CN104341320A - Preparation method of key intermediate VIII of saxagliptin - Google Patents
Preparation method of key intermediate VIII of saxagliptin Download PDFInfo
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- CN104341320A CN104341320A CN201310344897.5A CN201310344897A CN104341320A CN 104341320 A CN104341320 A CN 104341320A CN 201310344897 A CN201310344897 A CN 201310344897A CN 104341320 A CN104341320 A CN 104341320A
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- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 title claims abstract description 22
- 229960004937 saxagliptin Drugs 0.000 title claims abstract description 22
- 108010033693 saxagliptin Proteins 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims description 15
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 238000007059 Strecker synthesis reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 73
- 239000002253 acid Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000011347 resin Substances 0.000 claims description 8
- 229920005989 resin Polymers 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
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- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical class ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a new method for preparing a key intermediate of saxagliptin. According to the new method, 1-adamantanecarboxylic acid serving as a raw material is subjected to oxidization, maleation, reduction, oxidization, Strecker reaction, hydrolysis, protective group removal and other steps to finally obtain a key intermediate VIII of saxagliptin. The raw material related to the method is cheap and easily available; reaction conditions are mild and environmental friendliness is achieved; the prepared product has high optical purity and chemical purity and has good industrial production prospect. The chemical formula of the key intermediate of saxagliptin is as shown in the specification.
Description
Technical field
The invention belongs to technical field of organic synthesis.Be specially a kind of brand-new synthetic method of efficient dipeptidyl peptidase-4 (Dipeptidyl Peptidase4, DPP-4) inhibitor BMS-477118 key intermediate.
Background technology
BMS-477118 (saxagliptin) Bristol-Myers Squibb Co. and Astrazeneca AB of Britain cooperative research and development, and in the efficient dipeptidyl peptidase-4 of one (the Dipeptidyl Peptidase4 of listing on July 31st, 2009, DPP-4) inhibitor, by Selective depression DPP-4, endogenous glucagon-like-peptide-1 (Glucagon-like Peptide-1 can be raised, and glucose dependency pancreotropic hormone release polypeptide (Glucose-dependent Insulinotropic Peptide GLP-1), GIP) level, thus regulate blood sugar.
After having meal, GLP-1 secretes immediately at enteron aisle, and then stimulating pancreas produces glucose dependent insulin secretion, and glucagon suppression secretion simultaneously, postpones stomach emptying.Under physiological status, DPP-4 GLP-1 and GIP capable of being fast degraded, make it lose activity, and take DPP-4 inhibitor can make endogenous GLP-1 level raise 3 ~ 4 times, effective reduction glycolated hemoglobin (HbAlc) and postprandial blood sugar, and do not affect body weight, there is no obvious risk of hypoglycemia.Multinomial BMS-477118 clinical study consecutive publications, unanimously confirms that it reduces HbAlc, fasting plasma glucose (FPG), postprandial blood sugar (PPG) level and good tolerance and security effect.
BMS-477118 (saxagliptin) chemistry is by name: (1S; 3S; 5S)-2-[(2S)-2-amino-2-(3-hydroxyl three ring [3.3.1.13; 7] decane-1-base) ethanoyl]-2-azabicyclo [3.1.0] hexane-3-nitrile, chemical formula is as follows:
WO2005106011A2 discloses a kind of synthesis technique of BMS-477118, and this technique provides the scheme of the adamantine amino acid that several preparation structure VIII (as follows)-Boc-protects.
