CN108840816A - Acid imide midbody compound and its preparation method and application - Google Patents
Acid imide midbody compound and its preparation method and application Download PDFInfo
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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Abstract
The present invention discloses a kind of with formula（II）Acid imide midbody compound of shown structure and preparation method thereof can be used as the precursor compound that intermediate prepares anticoagulant Yi Dushaban.It takes with formula（I）The compound of structure is added in reaction dissolvent, and in the case where azo agents and ternary replace phosphorus effect, the compound comprising nucleophilic amino, which is introduced, has formula（I）In the compound of structure, 1 hydroxyl is converted into amino, while reversion occurs for configuration to get with formula（II）The intermediate of shown structure；Alkali is added in the acid imide intermediate, Deprotection is obtained with formula（III）The precursor compound of the Yi Dushaban of structure.The invention avoids use explosive or deadly poisonous compound and subsequent high-pressure hydrogenation to react in preparation process, the chiral purity of product can not only be substantially increased, moreover it is possible to reduce production cost, solve security risk present in production process, and the production cycle is greatly shortened, significantly improve production efficiency.
Description
Technical field
The present invention relates to organic chemical synthesis technical fields, and in particular to a kind of acid imide midbody compound and its system
Preparation Method and application.
Background technique
In coagulation process, the Stuart factor of activation（FXa）By factor（FII）Activation becomes fibrin ferment（FIIa）,
Promote fibrin to be formed, thrombus is consequently formed, thus FXa has become the major target class for developing anticoagulant of new generation.
Yi Dushaban is a kind of highly selective oral anticoagulant, can selectively, invertibity directly inhibits in FXa
The endogenous and extrinsic pathway of disconnected blood coagulation waterfall, and then inhibit the generation of fibrin ferment and thrombus, it is a kind of FXa retarding agent,
To 104 times of FIIa high of selectivity ratio of FXa.Domestic and international clinical test confirms that this product can be effectively suppressed and receives lower limb plastic surgery
The concurrent venous thromboembolism of patient with operation, and it is safe and reliable.
The effective component of commercially available Yi Dushaban is Yi Dushaban p-methyl benzenesulfonic acid monohydrate, and structure and preparation method are
It is disclosed in patent document CN103214414B：
。
In the preparation explanation of the patent document, the preparation route of the strongest p-methyl benzenesulfonic acid Yi Dushaban of feasibility is summarized
It is as follows：
。
In the preparation process of compound 6 to compound 10, methanesulfonic acid esterification, Azide have passed through, high-pressure hydrogenation restores,
At oxalates, the techniques such as purifying, total recovery is less than 25% in production process.The present inventor furthers investigate discovery, in compound
When the basic building completion of three chiral centres, so low yield is not suitable for industrialized production, and nitrine very much
Change reaction step directly to be fed intake with sodium azide and organic solvent, there is great production safety hidden danger.
And the technical solution recorded in patent document CN101263110 optimizes the production process of compound 8, uses phase instead and turns
Shifting catalyst dodecyl pyridinium chloride prepares Azide reagenl first, although the yield of reaction can be correspondingly improved, one
Determine to also avoid in degree to use brought danger while sodium azide and organic solvent, but its total recovery is only increased to
35% or so, it is not significant to the raising of total recovery.
In addition, the inventors discovered that the process yield of purification only has 80% during the compound of preparation structure formula 10,
It is analyzed in conjunction with chromatograms and LC-MS, and there are a large amount of chiral non-corresponding isomers 9a in the mother liquor after purification, content is about
Account for 15%.
Therefore, the production technology of existing Yi Dushaban intermediate at present, some presence greatly produce hidden danger, not only at
This is excessively high, and mesyl chloride has been used in production process, and sodium azide etc. is hypertoxic or easily makes quick-fried raw material and auxiliary material, and has
Total recovery is too low, and production cost is high.Currently, it would be highly desirable to optimize and improve the production technology of existing Yi Dushaban intermediate, to
Achieve the purpose that reduce production cost, improve production efficiency, control production risk.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of novel acid imide midbody compounds, and disclose it
Preparation method and the method that Yi Dushaban precursor is further prepared with it improve Yi Dushaban and its precursor to finally realize
Reaction yield reduces production cost, while reducing or eliminating the security risk in Yi Dushaban production preparation process.
