelled,
At 0～5 DEG C, add dioxane 504.0g (5.7mol), stir 10 minutes, add methyl tertiary butyl ether(MTBE) 504.0g
(5.7mol), 0～5 DEG C is stirred 60 minutes, and sucking filtration obtains crude product 33.1g, crude product purity 98.1%, crude yield 92.9%
B, the purification of compound 1 finished product
By crude product obtained above, add oxolane 504.0g (7.0mol), be stirred at room temperature molten clear after, be slowly added dropwise heptane 168.0g
(1.7mol), after being added dropwise to complete, stirring 30 minutes, sucking filtration is dried, and obtains product 29.3g, total recovery 82.3%, HPLC
Purity 99.8%.
Embodiment 7
The synthesis of crude compound solution shown in a, formula 1
Compound 42.0g (0.1mol), dichloromethane 168.0g (2.0mol) shown in formula 2 is added in 2000mL reaction bulb,
Stirring at normal temperature is dissolved, and after question response liquid dissolves clarification, cools to 5～10 DEG C, starts to drip the hydrogen chloride acetic acid second of 4 mol/L
Ester solution 150.0ml (0.6mol), control temperature 5～10 DEG C, stir 3.0 hours, HPLC monitors starting material left 0.4%, instead
Should be qualified, in reactant liquor, add methyl tertiary butyl ether(MTBE) 840.0g (9.5mol), stir 10 minutes, the supernatant is outwelled,
At 0～5 DEG C, add dioxane 504.0g (5.7mol), stir 10 minutes, add methyl tertiary butyl ether(MTBE) 504.0g
(5.7mol), 0～5 DEG C is stirred 30 minutes, and sucking filtration obtains crude product 25.0g, crude product purity 92.3%, crude yield 70.2%.
B, the purification of compound 1 finished product
By crude product obtained above, add oxolane 504.0g (7.0mol), be stirred at room temperature molten clear after, be slowly added dropwise heptane 168.0g
(1.7mol), after being added dropwise to complete, stirring 30 minutes, sucking filtration is dried, and obtains product 20.3g, total recovery 57.0%, HPLC
Purity 99.5%.
Embodiment 8
The synthesis of crude compound solution shown in a, formula 1
Type I compound 42.0g (0.1mol), dichloromethane 168.0g (2.0mol), room temperature is added in 2000mL reaction bulb
Stirring and dissolving, after question response liquid dissolves clarification, cools to 5～10 DEG C, starts to drip the hydrogen chloride methanol solution of 4 mol/L
150.0ml (0.6mol), control temperature 5～10 DEG C, stir 3.0 hours, HPLC monitors starting material left 1.0%, reacts qualified,
In reactant liquor, add methyl tertiary butyl ether(MTBE) 840.0g (9.5mol), stir 10 minutes, the supernatant is outwelled, at 0～5 DEG C
Lower addition dioxane 504.0g (5.7mol), stirs 10 minutes, adds methyl tertiary butyl ether(MTBE) 504.0g (5.7mol), 0～
5 DEG C are stirred 30 minutes, and sucking filtration obtains crude product 23.0g, crude product purity 93.5%, crude yield 64.6%.
B, the purification of compound 1 finished product
By crude product obtained above, add oxolane 504.0g (7.0mol), be stirred at room temperature molten clear after, be slowly added dropwise heptane 168.0g
(1.7mol), after being added dropwise to complete, stirring 30 minutes, sucking filtration is dried, and obtains product 18.8g, total recovery 52.8%, HPLC
Purity 99.6%.
Comparative example 1 (synthesizing compound 1 by other post processing modes)
The synthesis of compound 1 product
Compound 42.0g (0.1mol), dichloromethane 168.0g (2.0mol) shown in formula 2 is added in 2000mL reaction bulb,
Stirring at normal temperature is dissolved, and after question response liquid dissolves clarification, cools to 5～10 DEG C, starts to drip the hydrogen chloride dioxy six of 4 mol/L
Ring solution 150.0ml (0.6mol), control temperature 5～10 DEG C, stir 3.0 hours, HPLC monitors starting material left 0.07%,
It is qualified to react, and adds methyl tertiary butyl ether(MTBE) 840.0g (9.5mol), stir 10 minutes, the supernatant outwelled in reactant liquor,
Obtain grease, grease is adsorbed on bottle wall by being concentrated under reduced pressure to give white solid, sampling detection, purity 99.0%.
