CN100439331C - Intermediate of anti-AIDS medicine 'Nelfinavir' and its syntesizing process and application - Google Patents

Intermediate of anti-AIDS medicine 'Nelfinavir' and its syntesizing process and application Download PDF

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CN100439331C
CN100439331C CNB021361304A CN02136130A CN100439331C CN 100439331 C CN100439331 C CN 100439331C CN B021361304 A CNB021361304 A CN B021361304A CN 02136130 A CN02136130 A CN 02136130A CN 100439331 C CN100439331 C CN 100439331C
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马大为
邹斌
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention relates to a key intermediate, a synthetic method and purposes of nelfinavir. The right formula is the structural formula of the intermediate, wherein R is equal to hydrogen, benzyl, carbobenzoxy, tertiary butyloxycarbonyl, 3-acetoxy-2-methylbenzoyl, 3-hydroxy-2-methylbenzoyl and other acyl protecting groups; n is equal to 0, 1 or 2; R<1>=R<2>=H, R<1> and R<2> are equal to propylidene, R<1> and R<2> are equal to benzylidene, and R<1> and R<2> are equal to 3-pentylidene. The method of the present invention has the advantages of convenient synthetic method and easy acquisition of raw materials; in addition, the method is suitable for the industrial production of nelfinavir medicines.

Description

The intermediate of AIDS drug Na Feinawei, synthetic method and purposes
Technical field
The present invention relates to key intermediate, synthetic method and the purposes of a kind of Na Feinawei (Nelfinavir).
Background technology
Na Feinawei (Nelfinavir) is that the most effective a kind of human immunity lacks one of (HIV) viral inhibitor, and is used for clinical in 1997 by U.S. federal Food and Drug Administration (FDA) (FDA) approval.Because the extensive concern that its complex structure and vast market prospect cause the chemist.
Former synthetic in, most chemist all be with following mixture 1 or 2 as the key intermediates that synthesize Na Feinawei:
Figure C0213613000081
TakashiInaba etc. (J.Org..Chem.1998,63,7582) report synthetic route as follows:
Figure C0213613000091
Also use compound 2 as follows as the synthetic route of key intermediate (Takashi Inaba, J.Org..Chem.2000,65,1623):
Figure C0213613000092
Because synthetic intermediate 1 cis-selectivity route relatively poor and synthetic compound 2 is longer, so people are still constantly exploring new synthetic route.
Summary of the invention
The key intermediate that the purpose of this invention is to provide a kind of Na Feinawei (Nelfinavir),
The object of the invention also provides a kind of synthetic method of above-claimed cpd.This method raw material is easy to get, and route is shorter, is applicable to suitability for industrialized production.
Another object of the present invention provides a kind of purposes of above-claimed cpd.
Compound of the present invention has following structural formula:
Figure C0213613000101
Wherein, R=hydrogen (H), benzyl (Bn), carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), 3-acetoxyl group-2-methyl benzoyl, 3-hydroxy-2-methyl benzoyl, and the protecting group of other acyl group classes; N=0,1 or 2.R 1=R 2=H, R 1And R 2=propylidene base, R 1And R 2=benzal base, R 1And R 2=3-pentylidene base; Condition is: when R=carbobenzoxy-(Cbz), n=0, and R 1=R 2≠ H, R 1And R 2≠ propylidene base; When R=carbobenzoxy-(Cbz), n=2, R 1And R 2≠ H.
Compound of the present invention can also further describe and be the following structures formula:
Figure C0213613000102
Wherein, wherein, R=hydrogen, benzyl, tertbutyloxycarbonyl, 3 acetoxyl groups-2-methyl benzoyl, 3-hydroxy-2-methyl benzoyl, and the protecting group of other acyl group classes; N according to claim 1, R 3=R 4=methyl, R 3=R 4=ethyl, R 3=H and R 4=phenyl.
Compound of the present invention specifically is an example with following compound, can be the compound of following structural formula:
Figure C0213613000103
Figure C0213613000111
Figure C0213613000121
Synthetic above-claimed cpd method of the present invention can be passed through following (1) and (2), (3) and (4), (1), (2) and (5), (3), (4) and (6), (1), (2), (5) and (7), (1), (2), (5), (7) and (8) six kinds of methods are synthetic respectively.
