CN117964546A - Preparation method of nilaparib intermediate - Google Patents
Preparation method of nilaparib intermediate Download PDFInfo
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- CN117964546A CN117964546A CN202410366143.8A CN202410366143A CN117964546A CN 117964546 A CN117964546 A CN 117964546A CN 202410366143 A CN202410366143 A CN 202410366143A CN 117964546 A CN117964546 A CN 117964546A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 230000006340 racemization Effects 0.000 claims abstract description 22
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 87
- 239000000203 mixture Substances 0.000 claims description 60
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 14
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 14
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- SZTZMTODFHPUHI-JTQLQIEISA-N (3r)-3-(4-bromophenyl)piperidine Chemical compound C1=CC(Br)=CC=C1[C@@H]1CNCCC1 SZTZMTODFHPUHI-JTQLQIEISA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 18
- 238000001914 filtration Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000007670 refining Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
- 239000012452 mother liquor Substances 0.000 description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000004537 pulping Methods 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- -1 3- (4-bromophenyl) -1- (4- (piperidin-3-yl) -phenyl) piperidine Chemical compound 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000010009 beating Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- SZTZMTODFHPUHI-SNVBAGLBSA-N (3s)-3-(4-bromophenyl)piperidine Chemical compound C1=CC(Br)=CC=C1[C@H]1CNCCC1 SZTZMTODFHPUHI-SNVBAGLBSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical group [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- ZDFBKZUDCQQKAC-UHFFFAOYSA-N 1-bromo-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Br)C=C1 ZDFBKZUDCQQKAC-UHFFFAOYSA-N 0.000 description 1
- COUOFYDJUDASPJ-UHFFFAOYSA-N 4-piperidin-3-ylaniline Chemical compound C1=CC(N)=CC=C1C1CNCCC1 COUOFYDJUDASPJ-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 201000001342 Fallopian tube cancer Diseases 0.000 description 1
- 208000013452 Fallopian tube neoplasm Diseases 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 1
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 1
- 102100023652 Poly [ADP-ribose] polymerase 2 Human genes 0.000 description 1
- 101710144590 Poly [ADP-ribose] polymerase 2 Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 201000002628 peritoneum cancer Diseases 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- SWUANUQBXJNXGP-CYBMUJFWSA-N tert-butyl (3s)-3-(4-aminophenyl)piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC[C@H]1C1=CC=C(N)C=C1 SWUANUQBXJNXGP-CYBMUJFWSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Abstract
The invention belongs to the field of pharmaceutical chemistry preparation, and particularly relates to a preparation method of a nilaparib intermediate, which comprises the following steps: after the synthesized and resolved (R) -3- (4-bromophenyl) piperidine is added with a tert-butoxycarbonyl protecting group, the (R) -3- (4-bromophenyl) piperidine and potassium tert-butoxide undergo racemization reaction under the condition of a solvent to be converted into an S configuration, and the yield can be improved from 25% to above 53% after 2 times of circulation. The invention solves the problems that the prior art can not obtain the S-configuration compound with high yield and high purity, and the like, and has the advantages of simple operation, higher product purity, mild reaction, cost saving, suitability for industrial production and the like.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry preparation, in particular to a preparation method of an antitumor drug nilaparib intermediate.