After uncovered placement 3 minutes, the solid on bottle wall becomes viscous, and after 30 minutes, solid becomes grease.Detection purity only has 93.5%,
And product is unstable, purity is particularly easy to reduce.
The solid product of comparative example's gained is by condensing mode, directly grease is removed solvent and the solid that obtains, and
Non-precipitation from solution obtains, and this product is particularly easy to the moisture absorption, becomes grease, inconvenience purification.This kind of method prepares
Product contains hydrogen chloride due to surface, extremely unstable, airtight can only place, is extremely unfavorable for industrialized great production.
By the most uncovered placement of product of comparative example 1 with embodiment 5, testing result is as shown in table 1, table 2.
The study on the stability result of the finished product of table 1 comparative example 1
The study on the stability result of the finished product of table 2 embodiment of the present invention 5
By stability correction data it can be seen that the product stability prepared by the inventive method is apparently higher than need not first
The product that the commonsense method that mixed solvent processes obtains, and commonsense method is to draw dry by the organic solvent concentration of product surface,
To white solid, but the hydrogen chloride being affixed to surface is not left away, and causes the as easy as rolling off a log moisture absorption of product, the product surface after the moisture absorption
Covered by hydrochloric acid, cause product unstable, and do not have this problem by the method for the present invention, and simple to operate, product is received
Rate and purity are high, quite convenient for industrialized production.
In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " concrete example " or
The description of " some examples " etc. means that the specific features, structure, material or the feature that combine this embodiment or example description are contained in
In at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term necessarily for
It is identical embodiment or example.And, the specific features of description, structure, material or feature can be with in office one or more
Embodiment or example combine in an appropriate manner.Additionally, in the case of the most conflicting, those skilled in the art is permissible
The feature of the different embodiments described in this specification or example and different embodiment or example is combined and combines.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is exemplary,
Being not considered as limiting the invention, above-described embodiment can be entered by those of ordinary skill in the art within the scope of the invention
Row changes, revises, replaces and modification.
Claims (10)
1. the hydrochlorate of a dipeptide compounds, it is characterised in that described compound has the structure shown in formula 1,
2. the method for compound shown in a formula 1, it is characterised in that including:
(1) utilize the first organic solvent that compound shown in formula 2 is dissolved；
(2) by the second organic solvent exposure of the lysate of compound shown in formula 2 Yu hydrogen chloride, in order to obtain compound shown in formula 1
First crude product
Method the most according to claim 2, it is characterised in that farther include:
(3) by described first crude product and the 3rd organic solvent exposure, described first crude product is made to separate out with the form of grease；
(4) described grease and the first mixed solvent are contacted, cooling stirring, and isolated the second crude product.
Method the most according to claim 3, it is characterised in that farther include:
(5) described second crude product and the second mixed solvent are contacted, making beating stirring, and shown in isolated formula 1, the solid of compound is pure
Product.
Method the most according to claim 4, it is characterised in that described first organic solvent is selected from dichloromethane, dioxane,
At least one in oxolane and 2-methyltetrahydrofuran, preferably dichloromethane；
Optionally, described second organic solvent is in dioxane solution, ethyl acetate solution, methanol solution and aqueous isopropanol
At least one, preferably dioxane solution；
Optionally, described 3rd organic solvent is selected from methyl tertiary butyl ether(MTBE), heptane, at least one in hexane, preferably methyl-tert
Butyl ether；
Optionally, described first mixed solvent is the mixed solvent of dioxane and methyl tertiary butyl ether(MTBE)；
Optionally, described second mixed solvent is the mixed solvent of oxolane and heptane.
Method the most according to claim 2, it is characterised in that compound shown in described formula 2 and the weight of described first organic solvent
Amount ratio is (1:4)-(1:10), preferably 1:4；
Optionally, compound shown in described formula 2 is (1:5)-(1:20) with the mol ratio of the second organic solvent of described hydrogen chloride,
It is preferably 1:6；
Optionally, the concentration of the second organic solvent of described hydrogen chloride is 2-4 mol/L, preferably 4 mol/L.