In order to solve the above technical problems, the present invention adopts the following technical scheme that：
Design synthesizes a kind of acid imide midbody compound for having following structural formula：
Formula（II）,
Wherein, the R be selected from the phthalimide-based containing imide, tetrahydric phthalimide base, 3,4,5,
It is any in 6- tetrahydric phthalimide base, dimaleoyl imino, o-benzoic sulfimide base and its similar substituent group
It is a kind of.
Preferably, the compound is [(1R, 2S, 5S) -2-（Dimethylamino）- 5- [(1,3- phthalimide
Base) -2- carbonyl] cyclohexyl] t-butyl carbamate, structural formula is：
。
Another object of the present invention is to provide the acid imide intermediate compounds that one kind can prepare high-optical-purity
The method of object：
It takes described with formula（I）The compound of structure is added in reaction dissolvent, will in the case where azo agents and ternary replace phosphorus effect
Compound comprising nucleophilic amino introduces described with formula（I）In the compound of structure, by 1 hydroxyl during introducing
Be converted into amino, at the same make its configuration occur reversion to get.
。
The R is selected from：Phthalimide-based, tetrahydric phthalimide base, 3,4,5,6- tetrahydro O-phthalic
Imide, dimaleoyl imino, any one in o-benzoic sulfimide base.
Preferably, the reaction dissolvent is ethyl acetate, in toluene, tetrahydrofuran, ether, DMF, methyl tertiary butyl ether(MTBE)
It is at least one；
Preferably, the azo agents are diisopropyl azodiformate and/or diethyl azodiformate；
Preferably, the ternary replaces phosphorus reagent to be triphenylphosphine, tri-n-butyl phosphine, trimethyl-phosphine, tricyclohexyl phosphine, three octanoic acids
At least one of base phosphine；
Preferably, the compound containing nucleophilic amino be phthalimide, tetrahydric phthalimide, 3,4,5,6- tetra-
At least one of hydrogen phthalimide, maleimide, o-benzoic sulfimide.
Preferably, the temperature control of the reaction is -10 DEG C~30 DEG C, and the time control of reaction is 1~30h.
Preferably, the azo agents and the formula（I）The compound mole ratio of structure is 1：1~10；
Preferably, the ternary replaces phosphorus reagent and the formula（I）The compound mole ratio of structure is 1：1~10.
The present invention also provides a kind of methods for the preparation high-purity Yi Dushaban precursor compound that process is saved：
By the formula（II）Alkali is added in the compound of structure, and then Deprotection is obtained with formula（III）The compound of structure；
,
Wherein, the R is selected from：Phthalimide-based, tetrahydric phthalimide base, 3,4,5,6- tetrahydro O-phthalic
Imide, dimaleoyl imino, any one in o-benzoic sulfimide base.
Preferably, the alkali is sodium methoxide, magnesium methoxide, sodium tert-butoxide, potassium tert-butoxide, calcium methoxide, lithium hydroxide, hydroxide
At least one of potassium, sodium hydroxide, hydrazine hydrate.
Preferably, the temperature control of the reaction is 25 DEG C~80 DEG C；The time control of the reaction is 1~6h.
Preferably, the alkali and the formula（II）The compound mole ratio of structure is 1：1~10.
Compared with prior art, the beneficial technical effect of the present invention lies in：
1. the technology of the present invention route, which avoids, uses explosive or hypertoxic mesyl chloride and sodium azide and subsequent in preparation process
High-pressure hydrogenation reaction, the safety being inherently eliminated in the presence of traditional anticoagulant Yi Dushaban production process is hidden
Suffer from.
2. the Yi Dushaban production cycle can be greatly shortened in the method for the present invention, by " four in its conventional preparation techniques
Reaction step adds a step to purify "（Methanesulfonic acid esterification, Azide, high-pressure hydrogenation, at oxalates, oxalic acid salt refining）It is after simplification
" two-step reaction "（Light prolongs reaction, amino deprotection）, while the two steps can realize prepared by " one kettle way ", to greatly simplify
Production operation, and the chiral purity of product can also be greatly improved, the yield of original process can be shown from lower than 35%
What is write has been increased to 82% or more, achieves unexpected technical effect.
3. production cost can be greatly reduced in the method for the present invention, chemical synthesis raw material used is cheap and easy to get, at low cost, can
Efficiently obtain the intermediate product of high-optical-purity.