Background
Nilapachone is a PARP-1 and PARP-2 inhibitor with better S-configuration cell activity and BRAC selectivity. The clinical trial phase is entered in 2008, and the clinical trial phase III is excellent in treating patients with BRCA mutant breast cancer defective in HER2 and ovarian cancer sensitive to platinum-based chemotherapeutics. On day 3 and 27 of 2017, the FDA approved it for maintenance therapy in patients with recurrent platinum-sensitive epithelial ovarian cancer, fallopian tube cancer or peritoneal cancer. The compound of formula II (S) -3- (4-bromophenyl) piperidine is a key intermediate of nilaparib drugs and contains chiral units of drug molecules,
。
The present literature concerning resolution and synthesis of this intermediate mainly discloses a process for the preparation of the nilaparil intermediate (S) -3- (4-bromophenyl) piperidine as follows CN108409638a, example 6, using tartaric acid resolution, yields 89%, ee values 99.5%, but practically no reproducibility of the results reported in the patent, and in theory, chiral resolution, limit theoretical value of single yield 50%, impossibility to reach 89% as described in the patent, the specific synthetic route of this patent being as follows:
；
in the route reported in WO2014088984A1, (3S) - (4-bromophenyl) piperidine is prepared by using butyric anhydride as a raw material through a multi-step reaction, the whole route involves the use of special transaminase, the price is high, the process cost is increased, the process strategy involves the use of zinc reagent, and the anhydrous condition is demanding:
；
Literature (Organic Process Research & Development 2011, 15, 831-840) reports a method for the synthesis of (S) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester: 3-pyridine boric acid is taken as a raw material, is firstly coupled with 4-nitrobromobenzene to obtain 3- (4-nitrobenzene) pyridine, and is then subjected to catalytic reduction by platinum oxide to obtain 4- (piperidin-3-yl) aniline, and is split by tartaric acid, wherein the synthetic route is as follows:
；
In the above synthesis method, platinum dioxide is used for reduction of the pyridine ring, and the cost increases. In the chemical resolution process, although the synthesis of the tube II is quite simple, the core of the resolution is piperidine ring, but the separation efficiency is low, and the theoretical yield is only 50% at maximum, because chiral high performance liquid chromatography purification is still required in the later stage of the synthesis even after the diastereoisomer salt is recrystallized for a plurality of times, the cost is high, and the other half enantiomer of the piperidine cannot be recycled by racemization.
Disclosure of Invention
In order to solve the technical problems, the invention adopts the technical scheme that the compound of the formula II is recycled: SM1 is used as a raw material, a raceme compound I is generated under the condition of borane/tetrahydrofuran, after a tert-butoxycarbonyl protecting group is added into (R) -3- (4-bromophenyl) piperidine remained after resolution, racemization reaction is carried out with potassium tert-butoxide under the condition of dimethyl sulfoxide solvent to convert into an S configuration, the product is circulated continuously, the yield can be improved to more than 53% from the original 25% after 2 times of circulation, and the raw material cost can be greatly reduced. The method specifically comprises the following steps:
(1) SM1 is used as a raw material, and reacts with boron trifluoride diethyl ether and sodium borohydride in tetrahydrofuran solvent to generate a compound I, and L-tartaric acid is used for resolution to obtain a compound shown in a formula II and a mixture shown in a formula III; the S configuration in the mixture of the formula III accounts for 25% -30%;
；
(2) Reacting the mixture of formula III with di-tert-butyl dicarbonate in dichloromethane and aqueous sodium carbonate to obtain a mixture of formula IV; racemizing the mixture of the formula IV and potassium tert-butoxide to obtain a mixture of the formula V, wherein the S configuration of the mixture of the formula V accounts for 45% -50%;
；
(3) Removing tert-butoxycarbonyl from the mixture of the formula V under the conditions of hydrochloric acid and dichloromethane to obtain a mixture of the formula VI, and resolving the mixture of the formula VI by using L-tartaric acid to obtain a compound of the formula II and a mixture of the formula III;
；
(4) Repeating step (2) and step (3) at least 2 times for the mixture of formula III obtained in step (3);
In some preferred embodiments, the molar ratio of the mixture of formula IV to potassium tert-butoxide in step (2) is 1:0.5;
in some preferred embodiments, the reaction time of racemization reaction of the mixture of formula IV in step (2) and potassium tert-butoxide is 2-3 hours;
In some preferred embodiments, the reaction temperature of the racemization reaction of the mixture of formula IV in step (2) and potassium tert-butoxide is 40-45 ℃;
In some preferred embodiments, the mixture of formula IV in step (2) is racemized with potassium tert-butoxide in dimethyl sulfoxide solvent;
in some preferred embodiments, the S configuration in the mixture of formula III is 27%;
in some preferred embodiments, the S configuration in the formula V mixture is 49%.
The beneficial effects obtained by the invention are as follows:
(1) The inventor unexpectedly found that if no tert-butoxycarbonyl protecting group is added before racemization reaction occurs, direct alkali addition can generate non-target product 3- (4-bromophenyl) -1- (4- (piperidin-3-yl) -phenyl) piperidine which is difficult to remove in the subsequent step, and the subsequent reaction can be cleaner by adding the tert-butoxycarbonyl protecting group for re-reaction;
(2) During racemization recovery, specific alkali-tertiary potassium butoxide is selected, the reaction temperature is only 40-45 ℃, the reaction condition is milder, the reaction time is greatly shortened, and the reaction can be completed in 3 hours;
(3) In the racemization process, the molar ratio of the mixture of the formula IV to the potassium tert-butoxide is 1: when the reaction yield is 0.5, the reaction ratio is too high, which can lead to the increase of side reactions and further lower yield, and the reaction ratio is too low, which can lead to the insufficient racemization degree;
(4) By adopting the technical scheme of the invention, the comprehensive utilization rate of the product can be improved, the cost of raw materials is reduced, and the product with higher yield, purity and ee value is obtained, thereby being more beneficial to the industrial production of the product.