Figure C0213613000131
Under-78 °-0 ℃ of organic solvent neutralization, phenyl methyl sulfoxide and lithium diisopropyl amido reaction 0.1-2 hour, add (S)-sweet dew aldehyde, react and obtained pure product 2 in 0.5-2 hour, wherein, the mol ratio of phenyl methyl sulfoxide, lithium diisopropyl amido and (S)-sweet dew aldehyde is 1: 1-1.2: 0.8-1.2; Further the operation of recommending be in organic solvent and 0 ℃ under, phenyl methyl sulfoxide (1) and lithium diisopropyl amido (LDA) reaction 0.1-2 hour are cooled to-78 ℃, slowly add (S)-sweet dew aldehyde, reacted saturated ammonium chloride solution cancellation reaction 0.5-2 hour.Separatory obtains thick pure product 2 after the organic phase drying is spin-dried for.
In organic solvent and under 0--50 ℃, the organic amine compound that contains lone-pair electron on above-mentioned thick pure product 2, methylsulfonyl chloride (MsCl) and the nitrogen-atoms reacted 0.5-10 hour.Thick pure product 2, MsCl and the mol ratio that contains the organic amine compound of lone-pair electron are 1: 1-1.5: 1-10.This reacts available saturated nacl aqueous solution cancellation.The water ethyl acetate extraction merges organic phase and uses anhydrous sodium sulfate drying.Obtain product 3.
The organic amine compound that contains lone-pair electron on the described nitrogen-atoms can be benzyl lauryl amine, triethylamine, benzyl lauryl amine, Tributylamine, trioctylamine, diisopropyl ethyl amine, pyridine, bipyridine, 1,8-diazacyclo [4.3.0]-5-nonene, 1,8-diaza-dicyclo-[5,4,0]-hendecene-7 (DBU), N, O-two-(trimethyl silicon based) ethanamide, 4-(N, N-dimethyl)-pyridine or 1,4-diazacyclo [2.2.2] octane etc. or their mixture.The organic amine compound that contains lone-pair electron on the recommendation nitrogen-atoms is the mixture of triethylamine and DBU.
In polar solvent and under 30-100 ℃, above-claimed cpd 3 and excessive RNH 2Reacted 5-96 hour, and obtained compound 4.R as previously mentioned.This reaction is preferably in the tube sealing to be carried out.
(3)
Figure C0213613000141
Under organic solvent neutralization-78-0 ℃, compound 5 and butyllithium reaction 0.5-1 hour; Adding structural formula is
Figure C0213613000142
Phosphoryl chloride reaction 0.5-1 hour; With (S)-sweet dew aldehyde reaction 0.5-2 hour, obtain compound 6 again.Wherein, compound 5, butyllithium, above-mentioned phosphoryl chloride and (S)-sweet dew aldehyde mol ratio is followed successively by 1: 2-3: 1-1.5: 1-1.5.
In polar solvent, above-mentioned compound 6 and excessive RNH 2Back flow reaction 5-96 hour, obtain compound 7.
Figure C0213613000144
In anhydrous acetonitrile and under the room temperature, compound 4, sodium iodide and Lewis acid reacted 2-12 hour, obtained compound 8., wherein compound 4, sodium iodide, lewis acidic mol ratio are 1: 2-5: 2-5.Add more amount sodium iodide or Lewis acid during reaction to not influence of reaction.Described Lewis acid is boron trifluoride diethyl etherate (BF 3Et 2O), titanium tetrachloride (TiCl 4), titanous chloride (TiCl 3) etc.
Figure C0213613000145
Compound 7 is when the R=benzyl, and compound is 7a, under the effect of polar solvent catalyst neutralisation, and 30-100 ℃ and (10-100) * 10 5Under the Pa pressure, obtain 7b with hydrogen reaction.The weight ratio of 7a and catalyzer is 1: 0.001-0.1, the amount of more catalyzer is to not influence of reaction.Described catalyzer is palladium/carbon, palladium hydroxide/carbon, lanthanum niobium-nickel etc.
