CN102070514B - Method for preparing halofuginone intermediate - Google Patents
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Abstract
本发明公开了如式D或E所示的常山酮中间体的制备方法，其包括下列步骤：步骤(1)，将化合物F的溶液滴加到氯甲酸苄酯的溶液中，进行Van Braun反应，制得化合物E；步骤(2)，将步骤(1)所得化合物E进行Claisen重排反应，即可。该方法使得Van Braun反应能够进行完全、同时减少了氯甲酸苄酯的用量，提高了反应的效率，并且可在随后的Claisen重排反应中，选择性地得到2-位的产物。在本发明的一较佳实施例中，通过一锅法简化了操作过程，减少了溶剂的用量，提高了选择性，降低了反应的成本，减小了对环境的污染，为常山酮的大规模生产创造了良好的条件。 The invention discloses a preparation method of a hemosanone intermediate as shown in formula D or E, which comprises the following steps: step (1), adding the solution of compound F dropwise to the solution of benzyl chloroformate to carry out Van Braun reaction , to obtain compound E; in step (2), subject compound E obtained in step (1) to Claisen rearrangement reaction. The method enables the complete Van Braun reaction, reduces the amount of benzyl chloroformate, improves the efficiency of the reaction, and can selectively obtain the 2-position product in the subsequent Claisen rearrangement reaction. In a preferred embodiment of the present invention, the operation process is simplified by the one-pot method, the consumption of solvent is reduced, the selectivity is improved, the cost of reaction is reduced, and the pollution to the environment is reduced, which is the largest of hemosanone Scale production has created good conditions. 
Description
Technical field
The present invention relates to the preparation method of intermediate for halofuginone.
Background technology
Halofuginone hydrobromide (Halofuginone, Hal) is a kind of quinazoline ketones alkaloid, and it is the halo derivatives of febrifugin(e), generally its hydrobromate commonly used.Halofuginone hydrobromide has strong insecticidal activity, and multiple chicken coccidia is all had stronger inhibitory or killing effect.The halofuginone hydrobromide that adds 3ppm concentration in the feed can effectively be controlled 6 kinds of chicken Eimerias, can obviously control the coccidiosis clinical symptom after the medication, and suppresses egg capsule fully and discharge, and makes environment no longer contaminated, thereby reduces the possibility that infects again.(referring to J.Johnson, et al, Exp parasitol, 1970,28:30; J.Grant, etel.Parasitology Research, 1991,77:595)
Along with going deep into for halofuginone hydrobromide drug effect and pharmacological research, it is found that it can be suppressed to the synthetic type i collagen fiber of fibrocyte different in naturely, a kind of novel type i collagen synthetic inhibitor (referring to G.Spira, et al.J.Hepatol.2002,37:331).Halofuginone hydrobromide also can be used as the treatment research that medicine is used for the cancers such as bladder, prostate gland, mammary gland, skin, lung (referring to Z.Garish, et al.Prostate, 2002,51:73).
Halofuginone hydrobromide synthetic has several different methods, and wherein two kinds of methods commonly used are as follows:
Method 1:
Wherein, compd B
1Middle R is methyl or benzyl.
Method 2:
Wherein, compd B
1And B
2All can prepare by Compound D:
Wherein, compd B
1Middle R is methyl or benzyl.
Therefore, Compound D has important using value as the key intermediate of synthetic halofuginone hydrobromide.
The people such as Takeuchi have delivered the preparation method of Compound D and C at Synthesis among 1999, the 10:1814, its synthetic route is as follows:
Specifically comprise the following steps:
Step (1) splashes into Benzyl Chloride in the toluene solution of 3-pyridone, reflux 1 hour, and cooling is filtered, and the gained solid obtains compound G with ethyl acetate and ether washing, and yield is more than 90%;
Step (2) is dissolved in methyl alcohol with compound G and allyl bromide 98, adds sodium hydride in batches, reflux 4 hours.Be chilled to about 0 ℃, add NaBH in batches
4, stirred 0.5 hour under the room temperature.Reaction solution with 10% hcl acidifying, is used saturated KHCO again
3The solution alkalization through ethyl acetate extraction, drying, filtration, concentrated, purification by silica gel column chromatography, obtains compound F 17-hydroxy-corticosterone, and yield is more than 60%;
Step (3) under 0 ℃, is added drop-wise to 5～6eq. chloroformic acid benzyl ester in tetrahydrofuran (THF) (THF) solution of compound F 17-hydroxy-corticosterone, stirs 1 hour under room temperature after adding.Pour reaction solution into saturated KHCO
3In the solution, ethyl acetate extraction, drying, filtration, concentrated, purification by silica gel column chromatography [eluent: normal hexane: ethyl acetate=(0～30): (1～5)] obtain compd E, yield 90%.This is called Van Braun reaction by the reaction of benzyl on the carbalkoxy substituted nitrogen atom;
Step (4) under the argon shield, is dissolved in acetonitrile with compd E, under the room temperature, drips BF
3OEt
2Solution keeps stirring at room that the Claisen rearrangement reaction namely occured in 1.5 hours.Reaction finishes, and pours reaction solution into saturated KHCO
3In the solution, ethyl acetate extraction, purification by silica gel column chromatography (eluent: normal hexane: ethyl acetate=3: 1), obtain Compound D, yield 73%;
Step (5) is dissolved in methyl alcohol with Compound D, adds NaBH in batches
4Reduction obtains Compound C through aftertreatment, yield 97%.