Detailed Description
In order that the invention may be more readily understood, the invention will be further described with reference to the following examples. It should be understood that these examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention, and that the specific experimental methods not mentioned in the following examples are generally carried out in accordance with conventional experimental methods.
EXAMPLE 1 preparation of Compounds of formula II
Step one:
；
Step two:
；
step three:
；
Step one:
100g of SM1 was added to 500mL of tetrahydrofuran, and boron trifluoride diethyl etherate (212 g,4.0 eq) was added to the system at room temperature, followed by addition of sodium borohydride (56.4 g,4 eq) in portions. After the stirring is completed for more than 12 hours, sampling and central control are performed, after the central control is qualified, 300mL of methanol is slowly added into the system for quenching, then concentrated hydrochloric acid is dripped into the system, and the pH is adjusted to be 1-2. Concentrating until no fraction is obtained, adding dichloromethane (800 mL), dropwise adding 10% sodium hydroxide solution to adjust the pH to 9-10, separating liquid, extracting the water phase once again with dichloromethane (200 mL), combining organic phases, washing the organic phases once with 10% sodium chloride solution (500 mL), and concentrating under reduced pressure until no fraction is obtained to obtain the compound I. Dissolving the crude product without fraction by 1000mL of ethanol, adding L-tartaric acid (55.5 g, 1.0 eq), crystallizing and filtering, refluxing and pulping the filter cake by 200mL of ethanol for refining twice, cooling and filtering, adding 200mL of dichloromethane and 100mL of 25% sodium carbonate into the filter cake, stirring and layering, concentrating and drying an organic phase to obtain 22.1g of a compound of a formula II, wherein the yield is 25%, and the ee value is 99.88%;
Step two:
Concentrating the mixture of the formula III with the S configuration accounting for 25% -30% after resolution in the step one until no fraction is obtained, adding 800mL of dichloromethane and 300mL of 25% sodium carbonate aqueous solution and 80.0g of di-tert-butyl dicarbonate, stirring for 2h, standing for separating liquid, and concentrating an organic phase until no fraction is obtained to obtain 95.0g of mixture of the formula IV. Adding 500mL of dimethyl sulfoxide and 15.5g of potassium tert-butoxide, and stirring at 40 ℃ for 3 hours to react completely to obtain a mixture of the formula V with the S configuration accounting for 45% -50%;
Step three
800ML of methylene chloride was added to the mixture of formula V in the second step, and the mixture was washed 2 times with 300mL of 10% sodium chloride solution. 500mL of 2N hydrochloric acid was added and stirred overnight. 600mL of 10% sodium hydroxide aqueous solution is added, stirred and layered, the organic layer is washed with 300mL of 10% sodium chloride for 2 times, concentrated until no fraction is obtained to obtain a mixture VI, 800mL of ethanol and 40g L-tartaric acid are added, crystallization filtration is carried out, a filter cake is subjected to reflux beating refining twice by using 150mL of ethanol, cooling filtration is carried out, 120mL of dichloromethane and 60mL of 25% sodium carbonate are added into the filter cake, stirred and layered, and the organic phase is concentrated and dried to obtain 13.3g of a compound of a formula II. The mother liquor was recycled 2 times according to the above operation to obtain 7.3g and 4.2g of the compound of formula II, respectively. The mother liquor is recovered, the total 46.9g of the compound of the formula II obtained by the first resolution is added, the ee value is more than 99.8%, the purity is 99.2%, and the total yield is 53%;
comparative example 1 racemization screening of alkali species
Step one:
100.1g of SM1 was added to 500mL of tetrahydrofuran, and boron trifluoride diethyl etherate (212.2 g,4.0 eq) was added to the system at room temperature, followed by addition of sodium borohydride (56.3 g,4 eq) in portions. After the stirring is completed for more than 12 hours, sampling and central control are performed, after the central control is qualified, 300mL of methanol is slowly added into the system for quenching, then concentrated hydrochloric acid is dripped into the system, and the pH is adjusted to be 1-2. Concentrating until no fraction is obtained, adding dichloromethane (800 mL), dropwise adding 10% sodium hydroxide solution to adjust the pH to 9-10, separating liquid, extracting the water phase once again with dichloromethane (200 mL), combining organic phases, washing the organic phases once with 10% sodium chloride solution (500 mL), and concentrating under reduced pressure until no fraction is obtained to obtain the compound I. Dissolving the crude product without fraction with 1000mL of ethanol, adding L-tartaric acid (55.4 g, 1.0 eq), crystallizing and filtering, pulping and refining the filter cake with 200mL of ethanol twice, cooling and filtering, drying, 38.0g of the compound of the formula II, 26% yield and 99.9% ee value;