Scheme 1: use adamantyl bromine (1) to give alkylation to produce Alpha-hydroxy three ring [3.3.1.13,7] decane-1-acetic acid (A) by zinc chloride katalysis.Then use the method for Acetyl Chloride 98Min. esterification that Alpha-hydroxy three ring [3.3.1.13,7] decane-1-acetic acid (A) esterification is formed Alpha-hydroxy three ring [3.3.1.13,7] decane-1-methyl acetate (B).Then be oxidized Alpha-hydroxy three ring [3.3.1.13 via Swern, 7] hydroxyl oxygen on decane-1-methyl acetate (B) changes into α-one base three ring [3.3.1.13,7] decane-1-methyl acetate (C), again under concentrated nitric acid and the vitriol oil send out acting in conjunction hydroxylation to form 3-hydroxyl-alpha-one base three ring [3.3.1.13,7] decane-1-methyl acetate (D), 3-hydroxyl-alpha-one base three ring [3.3.1.13,7] decane-1-acetic acid (6) is formed through ester hydrolysis.And then use the enzyme enriched material (PDH/FDH) of ammonium formiate, Reduced nicotinamide-adenine dinucleotide, dithiothreitol (DTT) and partially purified Phenylalanine dehydrogenase/hydrogenlyase to process the acid of structure (6); this acid is made to carry out reductive amination process; finally use tert-Butyl dicarbonate process when not emanating; the structure (7) generated; to form the adamantine amino acid (8) that key intermediate Boc-protects, reaction formula is as follows:
In this scheme, reactions steps is long, in the preparation process of A to B, use the Swern oxidation adopted in the oxidising process of a large amount of Acetyl Chloride 98Min.s and B to C hydroxyl use a large amount of oxalyl chlorides, condition is very high to anhydrous requirement, the control of temperature is also very strict, and produce the dimethyl sulphide with strong odor in this process, serious environment pollution; The enzyme enriched material (PDH and FDH) being used Phenylalanine dehydrogenase and hydrogenlyase at the reduction amination of compound (6) is prepared very difficult, and it is expensive, institute in this way condition is harsh, and cost is high, is difficult to realize suitability for industrialized production.
The chloro-1-methoxyl group-vinyloxy group of scheme 2:(2,2-bis-)-trimethyl silane (3) is (EP0808824A3 slightly improving preparation with the method for the people such as Kuroda; Imashiro and Kuroda Tetrahedron Letters200142:1313-1315).Under zinc chloride impact, the chloro-7 sour methyl esters of diamantane-1-base-two that bromo diamantane (Reetz et al.Chem.Int.Ed.Engl.197918:72:Reetz and Heimbach Chem.Ber.1983116:3702-3707:Reetz et a1.Chem.Ber.1983116:3708-3724) produces (4) are processed with (3).Then use nitrogen oxide (nitric oxide) in concentrated sulfuric acid (4) diamantane-1-base-dichloro-acetic methyl ester to be given hydroxylation, (5) two of quantitative yield chloro-(3-hydroxy-adamant-1-base)-methyl acetate is provided.At room temperature (5) compound hydrolysis is produced (5a) two chloro-(3-hydroxy-adamant-1-base)-acetic acid with the methanol aqueous solution of sodium hydroxide, use weak base subsequently, preferred sodium bicarbonate, cause all forming 3-hydroxyl-alpha-one base three ring [3.3.1.13,7] decane-1-acetic acid (6) at pyroprocessing (5a) two chloro-(3-hydroxy-adamant-1-base)-acetic acid.Then the enzyme enriched material (PDH/FDH) of ammonium formiate, Reduced nicotinamide-adenine dinucleotide, dithiothreitol (DTT) and partially purified Phenylalanine dehydrogenase/hydrogenlyase is used to process the acid of structure (6); this acid is made to carry out reductive amination process; and tert-Butyl dicarbonate process is used when not emanating; the structure (7) generated; to form the adamantine amino acid that key intermediate Boc protects, reaction formula is as follows:
Scheme 2 is the same with scheme 1, step is long, at the hydroxylation procedures of compound (4) to compound (5), condition is harsh, and the reduction amination of compound (6) becomes the enzyme enriched material (PDH and FDH) of Phenylalanine dehydrogenase and the hydrogenlyase used equally time (7), prepare very difficult, and it is expensive, and due to compound (7) be amino acid, very difficult in the aftertreatment such as purifying of product, the program is difficult to realize suitability for industrialized production.
Summary of the invention
The present invention is directed to deficiency of the prior art, the preparation method of a kind of BMS-477118 key intermediate VIII is provided.
The technical solution adopted in the present invention is: the preparation method of BMS-477118 key intermediate VIII, key intermediate VIII
With compound VI II for raw material,
After nitrogen-atoms deprotection, protect again with tertbutyloxycarbonyl, obtain key intermediate VIII,
Wherein, R1 is (replacement) phenyl, R2 is hydroxyl, alkoxyl group.