There is following defective in above-mentioned preparation method:
A. in the step (3), the chloroformic acid benzyl ester amount that Van Braun reacts used is very large, is about 6 times of compound F 17-hydroxy-corticosterone amount of substance, and nonetheless, raw material also can't complete reaction.The existence of excessive chloroformic acid benzyl ester brings very large difficulty for the column chromatography for separation of product, need to use long chromatography column, carries out long gradient elution and just can be separated to sterling, and the repeatability of reaction is also poor;
B. in the step (3), the used excessive chloroformic acid benzyl ester of Van Braun reaction does not reclaim, and this reagent price is more expensive, increased the cost of reaction, and the toxicity of chloroformic acid benzyl ester large, have irritating smell, when preparing compd E in a large number, can cause detrimentally affect to environment;
C. in the step (4), the solvent acetonitrile toxicity of Claisen rearrangement reaction is larger, and reclaims, and in the pollution that has aggravated environment, has also increased reaction cost.
Summary of the invention
Technical problem to be solved by this invention is that to have overcome the consumption of the chloroformic acid benzyl ester that exists among the preparation method of existing intermediate for halofuginone too much, reaction is difficult to carry out fully, the aftertreatment difficulty, yield is not high, need to use the larger solvent of toxicity, cost is higher, seriously polluted, the defective that is unfavorable for extensive preparation, and provide a kind of preparation method of new intermediate for halofuginone, the method is so that Van Braun reaction can be carried out complete, reduced simultaneously the consumption of chloroformic acid benzyl ester, improved the efficient of reaction, and can in Claisen rearrangement reaction subsequently, optionally obtain the product of 2-position.In a preferred embodiment of the present invention, simplified operating process by one kettle way, reduced the consumption of solvent, improved selectivity, reduced the cost of reaction, reduced the pollution to environment, for good condition has been created in the scale operation of halofuginone hydrobromide.
Therefore, the present invention relates to a kind of preparation method suc as formula the intermediate for halofuginone shown in the E, it comprises the following steps: the solution of compound F 17-hydroxy-corticosterone is added drop-wise in the solution of chloroformic acid benzyl ester, carries out Van Braun reaction, gets final product.
Wherein, the method for described Van Braun reaction and condition all can be ordinary method and the condition of this type of reaction of this area except feed way.The present invention is following method and condition particularly preferably: wherein, the solution of described compound F 17-hydroxy-corticosterone is better is in tetrahydrofuran solution, dioxane solution and the toluene solution of compound F 17-hydroxy-corticosterone one or more, and better is the tetrahydrofuran solution of compound F 17-hydroxy-corticosterone.In the solution of described compound F 17-hydroxy-corticosterone, that the quality of compound F 17-hydroxy-corticosterone and the volume ratio of solvent are better is 0.2～0.8g/ml, and that better is 0.4g/ml.The solution of described chloroformic acid benzyl ester is better is in tetrahydrofuran solution, dioxane solution and the toluene solution of chloroformic acid benzyl ester one or more, and better is the tetrahydrofuran solution of chloroformic acid benzyl ester.In the solution of described chloroformic acid benzyl ester, that the volume ratio of chloroformic acid benzyl ester and solvent is better is 0.5～2ml/ml, and that better is 1ml/ml.The consumption of described chloroformic acid benzyl ester is better is 3～6 times of compound F 17-hydroxy-corticosterone molar weight, and better is 4 times.What the temperature of described Van Braun reaction was better is-5～30 ℃, and better is 0～25 ℃.The time of described Van Braun reaction is better finish with detection reaction till, be generally 1～3 hour.Described dropping can be the dropwise operation of this area routine, as dripping by instruments such as constant pressure funnel or syringes.Being controlled at that the speed of described dropping is better makes the interior temperature of reaction solution be no more than 0 ℃.