Detailed description of the invention：
Fig. 1 is one gained formula of embodiment（II）The chiral purity map figure of structure representation compound；
Fig. 2 is one gained formula of embodiment（II）The HNMR of structure representation compound is composed（CDCl3400M）Figure；
Fig. 3 is two gained formula of embodiment（III）The purity detecting figure of structure representation compound；
Fig. 4 is formula obtained by example IV（III）The purity detecting figure of structure representation compound；
Fig. 5 is formula obtained by example IV（III）The HNMR of structure representation compound is composed（DMSO 400M）Figure.
Specific embodiment
Illustrate the specific embodiment of the invention about analysis method with reference to the accompanying drawings and examples, by medicine
Technological development and verifying in object chemistry and Pharmaceutical Analysis technology scope, following scheme can be scientific and accurately verify gained
Compound and analysis to product purity.But following embodiment is used only to that the present invention will be described in detail, not in any way
It limits the scope of the invention.
Related instrument and equipment is routine instrument device unless otherwise instructed in the examples below；It is related
Reagent is commercially available conventional reagent unless otherwise instructed；Related detection test method is unless otherwise instructed routine
Method.
Embodiment one：Formula（II）The preparation of structural compounds and the verifying of structure and purity
1. by [(1R, 2R, 5S) -5- (dimethyl carbamoyl) -2- hydroxy-cyclohexyl] t-butyl carbamate 28.7g
（0.1mol), phthalimide 15.5（0.11mol）With triphenylphosphine 27.5g（0.11mol）It is added in tetrahydrofuran,
It will be dissolved with 22.1g again（0.11mol）The 250mL tetrahydrofuran solution of diisopropyl azodiformate is slowly added to, 0 DEG C of condition
Lower stirring half an hour, then react 10h at room temperature, with thin-layer chromatography monitoring reaction course, after the reaction was completed, to reactant
The stirring of 50ml saturated sodium chloride solution is added in system, then uses ethyl acetate（100ml×3）Reaction mixture is extracted, liquid separation is gone
Water phase, it is organic mix after be washed with water and wash and dry, organic phase is concentrated, sloughs partial solvent, concentration fluid column chromatography will be obtained
Obtain formula（II）38.7 g of structural compounds solid, yield are 93.2 %.
2. formula（II）The chiral analysis method of structural compounds
Chromatographic condition：
Chromatographic column：Chiral chromatographic column（CHIRALPAKIC chirality column length：250mm, internal diameter：4.6mm, packing material size：5μm）
Detection wavelength：210nm
Detector：UV detector
Mobile phase：N-hexane-dehydrated alcohol-diethylamine（55:45:0.1）
Sampling volume：20μl
Flow velocity：1.0ml/min
Column temperature：40℃
Diluent：Methanol-isopropanol（40：60）
The methods of experiments equally in embodiment three and other experimental programs similar with embodiment three confirmatory experiment or
It is used in production.
Resulting testing result is shown according to the method described above：Compound light HPLC map proves that Walden overturning is occurring
When chiral selectivity reached 99.7% or more.
Formula（II）Structure representation compound [(1R, 2S, 5S) -2-（Dimethylamino）- 5- [(1,3- phthalimide
Base) -2- carbonyl] cyclohexyl] characterize data of t-butyl carbamate is：
Fusing point：171.4~172.1 DEG C
Optical activity：[α]25 D= - 25.31（C=1, CH3OH）
Chiral purity map is as shown in Figure 1：Purity is 99.72%.
HNMR spectrum（CDCl3400M）As shown in Figure 2.
Embodiment two：Formula（III）The preparation of structural compounds and purity verifying
1. by the obtained formula of embodiment one（II）Structural compounds 38.0g（0.09mol）It is added in 250ml tetrahydrofuran,
Hydrazine hydrate 12.7g is added at room temperature（0.20mol）, 70 DEG C are warming up to, with thin-layer chromatography monitoring reaction course, after the reaction was completed,
The stirring of 50ml 1M sodium hydroxide solution is added into reaction system, again with toluene extracts reaction mixture, and vacuum concentration is de-
Remove toluene, then with 100ml acetone：Petroleum ether volume ratio is 1：3 mixed solvent recrystallization, cools to 0~5 DEG C of stirring and crystallizing mistake
Night, filtering are dried in vacuo to obtain 20.7 g of off-white powder, and yield 78.8% carries out purity according to following HPLC detection method and tests
Card, as a result as shown in figure 3, its purity is 99.22%.