Figure C0213613000151
Above-claimed cpd 8 is when R=hydrogen, and this compound is 8a, and in organic solvent, compound 8a and 3-acetoxyl group-2-tolyl acid and condensing agent reaction 1-3 days obtain compound 8b.The mol ratio of compound 8a and 3-acetoxyl group-2-tolyl acid and condensing agent is 1: 1-1.5: 1-5, described condensing agent is 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI), I-hydroxybenzotriazole (HOBt), N, N '-dicyclohexylcarbodiimide (DCC) or N-hydroxy-succinamide (HOSu) etc. and their mixture.
Figure C0213613000152
In polar solvent and under the room temperature-40 ℃,, obtain compound 9 with mineral acid acidifying compound 8b1-5 hour.The mol ratio of compound 8b and mineral acid is 1: 0.01-1.Described mineral acid is dilute hydrochloric acid, dilute sulphuric acid, dilute phosphoric acid etc.
In the method for the present invention, R does not have the condition restriction of above-claimed cpd as mentioned above, and described organic solvent can be ethanol, acetonitrile, tetrahydrofuran (THF), anhydrous diethyl ether, sherwood oil, benzene, methylene dichloride etc.Described polar solvent is methyl alcohol, ethanol, propyl alcohol, dimethyl sulfoxide (DMSO) (DMSO), N, dinethylformamide (DMF) or acetonitrile etc. and their mixed solvents thereof.
The key intermediate of Na Feinawei of the present invention (Nelfinavir) can be used for synthetic Na Feinawei medicine, simple synthetic method not only, and raw material is easy to get, and is a kind of method that is applicable to suitability for industrialized production.
Following examples help to understand the present invention, but are not limited to content of the present invention:
Embodiment 1 compound 3a's is synthetic:
Figure C0213613000161
Under 0 ℃, 5mlBuLi (1.6M) is added drop-wise in the 10ml dry tetrahydrofuran solution of Diisopropylamine (1.2ml), stirs half an hour, makes LDA (8mmol) solution.
1.027 gram phenyl methyl sulfone (7.33mmol) is dissolved in the 15ml exsiccant tetrahydrofuran (THF).After being chilled to 0 ℃, above-mentioned LDA solution is slowly added.After stirring half an hour, be cooled to-78 ℃.The 5ml tetrahydrofuran solution of 0.851 gram (S)-sweet dew aldehyde (6.55mmol) is slowly splashed into.React after one hour saturated ammonium chloride solution cancellation reaction.Water is quenched with ethyl acetate and is got, and merges organic phase.Behind the anhydrous sodium sulfate drying, be spin-dried for and obtain thick pure product.
Above-mentioned thick product is dissolved in the 10ml exsiccant methylene dichloride, add successively under 0 ℃ triethylamine (1.6ml, 11.6mmol), MsCl (0.63ml, 8mmol), DBU (2.35ml, 15.6mmol).Under this temperature, stirred 0.5 hour, be raised to 50 ℃ of reactions 2 hours again.Saturated nacl aqueous solution cancellation reaction.The water ethyl acetate extraction merges organic phase and uses anhydrous sodium sulfate drying.Sherwood oil: ethyl acetate=column chromatography obtained 1.15 gram 3a, yield 70% in 1: 1.
1HNMR(300MHz，CDCl 3)δ1.35(s，6H)，3.7(m，1H)，4.2(m，2H)，4.7(m，1H)，6.2(d，1H)，6.6(d，1H)，7.5-7.7(m，5H).
MS(m/z)252(M +)
HRMS, C 12H 16O 3S: calculated value 252.08291, measured value 252.08202.
Embodiment 1 compound 4a's is synthetic:
Figure C0213613000162
In tube sealing,, feed ammonia until becoming saturated solution with 100ml dissolve with methanol 381mg compound 3a.Sealing tube sealing post-heating to 60 ℃ reaction 18 hours.After the TLC detection reaction is intact, be spin-dried for solvent.Ethyl acetate: methyl alcohol=column chromatography obtained 333mg 4a in 10: 1, yield 81%.