Among the present invention, compared with prior art, by changing feed way, the solution of compound F 17-hydroxy-corticosterone is added drop-wise in the solution of chloroformic acid benzyl ester, so that Van Braun reaction can fully carry out, compound F 17-hydroxy-corticosterone can complete reaction, and the consumption of chloroformic acid benzyl ester also greatly reduces simultaneously, reaction has obtained better effect, and follow-up Claisen rearrangement reaction also has good selectivity.
The invention further relates to a kind of preparation method suc as formula the intermediate for halofuginone shown in the D, it comprises the following steps:
Step (1) is added drop-wise to the solution of compound F 17-hydroxy-corticosterone in the solution of chloroformic acid benzyl ester, carries out Van Braun reaction, makes compd E;
Step (2) is carried out the Claisen rearrangement reaction with step (1) gained compd E, gets final product.
Wherein, the preparation method of the compd E described in the step (1) is ditto described.
In the step (2), the method for described Claisen rearrangement reaction and condition all can be ordinary method and the condition of this type of reaction of this area.The present invention is following method and condition particularly preferably: in the organic solvent, compd E is reacted under 50～80 ℃ condition, get final product.Wherein, described organic solvent can be the conventional solvent of this type of reaction of this area, one or more that better is in dioxane, toluene and the tetrahydrofuran (THF), and better is tetrahydrofuran (THF).What the temperature of described reaction was better is 65～70 ℃, and better is the reflux temperature of tetrahydrofuran (THF).The time of described reaction is better finish with detection reaction till, be generally 2～3 hours.
Preferably, Compound D is made by following method: step (1) gained reaction mixture is directly carried out the described Claisen rearrangement reaction of step (2), get final product.This is by one kettle way and prepares Compound D.This method has been simplified experimental implementation, saved the cost of reaction, and total recovery is higher than the yield that carries out separately two-step reaction in the prior art.
In a preferred embodiment of the present invention, when carrying out the Claisen rearrangement reaction, reclaim solvents tetrahydrofurane by air distillation, after tetrahydrofuran (THF) has steamed, reclaim chloroformic acid benzyl ester by underpressure distillation again, thereby improved the utilization ratio of solvent and reagent, also reduced the detrimentally affect that environment is caused.
Without prejudice to the field on the basis of common sense, but above-mentioned each preferred feature arbitrary combination among the present invention namely gets the preferred embodiments of the invention.
Raw material described in the present invention or reagent except specifying, equal commercially available getting.
Positive progressive effect of the present invention is: the consumption of chloroformic acid benzyl ester can be carried out fully, reduced simultaneously to the VanBraun reaction among the preparation method of intermediate for halofuginone of the present invention, improved the efficient of reaction, and can in Claisen rearrangement reaction subsequently, optionally obtain the product of 2-position.In preferred embodiment of the present invention, simplified operating process by one kettle way, reduced the consumption of solvent, improved selectivity, reduced the cost of reaction, reduced the pollution to environment, for good condition has been created in the scale operation of halofuginone hydrobromide.
Embodiment
The below further specifies the present invention with embodiment, but the present invention is not limited.
Used raw material or reagent is except specifying among the embodiment, all commercially available getting.
Room temperature described in the embodiment all refers to 20～35 ℃.
The preparation method of compound F 17-hydroxy-corticosterone is referring to document Takeuchi, et al.Synthesis, 1999,10:1814.
The preparation of embodiment 1 compound G
N
2Protection is lower, and 1.9g (20mmol) 3-pyridone joins in the 15ml toluene, and property adding 2.4ml (21mmol) benzyl chlorine is heated to backflow again, and insolubles fades away, the solution clarification.Along with the carrying out of reaction, the solution bottom has oily liquids to generate, reflux 1 hour, and stopped heating, cooling, the bottom oily liquids is become solid, pours out upper solution, and solid mortar porphyrize is again with ethyl acetate washing three times, then with the ether washing once.Vacuum-drying obtains compound G 4.0g, yield 91%, fusing point: 159～161 ℃ (literature value: 159～160 ℃).