2. verifying the HPLC detection method of purity
Inspection method：HPLC method（Two V D of annex of Chinese Pharmacopoeia version in 2010）
Chromatographic condition：
Chromatographic column：Octadecylsilane chemically bonded silica column（It is long：250mm, internal diameter：4.6mm, packing material size：5μm）
Detection wavelength：210nm
Detector：UV detector
Mobile phase A：0.02mol/L dipotassium hydrogen phosphate solution（With phosphorus acid for adjusting pH to 7.0）Acetonitrile（90:10）
Mobile phase B：0.02mol/L dipotassium hydrogen phosphate solution（With phosphorus acid for adjusting pH to 7.0）Acetonitrile（30:70）
Gradient elution is carried out by 1 program of table：
1 gradient of table
| Time | Mobility A | Mobility B |
| 0 | 100 | 0 |
| 19 | 40 | 60 |
| 31 | 40 | 60 |
| 38 | 100 | 0 |
| 45 | 100 | 0 |
Sampling volume：20μl
Flow velocity：1.0ml/min.
Embodiment three：Formula（II）The preparation of industrialization of structural compounds
300L is added in 1000L reaction kettle and newly opens a barrel tetrahydrofuran, is added with stirring [(1R, 2R, 5S) -5- (dimethylamino
Formyl) -2- hydroxy-cyclohexyl] 11.7 kg of t-butyl carbamate（40.8mol) and 6.6 kg of phthalimide
（44.8mol）11.7 kg of triphenylphosphine（44.8mol）, -5 DEG C are cooled to hereinafter, will be dissolved with again with brine ice under stirring
6.8 kg（44.8mol）The 200L tetrahydrofuran solution of diisopropyl azodiformate is pumped into reaction kettle, and control temperature does not surpass
0 DEG C is crossed, is stirred half an hour under heat-retaining condition after addition, logical circulating water natural is warming up to room temperature, timing after replacing brine ice
10h is reacted, detects reaction process with thin-layer chromatography, it is spare after the reaction was completed.
Example IV：Formula（III）The preparation of industrialization of structural compounds and the structural identification of product and purity are verified
Embodiment three after reaction, 40kg hydrazine hydrate is added into reaction kettle in batches（100mol）, steaming is opened after addition
Vapour is warming up to 75 DEG C, is monitored after reaction progress 4h by HPLC and is reacted to formula（II）The midbody compound of structure less than 0.1% with
Under, after cool to 25 DEG C, 1 M dilute hydrochloric acid of 300L and 200 L methylene chloride are added in reaction kettle, keeps the temperature 25 DEG C and stirs 30 minutes
It stands afterwards and separates methylene chloride, add 100 L methylene chloride washing reaction liquid again, separate dichloromethane layer.In reaction kettle
100L 1M sodium hydroxide solution is added, after detection pH is not less than 12, the extraction of 300 L toluene is added, extracts arrive water three times respectively
Without product in layer.Combining methylbenzene layer vacuum concentration.After removing is concentrated in toluene completely, 20L acetone is added in reaction system, allows solid
It is completely dissolved, is transferred in 100L glass kettle and cools down, add 60L petroleum ether after the precipitation of a large amount of solids, control crystallization temperature 0
~5 DEG C of stirring 8h.After be centrifuged, dry, obtain 9.7 kg off-white powders, purity：99.16%, two step total recoverys are 82.9 %.
Formula（III）The characterize data of structural compounds：
Fusing point：121.7-121.0℃
Optical activity：[α]25 D= - 48.81（C=1, CH3OH ）
Purity verifying is carried out according to the HPLC detection method in embodiment two, as a result as shown in figure 4, products therefrom purity is
99.16%。
HNMR spectrum（DMSO 400M）As shown in Figure 5.
Product of the present invention has had reached the quality standard of subsequent production needs, does not need further to be made into oxalates, both
Reduce Chemical Manufacture operation, and yield can be improved, further decrease production cost, shortens the production cycle；It eliminates cumbersome
Methanesulfonic acid esterification；Dangerous sodium azide and high-pressure catalytic hydrogenation are avoided, expensive metallic catalyst is equally eliminated,
Yield is increased to 82.9% by original 35% by the chiral purity for increasing product；Process costs can not only be reduced, moreover it is possible to contract
The cost of production greatly reduces in short production cycle, can finally obtain the intermediate of the high-optical-purity of high yield pulp1, i.e. formula
（II）Structural compounds.
To sum up, present invention process is simple, at low cost, and yield is high, and product optical purity is high, and pollution is small, and it is raw to be suitable for industry
It produces.