Compound VI I take compound VI as raw material,
Compound VI I is converted under acid effect,
Wherein, R1 is (replacement) phenyl, and R2 is hydroxyl, alkoxyl group.
Wherein, compound VI, with after dissolution with solvents, adds acid, through heating, stir, filter, ammoniacal liquor dissociates, after concentrated liquor compound VI I.
Wherein, acid is mineral acid, and example hydrochloric acid, sulfuric acid etc., also can be various acidic resins, as acidic ion exchange resin.
Compound VI with compound V for raw material,
Compound VI is transformed to obtain under alkali effect,
Wherein, R1 is (replacement) phenyl, R2 is hydroxyl, alkoxyl group.
Wherein, alkali is mineral alkali, as sodium carbonate, and salt of wormwood, lithium hydroxide, sodium hydroxide, cesium carbonate, potassium hydroxide, potassiumphosphate etc., preferred salt of wormwood.
Compound V take compound III as raw material,
With compound IV
Through Strecker reaction, obtain compound V.
Wherein, R1 can be (replacement) phenyl, R2 is hydroxyl, alkoxyl group.
Concrete reaction formula involved in the present invention is as follows:
For achieving the above object, the concrete technical scheme taked of the present invention is as follows:
The first step, under low temperature, first concentrated nitric acid is added drop-wise in the vitriol oil, then adamantanecarboxylic acid is added in batches, reaction mixture is poured in frozen water, filters, and washing, can obtain Compound I after drying.
Second step, in non-proton organic solvent, under organic bases existent condition, adds protic organic solvent again by after Compound I acid anhydrides, is alcohol, obtains Compound II per with reductive agent reduction acid anhydrides.
In second step reaction, Compound I acid anhydrides, then generate Compound II per through reduction.Reductive agent is various reductive agent, preferred sodium borohydride.Anhydride reagent is various haloformate, preferred Vinyl chloroformate.Reduction reaction is generally carried out in alcoholic solvent, preferred Virahol.This step reaction is actually two-step reaction, and the present invention is groped by a large amount of conditions, reduces middle aftertreatment link, makes reaction be condensed to one pot and sends out, greatly save time and cost.Reaction terminates rear Compound II per can by ordinary method as extraction, and filter, making beating, the method purifying such as recrystallization obtain.
3rd step, in the mixing solutions of water and organic solvent, in the basic conditions, take TEMPO as catalyzer, Compound II per, under the effect of oxygenant, obtains compound III.
In three-step reaction, Compound II per obtains compound III, the preferred clorox of oxygenant through oxidation, and its consumption is at least 1 equivalent of Compound II per, preferably 1 to 2 equivalents; Catalyzer TEMPO consumption is at least 0.1 equivalent of Compound II per, preferably 0.1 to 0.2 equivalent; Temperature during oxidizing reaction must not higher than 10 degree.After reaction terminates, compound III can by ordinary method as extraction, and washing, the method purifying such as organic solvent making beating obtain.
4th step, in the mixed molten liquid of water and protic solvent, compound III and IV are obtained by reacting compound V through Strecker.
In four-step reaction, compound III and compound IV are obtained by reacting compound V through Strecker, and this reaction is carried out in water, and temperature of reaction is between room temperature to 100 is spent, and preferably 90 degree are carried out; After reaction terminates, compound V can by ordinary method as crossed post, and making beating, the method purifying such as recrystallization obtain.
5th step, in protic flux, under alkaline condition, compound V is through hydrolysis, and cyano group becomes acid amides, obtains compound VI.
In the 5th step reaction, compound V is hydrolyzed in the basic conditions and obtains compound VI, and temperature of reaction is between room temperature to 45 is spent, and preferably 45 degree are reacted; Alkali is various mineral alkali, preferred salt of wormwood.After reaction terminates, compound VI can by ordinary method as crossed post, and making beating, the method purifying such as recrystallization obtain.
6th step, compound VI, in acid condition through resin cation (R.C.) ion-exchange, makes acid amides be converted into carboxyl, thus generates compound VI I.