The preparation of embodiment 2 compound F 17-hydroxy-corticosterones
N
2Protection is lower; 3.8g (17mmol) compound G is dissolved in 10ml methyl alcohol; add 1.6ml (19mmol) 3-bromopropylene; take by weighing the sodium hydride of 0.60g (20mmol) 80%; join in the mentioned solution in batches, refluxed 4 hours, be chilled to 0 ℃; add 0.72g (19mmol) sodium borohydride in batches, keep 0 ℃ of reaction 30 minutes.Reaction finishes, and pH to 7～8 are regulated with saturated sodium bicarbonate solution again in the salt acid for adjusting pH to 5 of usefulness 3mol/l～6, ethyl acetate extraction (10ml * 4), merge organic phase, saturated common salt water washing three times, drying, steaming desolventizes, get crude product 2.4g, use again the quick wash-out of simple and easy short silicagel column (eluent: sherwood oil), get colourless oil liquid 2.3g, yield 60%, its Structural Identification data are as follows:
1H NMR (CDCl
3): δ 2.16～2.19 (2H, m), 2.52 (2H, t, J=5.7Hz), 2.95 (2H, d, J=1.3Hz), (3.60 2H, s), 4.20 (2H, d, J=5.5Hz), 4.66 (1H, t, J=3.8Hz), 5.18～5.20 (1H, m), 5.27～5.31 (1H, m), 5.91～5.97 (1H, m), 7.24～7.35 (5H, m).
The preparation of embodiment 3 Compound D
N
2Protection is lower, and 6ml (42mmol) chloroformic acid benzyl ester is dissolved in the 6ml tetrahydrofuran (THF), under 0 ℃, to the 6ml tetrahydrofuran solution that wherein drips 2.40g (10.5mmol) compound F 17-hydroxy-corticosterone, after adding, keeps 0 ℃ to react 15 minutes, rises to room temperature, restir 2 hours.Slowly be warming up to backflow, tetrahydrofuran (THF) is reclaimed in air distillation, approximately 4ml of chloroformic acid benzyl ester is reclaimed in underpressure distillation again, resistates purification by silica gel column chromatography (eluent: sherwood oil: ethyl acetate=20: 1), obtain faint yellow viscous liquid 2.5g, two-step reaction total recovery 70%, the Structural Identification data of product are as follows:
1H NMR (CDCl
3): δ 1.88～1.93 (2H, m), 2.41～2.52 (2H, m), 3.22～3.26 (1H, m), 4.07～4.19 (1H, m), 4.58～4.69 (1H, m), 5.04～5.15 (4H, m), (5.15 2H, s), 5.51～5.75 (1H, m), 7.29～7.36 (5H, m).
The preparation of embodiment 4 Compound C
N
2Protection is lower, and 1.45g (5.3mmol) Compound D is dissolved in 5ml methyl alcohol, is chilled to below 0 ℃, adds 0.24g (6.3mmol) sodium borohydride in batches, keeps stir about below 0 ℃ 1 hour to reacting completely.Reaction solution is slowly poured in the hydrochloric acid of 20ml 10% into ethyl acetate extraction (5ml * 4), saturated common salt water washing (3ml * 3), anhydrous sodium sulfate drying, steaming desolventizes, and gets pale yellow oily liquid body 1.33g, yield 95%, its Structural Identification data are as follows:
1H NMR (CDCl
3): δ 1.44～1.53 (2H, m), 1.61～1.75 (2H, m), 2.26～2.41 (2H, m), 2.66～2.71 (1H, m), 3.74～3.93 (2H, m), 4.43 (1H, s), 4.90～5.06 (4H, m), 5.65～5.66 (1H, m), 7.19～7.30 (5H, m).
The preparation of embodiment 5 Compound D
N
2Protection is lower, and 7.5ml (52.5mmol) chloroformic acid benzyl ester is dissolved in the 6ml dioxane, under 0 ℃; to the 6ml dioxane solution that wherein drips 2.40g (10.5mmol) compound F 17-hydroxy-corticosterone, after adding, keep 0 ℃ of reaction 15 minutes; be warming up to 30 ℃, restir 2 hours.Slowly be warming up to 80 ℃, keep 80 ℃ of reactions.Reaction finishes, reclaim respectively dioxane and chloroformic acid benzyl ester, resistates purification by silica gel column chromatography (eluent: sherwood oil: ethyl acetate=20: 1), obtain faint yellow viscous liquid 2.39g, two-step reaction total recovery 67%, the Structural Identification data of product are with embodiment 3.