The present invention is described in detail above in conjunction with drawings and examples, inventor develops from synthesis technology and product
Two aspect of purity analysis detection is to acid imide midbody compound（II）With oral anticoagulant Yi Dushaban precursor compound
（III）It has made intensive studies, and demonstrates target product of the present invention with scientific and rigorous verification method and experimental data
The certainty of structure and the reasonability of synthesis technology.
But person of ordinary skill in the field is it is understood that without departing from the purpose of the present invention, it can be with
Each design parameter in above-described embodiment is changed, multiple specific embodiments are formed, is common change of the invention
Change range, is no longer described in detail one by one herein.
Claims (10)
1. a kind of acid imide midbody compound, which is characterized in that its structural formula is：
Formula（II）,
Wherein, the R is selected from：Phthalimide-based, tetrahydric phthalimide base, 3,4,5,6- tetrahydro O-phthalic
Imide, dimaleoyl imino, any one in o-benzoic sulfimide base.
2. acid imide midbody compound according to claim 1, which is characterized in that the compound be [(1R, 2S,
5S)-2-（Dimethylamino）- 5- [(1,3- phthalimide-based) -2- carbonyl] cyclohexyl] t-butyl carbamate,
Structural formula is：
。
3. the preparation method of acid imide midbody compound described in claim 1, which is characterized in that include the following steps：
It takes described with formula（I）The compound of structure is added in reaction dissolvent, will in the case where azo agents and ternary replace phosphorus effect
Compound comprising nucleophilic amino introduces described with formula（I）In the compound of structure, by 1 hydroxyl during introducing
Be converted into amino, at the same configuration occur reversion to get；
Wherein, the R is selected from：Phthalimide-based, tetrahydric phthalimide base, 3,4,5,6- tetrahydro O-phthalic
Imide, dimaleoyl imino, any one in o-benzoic sulfimide base.
4. the preparation method of acid imide midbody compound according to claim 3, it is characterised in that：
The reaction dissolvent is at least one of ethyl acetate, toluene, tetrahydrofuran, ether, DMF, methyl tertiary butyl ether(MTBE)；
The azo agents are diisopropyl azodiformate and/or diethyl azodiformate；
The ternary replaces phosphorus reagent in triphenylphosphine, tri-n-butyl phosphine, trimethyl-phosphine, tricyclohexyl phosphine, three sad base phosphines
At least one；
The compound containing nucleophilic amino is phthalimide, tetrahydric phthalimide, 3,4,5,6- tetrahydro neighbour
At least one of phthalimide, maleimide, o-benzoic sulfimide.
5. the preparation method of acid imide midbody compound according to claim 3, which is characterized in that the reaction
Temperature control is -10 DEG C~30 DEG C, and the time control of reaction is 1~30h.
6. the preparation method of imines midbody compound according to claim 3, it is characterised in that：
The azo agents and the formula（I）The compound mole ratio of structure is 1：1~10；
The ternary replaces phosphorus reagent and the formula（I）The compound mole ratio of structure is 1：1~10.
7. a kind of preparation method of Yi Dushaban precursor compound, it is characterised in that：
By formula described in claim 1（II）Alkali is added in the compound of structure, and then Deprotection is obtained with formula（III）Structure
Compound；
Wherein, the R is selected from：Phthalimide-based, tetrahydric phthalimide base, 3,4,5,6- tetrahydro O-phthalic
Imide, dimaleoyl imino, any one in o-benzoic sulfimide base.
8. the preparation method of Yi Dushaban precursor compound according to claim 7, which is characterized in that the alkali is methanol
Sodium, magnesium methoxide, sodium tert-butoxide, potassium tert-butoxide, calcium methoxide, lithium hydroxide, potassium hydroxide, sodium hydroxide, in hydrazine hydrate at least
It is a kind of.
9. the preparation method of Yi Dushaban precursor compound according to claim 7, which is characterized in that the temperature of the reaction
Degree control is 25 DEG C~80 DEG C；The time control of the reaction is 1~6h.
10. the preparation method of Yi Dushaban precursor compound according to claim 7, which is characterized in that the alkali and institute
State formula（II）The compound mole ratio of structure is 1：1~10.
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| KR20210066404A (en) * | 2019-11-28 | 2021-06-07 | 동방에프티엘(주) | A novel synthetic route for the production of optically active diamine derivative and thiazole derivate |
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