In six-step process, compound VI generates compound VI I through resin cation (R.C.) ion-exchange in acid condition, and compound VI is reacted in water, and temperature of reaction, between room temperature to 100 is spent, is preferably reacted at 100 degree.Compound VI I can be dissociated by ammoniacal liquor, and concentrated ammoniacal liquor of removing obtains pure product.
7th step, compound VI I goes up protecting group again after nitrogen-atoms Deprotection, namely generates the key intermediate VIII preparing BMS-477118.
In the 7th step reaction, compound VI I reacts in alcoholic solution, and temperature of reaction is between room temperature to 50 is spent.After reaction terminates, compound VI II can by ordinary method as crossed post, and making beating, the method purifying such as recrystallization obtain.
In this patent, unless otherwise mentioned:
" alkyl " comprises straight chain and the side chain of 1-8 carbon atom, comprises such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group etc.
" aryl " represents non-substituted carbon family aromatic group, such as phenyl, naphthyl etc., is good with phenyl.
" aralkyl " represents the alkyl containing 1-6 carbon atom replaced containing aryl, such as benzyl, styroyl etc.
Herein unless otherwise mentioned, the substituting group on aryl and aralkyl is one or more methyl or halogen, is good with one or two.
Compared with prior art, the present invention has following obvious advantage:
1. starting raw material of the present invention is as diamantane-1-formic acid, and benzene glycinol etc. is the raw material that generally adopts of organic drug synthesis field, low price and easily obtaining.
2. in the present invention, each step reaction temperature is all between-5 degree are to 100 degree, and major part reaction is solvent with water, and the requirement of reaction conditions to solvent is low, and simple and safe operation is environmentally friendly, easily carries out suitability for industrialized production.
3. in the present invention, each intermediate does not all need column chromatography purification, is such as extracted by ordinary method, making beating, and filter, crystallization, the working method such as recrystallization obtain, and aftertreatment is simple and convenient, realize large-scale production than being easier to.
4. the present invention is with diamantane-1-formic acid for starting raw material, and be obtained by reacting chirality adamantine amino acid VII through 7 steps, total recovery reaches 14%.The chemical purity of finished product is greater than 98%, and optical purity reaches more than 99%.
Accompanying drawing explanation
Fig. 1 is the structural analysis collection of illustrative plates of Compound II per in the present invention;
Fig. 2 is the structural analysis collection of illustrative plates of compound III in the present invention:
Fig. 3 is the structural analysis collection of illustrative plates of compound V in the present invention;
Fig. 4 is the structural analysis collection of illustrative plates of compound VI in the present invention;
Fig. 5 is the structural analysis collection of illustrative plates of compound VI I in the present invention;
Fig. 6 is the structural analysis collection of illustrative plates of compound VI II in the present invention..
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
In embodiment one and embodiment two: H1 is Compound I; H2 is Compound II per; H3 is compound III; H4, H4 ' be compound IV; H5, H5 ' be compound V; H6, H6 ' be compound VI; H7, H7 ' be compound VI I.
As shown in Figures 1 to 6,
Embodiment one:
The first step,
In dry there-necked flask, concentrated nitric acid (65%, 11mL, 0.11mol, 1.leq) is added drop-wise in the vitriol oil (110mL) below 10 DEG C.Add, diamantane-1-formic acid (18g, 0.1mol, leq) slowly joins in reaction below 10 DEG C.Add, 10-15 degree stirs 1-2 hour.TLC plate detection reaction, without raw material.Urea (15.2g, 0.25mol, 2.5eq) is dissolved in 200mL water, then cools to 0 DEG C, the acid solution of having reacted is added drop-wise in the urea soln of preparation below 15 DEG C, slowly adds, and releases a large amount of bubble.Add, 5-10 DEG C of reaction 0.5h.Filter, and wash twice solid with water.60 DEG C, forced air drying, obtains compound as white solid H1.Output: 15.6g, yield: 79.5%.