The preparation of embodiment 6 Compound D
N
2Protection is lower, and 9ml (63mmol) chloroformic acid benzyl ester is dissolved in 6ml toluene, under-5 ℃, to the 6ml toluene solution that wherein drips 2.40g (10.5mmol) compound F 17-hydroxy-corticosterone, after adding, keeps-5 ℃ of reactions.Treat that Van Braun reaction carries out slowly being warming up to 50 ℃ fully, keep 50 ℃ of reactions.Reaction finishes, reclaim respectively toluene and chloroformic acid benzyl ester, resistates purification by silica gel column chromatography (eluent: sherwood oil: ethyl acetate=20: 1), obtain faint yellow viscous liquid 2.46g, two-step reaction total recovery 69%, the Structural Identification data of product are with embodiment 3.
Claims (1)
1. preparation method suc as formula the compound shown in the C is characterized in that:
N
2Protection is lower, and 1.9g 3-pyridone joins in the 15ml toluene, and property adding 2.4ml benzyl chlorine is heated to backflow again; insolubles fades away, the solution clarification, and along with the carrying out of reaction, the solution bottom has oily liquids to generate; reflux 1 hour, stopped heating, cooling; the bottom oily liquids is become solid, pours out upper solution, solid mortar porphyrize; with ethyl acetate washing three times, then wash once vacuum-drying with ether again; obtain compound G 4.0g, yield 91%
N
2Protection is lower, and 3.8g compound G is dissolved in 10ml methyl alcohol, adds the 1.6ml3-bromopropylene; take by weighing the sodium hydride of 0.60g 80%, join in the mentioned solution in batches, refluxed 4 hours; be chilled to 0 ℃, add the 0.72g sodium borohydride in batches, keep 0 ℃ of reaction 30 minutes; reaction finishes, and pH to 7～8 are regulated with saturated sodium bicarbonate solution again in the salt acid for adjusting pH to 5 of usefulness 3mol/L～6; ethyl acetate extraction; 10ml * 4 merge organic phase, saturated common salt water washing three times; dry; steaming desolventizes, and gets crude product 2.4g, uses the quick wash-out of simple and easy short silicagel column again; eluent: sherwood oil; get colourless oil liquid 2.3g, yield 60%
N
2Protection is lower, and the 6ml chloroformic acid benzyl ester is dissolved in the 6ml tetrahydrofuran (THF), under 0 ℃; to the 6ml tetrahydrofuran solution that wherein drips the 2.40g compound F 17-hydroxy-corticosterone, after adding, keep 0 ℃ of reaction 15 minutes; rise to room temperature, restir 2 hours slowly is warming up to backflow; tetrahydrofuran (THF) is reclaimed in air distillation, and chloroformic acid benzyl ester 4ml, resistates purification by silica gel column chromatography are reclaimed in underpressure distillation again; eluent: sherwood oil: ethyl acetate=20: 1; obtain faint yellow viscous liquid 2.5g, two-step reaction total recovery 70%
N
2Protection is lower, and the 1.45g Compound D is dissolved in 5ml methyl alcohol, is chilled to below 0 ℃; add the 0.24g sodium borohydride in batches, keep stirring below 0 ℃ 1 hour to reacting completely, reaction solution is slowly poured in the hydrochloric acid of 20ml 10%; ethyl acetate extraction; 5ml * 4, saturated common salt water washing, 3ml * 3; anhydrous sodium sulfate drying; steaming desolventizes, and gets pale yellow oily liquid body 1.33g, yield 95%.
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| CN102603615B (en) * | 2012-02-22 | 2013-11-13 | 中国海洋大学 | Intermediates of 2-acetonyl-3-methoxy piperidine and preparation method of 2-acetonyl-3-methoxy piperidine |
| CN103204801A (en) * | 2013-04-12 | 2013-07-17 | 兰州远辉生物科技有限公司 | Synthesis method for N-Boc-3-piperidone |
| CN103204799B (en) * | 2013-05-06 | 2015-04-15 | 青岛农业大学 | (2S,3R)-1-substituted benzyl-2-allyl-3-hydroxypiperidine and preparation method thereof |
| CN103304472A (en) * | 2013-06-15 | 2013-09-18 | 扬州天和药业有限公司 | Method for synthesizing 1-BOC-3-piperidone |
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| Yasuo Takeuchi,et al.Synthesis of D/L-Febrifugine and D/L-Isofebrifugine.《Synthesis》.1999,(第10期),1814-1818. * |
| 冯永斌.非甾体抗炎药达布飞龙和生物碱常山酮的合成.《CNKI(中国优秀硕士学位论文全文数据库工程科技I辑)》.2006,(第12期),32-38. * |
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