1HNMR(300MHz，CDCl 3)δ1.3(m，6H)，1.7(bs，2H)，2.1(m，1H)，3.0(m，1H)，3.8(m，1H)，4.1(m，2H)，7.5-7.7(m，5H).
ESI?MS：270(M+H)
Embodiment 3 compound 8a's is synthetic:
Compound 4a (110mg 0.4mmol) is dissolved in 8ml exsiccant second cyanogen, and the adding sodium iodide (215mg, 1.4mmol).Solid dissolving postcooling to 0 ℃ slowly adds BF 3Et 2O (0.15ml, the dry second cyanogen of 2ml 1.2mmol) solution.React after one hour, the TLC detection reaction is intact.Dilute with ethyl acetate after being spin-dried for solvent.Use saturated nacl aqueous solution successively, 15% hypo solution washing organic phase.Anhydrous sodium sulfate drying.Ethyl acetate: methyl alcohol=column chromatography obtained 75mg compound 7 in 20: 1, productive rate 72.5%.
1HNMR(300MHz，CDCl 3)1.35(s，3H)，1.41(s，3H)，1.6(bs，2H)，2.9(m，2H)，3.1(d，1H)，3.8(t，1H)，4.05(t，1H)，4.1(b，1H)，7.2-7.4(m，5H).
ESI?MS?254(M+H)。
Embodiment 4 compound 8b and 8c's is synthetic:
Figure C0213613000172
(254mg 1mmo1) is dissolved in the 10ml exsiccant tetrahydrofuran (THF) compound 7.Add successively 3-acetoxyl group-2-tolyl acid (188mg, 1mmol), EDCI (557mg, 3mmol), HOBt (392mg, 3mmol).Reaction added the ethyl acetate dilution after 24 hours under the room temperature.Organic phase is washed with saturated nacl aqueous solution.Anhydrous sodium sulfate drying.Sherwood oil: ethyl acetate=careful column chromatography obtained 289mg8b (productive rate 70%) and 74mg8c (productive rate 17%) in 3: 1.
8b
1HNMR(300MHz，CDCl 3)δ1.3(s，3H)，1.4(s，3H)，2.2(S，3H)，(2.3(s，3H)，3.2(dt，2H)，3.75(t，1H)，4.08(t，1H)，4.35(q，1H)，4.5(t，1H)，7.0-7.5(m，8H).
ESI?MS?430(M+H)
HRMS?calcd?for?C 23H 27NO 5SNa?452.15022(M+Na)，found?452.14969
8c
1HNMR(300MHz，CDCl 3)δ1.3(s，3H)，1.4(s，3H)，2.2(s，3H)，2.35(s，3H)，3.3(dq，2H)，3.85(q，1H)，4.05(t，1H)，4.25(q，1H)，4.3(m，1H)，7.0-7.5(m，8H).
ESI?MS?430(M+H)
HRMS, C 23H 27NO 5S Na (M+Na): calculated value 452.1502148, measured value 452.1508190.
Synthesizing of embodiment 5 compounds 9:
(300mg 0.7mmol) is dissolved in the 10ml methyl alcohol compound 8a, adds the hydrochloric acid of 1ml 1N.Be heated to 40 ℃ of reactions 1.5 hours, the TLC detection reaction is complete.Be spin-dried for solvent, wash with saturated sodium bicarbonate solution ethyl acetate dilution back.Separatory, the organic phase anhydrous sodium sulfate drying.Sherwood oil: ethyl acetate=column chromatography obtained 245mg product 9 in 1: 3, productive rate 90%.
1HNMR(300MHz，CDCl 3)δ2.3(s，3H)，2.35(s，3H)，2.65(brs，2H)，2.95(m，1H)，3.3(m，2H)，3.65(q，2H)，4.08(brd，1H)，4.35(q，1H)，7.0-7.5(m，8H).
ESI?MS?390(M+1)
HRMS, C 20H 23NO 5Sna (M+Na): calculated value 412.11892, measured value 412.11348.