1H-NMR(400MHz，DMSO-d6)δ1.625-1.634(m，6H)，1.485-1.531(m，6H)，2.11(m，1H)。
Second step,
In dry there-necked flask, add compound H 1 (7.84g, 0.04mol, leq) and appropriate methylene dichloride, then add triethylamine (5g, 0.05mol, 1.25eq).Be cooled to 0 DEG C, drip Vinyl chloroformate (4.34g, 0.04mol, leq).After reacting completely, add 62.7mL Virahol, and then add sodium borohydride (2.28g, 0.06mol, 1.5eq), temperature raises, and releases a large amount of gas.Add, at room temperature react 1 hour.After reacting completely, add acetic acid (6.4g, 0.11mol, 2.64eq) and sodium bicarbonate (20.2g, 0.24mol, 6eq), stirred at ambient temperature 20 minutes.Concentrated except desolventizing, add methyl alcohol making beating, filter and remove salt, by methanol wash, concentrated dry crude product 24g, column chromatography obtains solid chemical compound H26.45g (structural analysis collection of illustrative plates is as Fig. 1), yield: 88%.
1H-NMR(400MHz，DMSO-d6)：δ1.292(m，6H)，1.460-1.549(m，6H)，2.074(m，2H)，2.991-3.002(m，2H)，3.333-3.354(m，2H)，4.328-4.383(m，1.36H)。
3rd step,
Under room temperature, compound H 2 (1.82g, 0.01mol, leq) is suspended in methylene dichloride (27.3mL).Add Potassium Bromide (0.06g, 0.0005mol, 0.05eq), saturated sodium bicarbonate aqueous solution (18.2mL) successively.Be cooled to 5 DEG C, add TEMPO (0.078g, 0.0005mol, 0.05eq), then below i0 DEG C, drip chlorine bleach liquor (20mL, 0.01mol, leq), add, react 20 minutes.Reaction color from depth to shallow.TLC shows without raw material.Leave standstill, layering, organic layer with saturated common salt water washing once, dry, concentrated, the compound H 3 (1.28g) (structural analysis collection of illustrative plates is as Fig. 2) that column chromatography purification obtains, yield: 71.1%.
1H-NMR(400MHz，CDCl
3)δ1.632-1.743(m，12H)，2.329(m，2H)，9.364(m，1H)。
4th step,
Compound H 3 (8.1g, 0.045mol, leq) is suspended in water (113mL), is cooled to 0-5 degree, then add sodium bisulfite (4.7g, 0.045mol, leq).Stir 30min and dissolve clarification.Add potassium cyanide (3.18g, 0.0468mol, 1.04eq), temperature 5 degree.Drip the ethanolic soln (6.16g/41mL, 0.045mol, 1eq) of compound H 4.Add, be warming up to room temperature reaction 2h.Then be warming up to 90 degree, stir 16h.TLC shows that reaction completes.Be cooled to 30 degree, add ethyl acetate (160mL), stir 30min.Leave standstill, layering.Collect organic phase, use saturated common salt water washing, dried over sodium sulfate, concentrate to obtain crude product.Column chromatography purification obtains compound H 5 (structural analysis collection of illustrative plates is as Fig. 3) and isomer.13.7g altogether, yield 93%.)
1H-NMR(400MHz，CDCl
3)：δ0.826-0.876(m，1H)，1.450-1.771(m，15H)，2.534(m，1H)，2.953(m，1H)，3.508-3.558(m，1H)，3.754-3.791(m，1H)，4.030-4.064(m，1H)，7.299-7.351(m，5H)。
5th step,
Compound H 5 (1g, 0.00307mol, leq) is dissolved in methyl alcohol (10mL), then adds lithium hydroxide (74mg, 0.00307mol, leq).Insoluble.Be cooled to 5 degree, add methyl-sulphoxide (958mg, 0.0123mol, 4eq), temperature 5 degree.Drip hydrogen peroxide (1.4mL0.0123mol, 4eq), temperature is 8 degree.Add, stir under 45 degree and spend the night.Be cooled to 30 degree, add water (20mL) and triethylamine (40mL) stirs 30min.Leave standstill, layering.Collect organic phase, aqueous phase is extracted with ethyl acetate (40mL × 2), merges organic phase saturated common salt solution washing, dried over sodium sulfate, concentrates to obtain crude product.Purification by silica gel column chromatography obtains compound H 6 (structural analysis collection of illustrative plates is as Fig. 4), altogether 690mg, yield: 65%.