Method the most according to claim 4, it is characterised in that compound shown in described formula 2 and the weight of described 3rd organic solvent
Amount ratio is (1:15)-(1:25), preferably 1:20；
Optionally, compound shown in described formula 2 is 1:24 with the weight ratio of described first mixed solvent；
Optionally, compound shown in described formula 2 is 1:16 with the weight ratio of described second mixed solvent.
Method the most according to claim 5, it is characterised in that dioxane and methyl tertiary butyl ether(MTBE) in described first mixed solvent
Weight ratio be 1:1；
Optionally, in described second mixed solvent, the weight ratio of oxolane and heptane is 3:1；
Optionally, by described second crude product and the second mixed solvent way of contact it is: in described second crude product, first add oxolane,
Stir 30-60 minute, preferably 30-40 minute, add heptane, pull an oar under room temperature.
Method the most according to claim 2, it is characterised in that in step (2), by solution and the chlorine of compound shown in formula 2
The second organic solvent exposure changing hydrogen is carried out, preferably at 5 degrees Celsius-10 degrees Celsius under subzero 2 degrees Celsius-12 degrees Celsius
Under carry out；
Optionally, in step (2), the time of described contact is 3-4 hour；
Optionally, in step (2), by compound shown in HPLC monitoring formula 2, when compounds content shown in formula 2 is less than 2.0 weights
During amount %, stopped reaction.
Method the most according to claim 3, it is characterised in that in step (4), the temperature of described cooling stirring is 0-10
Degree Celsius, preferably 0-5 degree Celsius；
Optionally, in step (4), the mode of described separation is sucking filtration；
Optionally, in step (5), described second crude product and the second mixed solvent are contacted, room temperature making beating sucking filtration, obtain after drying
The solid pure product of compound shown in formula 1；
Optionally, the purity of the solid pure product of compound shown in described formula 1 is more than 99.5%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022206870A1 (en) * | 2021-03-31 | 2022-10-06 | Remegen Co., Ltd. | Preparation and purification process of monomethyl auristain e compound |
| WO2023193730A1 (en) * | 2022-04-08 | 2023-10-12 | 荣昌生物制药(烟台)股份有限公司 | Method for preparing and purifying monomethyl auristantin e intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5635483A (en) * | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
| CN104903351A (en) * | 2012-11-07 | 2015-09-09 | 辉瑞公司 | Anti-notch3 antibodies and antibody-drug conjugates |
| WO2015162293A1 (en) * | 2014-04-25 | 2015-10-29 | Pierre Fabre Medicament | Antibody-drug-conjugate and its use for the treatment of cancer |
| CN105408318A (en) * | 2013-04-25 | 2016-03-16 | 皮埃尔法布雷医药公司 | Derivatives of dolastatin 10 and auristatins |
-
2016
- 2016-05-09 CN CN201610299415.2A patent/CN105968038A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5635483A (en) * | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
| CN104903351A (en) * | 2012-11-07 | 2015-09-09 | 辉瑞公司 | Anti-notch3 antibodies and antibody-drug conjugates |
| CN105408318A (en) * | 2013-04-25 | 2016-03-16 | 皮埃尔法布雷医药公司 | Derivatives of dolastatin 10 and auristatins |
| WO2015162293A1 (en) * | 2014-04-25 | 2015-10-29 | Pierre Fabre Medicament | Antibody-drug-conjugate and its use for the treatment of cancer |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022206870A1 (en) * | 2021-03-31 | 2022-10-06 | Remegen Co., Ltd. | Preparation and purification process of monomethyl auristain e compound |
| WO2023193730A1 (en) * | 2022-04-08 | 2023-10-12 | 荣昌生物制药(烟台)股份有限公司 | Method for preparing and purifying monomethyl auristantin e intermediate |
| TWI843512B (en) * | 2022-04-08 | 2024-05-21 | 大陸商榮昌生物製藥（煙臺）股份有限公司 | Method of preparing and purifying an intermediate of methyl auristatin e |
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