Embodiment 6Nelfinavir's is synthetic:
Figure C0213613000191
Compound 9 (38mg 0.1mmol) is dissolved in 5ml exsiccant methylene dichloride, and the adding triethylamine (55 μ L, 0.4mmol), benzene sulfonyl chloride (20mg, 0.1mmol), DMAP (2mg, cat.).After reaction was spent the night, the TLC detection reaction was complete.Add saturated nacl aqueous solution washing organic phase, the water ethyl acetate extraction.Merge organic phase, anhydrous sodium sulfate drying.Crude product after being spin-dried for is dissolved in the 5ml anhydrous methanol, and adding compound 10 (36mg, 0.15mmol), salt of wormwood (70mg, 0.51mmol).Heating reflux reaction 24 hours, TLC are followed the tracks of reaction and are finished.Be spin-dried for solvent, wash with saturated nacl aqueous solution behind the acetic acid ethyl dissolution.The water ethyl acetate extraction merges organic phase, anhydrous sodium sulfate drying.Sherwood oil: ethyl acetate=column chromatography obtained final product Nelfianvir33mg in 1: 1, two step productive rates 59%.

Claims (7)

1. the key intermediate of Yi Zhong Na Feinawei, it has following structural formula:
Figure C021361300002C1
Wherein, R=hydrogen, benzyl, carbobenzoxy-(Cbz), tertbutyloxycarbonyl, 3-acetoxyl group-2-methyl benzoyl or 3-hydroxy-2-methyl benzoyl; N=0,1 or 2, R 1=R 2=H, R 1And R 2=propylidene base, R 1And R 2=benzal base, R 1And R 2=3-pentylidene base; Condition is: when R=carbobenzoxy-(Cbz), n=0, and R 1=R 2≠ H and R 1And R 2≠ propylidene base or pentylidene base; When R=carbobenzoxy-(Cbz), n=2, R 1And R 2≠ H.
2. the key intermediate of a kind of Na Feinawei as claimed in claim 1 is characterized in that having following structural formula:
Figure C021361300002C2
Perhaps
Figure C021361300002C3
Wherein, R=hydrogen, benzyl, tertbutyloxycarbonyl, 3-acetoxyl group-2-methyl benzoyl or 3-hydroxy-2-methyl benzoyl; N according to claim 1, R 3=R 4=methyl, R 3=R 4=ethyl, R 3=H and R 4=phenyl.
3. the key intermediate of a kind of Na Feinawei as claimed in claim 1 is characterized in that having following structural formula:
Figure C021361300002C4
Figure C021361300003C1
Figure C021361300004C1
4. the synthetic method of the key intermediate of a kind of Na Feinawei as claimed in claim 1, it is characterized in that by following (1) and (2), (3) and (4), (1), (2) and (5), (3), (4) and (6), (1), (2), (5) and (7), (1), (2), (5), (7) and (8) six kinds of methods are synthetic respectively:
(1) under-78 ℃-0 ℃ of organic solvent neutralization, phenyl methyl sulfoxide and lithium diisopropyl amido reaction 0.1-2 hour, adding (S)-sweet dew aldehyde reacts and obtained structural formula in 0.5-2 hour and be
Figure C021361300005C1
Alcohol product 2, wherein, the mol ratio of phenyl methyl sulfoxide, lithium diisopropyl amido and (S)-sweet dew aldehyde is 1: 1-1.2: 0.8-1.