1H-NMR(400MHz，CDC13)：δ1.168-1.646(m，12H)，2.048(m，2H)，2.327-2.357(m，1H)，2.623-2.652(m，1H)，3.157-3.342(m，5H)，3.440-3.471(m，1H)，4.322-4.336(m，1H)，4.899-4.928(m，1H)，6.930(m，1H)，7.190-7.301(m，5H)。
6th step,
Compound H 6 (0.6g, 0.00174mol, leq) is joined in 30mL water, then adds H type resin cation (R.C.) (12g).H type resin cation (R.C.) uses front ethanol and deionization washing.Add, be warming up to 100 degree, and react 16h under 100 degree, HPLC display reacts completely.Be cooled to 30 degree, elimination liquid, 5mL deionization is washed.Product is gone out by ammoniacal liquor desorption.Evaporated under reduced pressure, obtains H7 (500mg) (structural analysis collection of illustrative plates is as Fig. 5), yield 83%.
1H-NMR(400MHz，DMSO-d6)：δ1.227-1.257(m，3H)，1.432-1.584(m，9H)，2.069(m，2H)，2.419(m，1H)，3.257-3.500(m，5H)，4.376(m，1H)，7.221-7.325(m，5H)。
7th step,
Compound H 7 (400mg) is joined in methyl alcohol (10mL), then adds acetic acid (3mL), water (4mL).Stirring and dissolving adds 25% palladium hydroxide/carbon (200mg), passes into 50-60psi hydrogen, and 40 degree of reactions are spent the night.LCMS display reacts completely, and filters, filtrate reduced in volume.Crude product (300mg) is obtained after evaporated under reduced pressure, add methyl alcohol (3mL), the aqueous sodium hydroxide solution (3mL) of tetrahydrofuran (THF) (3mL) and 1M, adds tert-Butyl dicarbonate (600mg), 50 degree of reaction 2-3h.After LCMS display reacts completely, adjust pH to 3 with the hydrochloric acid of 2M after being cooled to room temperature, dichloromethane extraction, saturated common salt is washed, concentrating under reduced pressure after dried over sodium sulfate.Key intermediate VIII250mg product (structural analysis collection of illustrative plates is as Fig. 6) is obtained after column chromatography purification.Yield 70%.
1H-NMR(400MHz，DMSO-d6)：δ1.376-1.531(m，22H)，2.070(m，2H)，3.664-3.686(m，1H)，4.403(m，1H)，6.814-6.837(m，1H)，12.40(m，1H)。
Embodiment two:
The first step, second step, the 3rd step are identical with embodiment one.
4th step,
Compound H 3 (3.58g, 0.00199mol, leq) is suspended in 50mL water, is cooled to 0-5 degree, then add sodium bisulfite (2.07g, 0.00199mol, 1eq).Stir 30min and dissolve clarification.Add potassium cyanide (0.135g, 0.00207mmol, 1.04eq), temperature 5 degree.Drip the ethanolic soln (3.0g/18mL, 0.00199mmol, leq) of another kind of compound H 4 '.Add, be warming up to room temperature reaction 2h.Then be warming up to 90 degree, stir 16h.TLC shows that reaction completes.Be cooled to 30 degree, add triethylamine (72mL), stir 30min.Leave standstill, layering.Collect organic phase, use saturated common salt water washing, dried over sodium sulfate, concentrate to obtain crude product.Column chromatography purification obtains another kind of compound H 5 ' and isomer.6.1g, yield 90.2%. altogether)
5th step,
Compound H 5 ' (1g, 0.00294mol, 1eq) is dissolved in methyl alcohol (10mL), then adds lithium hydroxide (71mg, 0.00294mol, leq).Insoluble.Be cooled to 5 degree, add methyl-sulphoxide (920mg, 0.0118mol, 4eq), temperature 5 degree.Drip hydrogen peroxide (1.4mL0.0118mol, 4eq), temperature 8 degree.Add, stir under 45 degree and spend the night.Be cooled to 30 degree, add water (20mL), triethylamine (40mL) stirs 30min.Leave standstill, layering.Collect organic phase, aqueous phase is extracted with ethyl acetate (40mL × 2), merges organic phase saturated common salt solution washing, dried over sodium sulfate, concentrates to obtain crude product.Purification by silica gel column chromatography obtains compound H 6 ', altogether 670mg, yield: 63.6%.