Step two:
Concentrating the mixture of the formula III with the S configuration ratio of 25% -30% after resolution in the step one until no fraction is obtained, adding 800mL of dichloromethane and 300mL of 25% sodium carbonate aqueous solution and 80.3g of di-tert-butyl dicarbonate, stirring for 2h, standing for separating liquid, and concentrating an organic phase until no fraction is obtained, thus obtaining 94.8g of mixture of the formula IV. Then 500mL of dimethyl sulfoxide and 15.4g of potassium hydroxide are added, and the mixture is stirred overnight at 100-110 ℃, and chiral chromatography shows S: the R ratio is still 1:2, substantially no racemization occurs;
As can be seen from the experiments of the embodiment 1 and the comparative example 1, in the reaction of racemizing the mixture IV into the mixture V, the influence of the type of the alkali on the racemization reaction is extremely important, and the experiment personnel surprisingly find that the reaction temperature only needs 40-50 ℃ when the specific alkali-tertiary potassium butoxide is selected in the experiment scheme, so that the reaction condition is milder, the reaction time is greatly shortened, and the reaction can be completed only by 3 hours.
Comparative example 2 racemization reaction base dosage screening
1. Step one:
100g of SM1 was added to 500mL of tetrahydrofuran, and boron trifluoride diethyl etherate (211.8 g,4.0 eq) was added to the system at room temperature, followed by addition of sodium borohydride (56.5 g,4 eq) in portions. After the stirring is completed for more than 12 hours, sampling and central control are performed, after the central control is qualified, 300mL of methanol is slowly added into the system for quenching, then concentrated hydrochloric acid is dripped into the system, and the pH is adjusted to be 1-2. Concentrating until no fraction is obtained, adding dichloromethane (800 mL), dropwise adding 10% sodium hydroxide solution to adjust the pH to 9-10, separating liquid, extracting the water phase once again with dichloromethane (200 mL), combining organic phases, washing the organic phases once with 10% sodium chloride solution (500 mL), and concentrating under reduced pressure until no fraction is obtained to obtain the compound I. Dissolving the crude product without fraction by 1000mL of ethanol, adding L-tartaric acid (55.6 g, 1.0 eq), crystallizing and filtering, refluxing and pulping the filter cake by 200mL of ethanol for refining twice, cooling and filtering, adding 200mL of dichloromethane and 100mL of 25% sodium carbonate into the filter cake, stirring and layering, concentrating and drying an organic phase to obtain 22.4g of a compound of a formula II, wherein the yield is 25%, and the ee value is 99.8%;
Step two:
Concentrating the mixture of the formula III with the S configuration ratio of 25% -30% after resolution in the step one until no fraction is obtained, adding 800mL of dichloromethane and 300mL of 25% sodium carbonate aqueous solution and 80.2g of di-tert-butyl dicarbonate, stirring for 2h, standing for separating liquid, and concentrating an organic phase until no fraction is obtained, thus obtaining 95.1g of mixture of the formula IV. Then 500mL of dimethyl sulfoxide and 31.0g of potassium tert-butoxide are added, and stirring is carried out for 3 hours at 45 ℃ to obtain a mixture of the formula V with the S configuration accounting for 45-50%;
Step three
To the mixture of formula V, 800mL of methylene chloride was added and washed 2 times with 300mL of 10% sodium chloride solution. 500mL of 2N hydrochloric acid was added and stirred overnight. 600mL of 10% sodium hydroxide aqueous solution is added, stirred and layered, the organic layer is washed with 300mL of 10% sodium chloride for 2 times, concentrated until no fraction is obtained to obtain a mixture VI, 800mL of ethanol and 40.2g L-tartaric acid are added, crystallization and filtration are carried out, a filter cake is subjected to reflux beating refining twice with 150mL of ethanol, cooling and filtration are carried out, 80mL of dichloromethane and 40mL of 25% sodium carbonate are added into the filter cake, stirred and layered, and an organic phase is concentrated and dried to obtain 9.1g of a compound of formula II. The mother liquor was recycled 2 times according to the above operation to obtain 4.85g and 2.42g of the compound of formula II, respectively. The mother liquor is recovered, the total amount of 38.8g of the compound of the formula II obtained by the first resolution is greater than 99.8%, the ee value is 99.0%, and the total yield is 43%.