Figure C021361300005C2
In organic solvent and under 0-50 ℃, the organic amine compound reaction that contains lone-pair electron on above-mentioned pure product 2, methylsulfonyl chloride and the nitrogen-atoms obtained structural formula in 0.5-10 hour and is
Figure C021361300005C3
Product 3, pure product
2, methylsulfonyl chloride and the mol ratio that contains the organic amine compound of lone-pair electron are 1: 1-1.5: 1-10;
(2) in polar solvent and under 30-100 ℃, above-claimed cpd 3 and excessive RNH 2Reacted 5-96 hour, and obtained structural formula and be
Figure C021361300005C4
Compound 4;
(3) under organic solvent neutralization-78-0 ℃, structural formula is
Figure C021361300005C5
Compound 5 and butyllithium reaction 0.5-1 hour; Adding structural formula is
Figure C021361300005C6
Phosphoryl chloride reaction 0.5-1 hour; Again with (S)-sweet dew aldehyde reaction 0.5-2 hour, obtain structural formula and be
Figure C021361300005C7
Compound 6, wherein, compound 5, butyllithium, above-mentioned phosphoryl chloride and (S)-sweet dew aldehyde mol ratio is followed successively by 1: 2-3: 1-1.5: 1-1.5;
(4) in polar solvent, above-mentioned compound 6 and excessive RNH 2Back flow reaction 5-96 hour, obtain structural formula and be
Figure C021361300005C8
Compound 7;
(5) in anhydrous acetonitrile and under the room temperature, above-claimed cpd 4, sodium iodide and Lewis acid reacted 2-12 hour, obtained structural formula and were
Figure C021361300006C1
Compound 8, wherein compound 4, sodium iodide, lewis acidic mol ratio are 1: 2-5: 2-5;
(6) under the effect of polar solvent catalyst neutralisation, 30-100 ℃ and (10-100) * 10 5Under the Pa pressure, structural formula is
Figure C021361300006C2
Compound 7a and hydrogen reaction obtain structural formula and be
Figure C021361300006C3
Compound 7b, the weight ratio of 7a and catalyzer is 1: 0.001-0.1, described catalyzer are palladium/carbon, palladium hydroxide/carbon, lanthanum niobium-nickel;
(7) in organic solvent, structural formula is
Figure C021361300006C4
Compound 8a and 3-acetoxyl group-2-tolyl acid and condensing agent reaction 1-3 days, obtain structural formula and be
Figure C021361300006C5
Compound 8b, the mol ratio of compound 8a and 3-acetoxyl group-2-tolyl acid and condensing agent is 1: 1-1.5: 1-5;
(8) in polar solvent and under the room temperature-40 ℃,, obtain structural formula and be with mineral acid acidifying compound 8b 1-5 hour
Figure C021361300006C6
Compound 9, the mol ratio of compound 8b and mineral acid is 1: 0.01-1;
R and does not have the described condition restriction of claim 1 according to claim 1 in above-mentioned; Described mineral acid is dilute hydrochloric acid, dilute sulphuric acid or dilute phosphoric acid; Described organic solvent is ethanol, acetonitrile, tetrahydrofuran (THF), anhydrous diethyl ether, sherwood oil, benzene or methylene dichloride; Described polar solvent is methyl alcohol, ethanol, propyl alcohol, dimethyl sulfoxide (DMSO), N, dinethylformamide or acetonitrile and their mixed solvents thereof; The organic amine compound that contains lone-pair electron on the described nitrogen-atoms is benzyl lauryl amine, triethylamine, benzyl lauryl amine, Tributylamine, trioctylamine, diisopropyl ethyl amine, pyridine, bipyridine, 1,8-diazacyclo [4.3.0]-5-nonene, 1,8-diaza-dicyclo-[5,4,0]-hendecene-7, N, O-two-(trimethyl silicon based) ethanamide, 4-(N, N-dimethyl)-pyridine or 1,4-diazacyclo [2.2.2] octane or their mixture; Described Lewis acid is a boron trifluoride diethyl etherate, titanium tetrachloride or titanous chloride; Described condensing agent is 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride, I-hydroxybenzotriazole, N, N '-dicyclohexylcarbodiimide or N-hydroxy-succinamide and their mixture.
5. the synthetic method of the key intermediate of a kind of Na Feinawei as claimed in claim 4, the organic amine compound that it is characterized in that containing on the described nitrogen-atoms lone-pair electron is triethylamine and 1, the mixture of 8-diaza-dicyclo-[5,4,0]-hendecene-7.
6. the synthetic method of the key intermediate of a kind of Na Feinawei as claimed in claim 4 is characterized in that reaction (2) is to carry out in tube sealing.
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