6th step,
Compound H 6 ' (0.5g, 0.00139mol, leq) is joined in water (25mL), then adds H type resin cation (R.C.) (10g).H type resin cation (R.C.) uses front ethanol and deionization washing.Add, be warming up to 100 degree, and react 16h under 100 degree, HPLC display reacts completely.Be cooled to 30 degree, elimination liquid, deionized water (5mL) is washed.Product is gone out by ammoniacal liquor desorption.Evaporated under reduced pressure, obtains H7 ' (450mg), yield 89.8%.
7th step,
Compound H 7 ' (400mg) is joined in methyl alcohol (10mL), then adds acetic acid (3mL), water (4mL).Stirring and dissolving adds 25% palladium hydroxide 2/ carbon (200mg), passes into 50-60Psi hydrogen, and 40 degree of reactions are spent the night.LCMS display reacts completely, and filters, filtrate reduced in volume.Obtain 300mg crude product after evaporated under reduced pressure, add methyl alcohol (3mL), the aqueous sodium hydroxide solution (3mL) of tetrahydrofuran (THF) (3mL) and 1M, adds tert-Butyl dicarbonate (600mg), 50 degree of reaction 2-3h.After LCMS display reacts completely, adjust pH to 3 with the hydrochloric acid of 2M after being cooled to room temperature, dichloromethane extraction, saturated common salt is washed, concentrating under reduced pressure after dried over sodium sulfate.Key intermediate VIII260mg product is obtained after column chromatography purification.Yield 71.8%.
The foregoing is only and embody the preferred embodiment of the principle of the invention, therefore do not limit protection scope of the present invention, every equalization change done according to the present invention with modify within the scope of the claims of all containing in the present invention.
Claims (7)
1. the preparation method of BMS-477118 key intermediate VIII, is characterized in that: key intermediate VIII
With compound VI I for raw material,
After nitrogen-atoms deprotection, protect again with tertbutyloxycarbonyl, obtain key intermediate VIII,
Wherein, R1 is (replacement) phenyl, R2 is hydroxyl, alkoxyl group.
2. the preparation method of BMS-477118 key intermediate VIII as claimed in claim 1, is characterized in that: described compound VI I take compound VI as raw material,
Compound VI I is converted under acid effect,
Wherein, R
1for (replacement) phenyl, R
2for hydroxyl, alkoxyl group.
3. the preparation method of BMS-477118 key intermediate VIII as claimed in claim 2, is characterized in that: described compound VI, with after dissolution with solvents, adds acid, through heating, stir, filter, ammoniacal liquor dissociates, after concentrated liquor compound VI I.
4. the preparation method of BMS-477118 key intermediate VIII as claimed in claim 2 or claim 3, is characterized in that: described acid is mineral acid or acidic resins.
5. the preparation method of BMS-477118 key intermediate VIII as claimed in claim 2, is characterized in that: described compound VI with compound V for raw material,
Compound VI is transformed to obtain under alkali effect,
Wherein, R
1for (replacement) phenyl, R
2for hydroxyl, alkoxyl group.
6. the preparation method of BMS-477118 key intermediate VIII as claimed in claim 5, is characterized in that: described alkali is mineral alkali.
7. the preparation method of BMS-477118 key intermediate VIII as claimed in claim 5, is characterized in that: described compound V take compound III as raw material,
With compound IV
Through Strecker reaction, obtain compound V,
Wherein, R
1can be (replacement) phenyl, R
2for hydroxyl, alkoxyl group.
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| WO2013111158A2 (en) * | 2012-01-03 | 2013-08-01 | Msn Laboratories Limited | Process for the preparation of dpp-iv inhibitor |
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| WO2013111158A2 (en) * | 2012-01-03 | 2013-08-01 | Msn Laboratories Limited | Process for the preparation of dpp-iv inhibitor |
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