2. Step one:
100.2g of SM1 was added to 500mL of tetrahydrofuran, and boron trifluoride diethyl etherate (211.9 g,4.0 eq) was added to the system at room temperature, followed by addition of sodium borohydride (56.3 g,4 eq) in portions. After the stirring is completed for more than 12 hours, sampling and central control are performed, after the central control is qualified, 300mL of methanol is slowly added into the system for quenching, then concentrated hydrochloric acid is dripped into the system, and the pH is adjusted to be 1-2. Concentrating until no fraction is obtained, adding dichloromethane (800 mL), dropwise adding 10% sodium hydroxide solution to adjust the pH to 9-10, separating liquid, extracting the water phase once again with dichloromethane (200 mL), combining organic phases, washing the organic phases once with 10% sodium chloride solution (500 mL), and concentrating under reduced pressure until no fraction is obtained to obtain the compound I. Dissolving the crude product without fraction by 1000mL of ethanol, adding L-tartaric acid (55.5 g, 1.0 eq), crystallizing and filtering, refluxing and pulping the filter cake by 200mL of ethanol for refining twice, cooling and filtering, adding 200mL of dichloromethane and 100mL of 25% sodium carbonate into the filter cake, stirring and layering, concentrating and drying an organic phase to obtain 22.3g of a compound of a formula II, wherein the yield is 25%, and the ee value is 99.8%;
Step two:
Concentrating the mixture of the formula III with the S configuration ratio of 25% -30% after resolution in the step one until no fraction is obtained, adding 800mL of dichloromethane and 300mL of 25% sodium carbonate aqueous solution and 80.3g of di-tert-butyl dicarbonate, stirring for 2h, standing for separating liquid, and concentrating an organic phase until no fraction is obtained, thus obtaining 95.3g of mixture of the formula IV. Then 500mL of dimethyl sulfoxide and 10.0g of potassium tert-butoxide are added, and stirring is carried out for 3 hours at 45 ℃ to obtain 94.0g of a mixture of the formula V with the S configuration accounting for 35-40%;
Step three
To the mixture of formula V, 800mL of methylene chloride was added and washed 2 times with 300mL of 10% sodium chloride solution. 500mL of 2N hydrochloric acid was added and stirred overnight. 600mL of 10% sodium hydroxide aqueous solution is added, stirred and layered, the organic layer is washed with 300mL of 10% sodium chloride for 2 times, concentrated until no fraction is obtained to obtain a mixture VI, 800mL of ethanol and 40.1g L-tartaric acid are added, crystallization and filtration are carried out, a filter cake is subjected to reflux beating refining twice with 150mL of ethanol, cooling and filtration are carried out, 80mL of dichloromethane and 40mL of 25% sodium carbonate are added into the filter cake, stirred and layered, and the organic phase is concentrated and dried to obtain 6.9g of a compound of formula II. The mother liquor was recycled 2 times according to the above operation to obtain 3.4g and 1.7g of the compound of formula II, respectively. The mother liquor is recovered, and the total 34.3g of the compound of the formula II obtained by the first resolution is obtained, the ee value is more than 99.8%, the purity is 99.0%, and the total yield is 38%.
As can be seen from examples 1, comparative examples 1 and 2, in the reaction in which the mixture IV was racemized to the mixture V, the influence of the amount of the base on the racemization reaction was extremely important, and the specific amount of the base selected in example 1 was used to make the reaction more sufficient, and too high an amount of the base would cause the side reaction to increase and the yield to be lower, and too low an amount would cause the racemization reaction to be insufficient.
Comparative example 3 direct addition of base racemization without di-tert-butyl dicarbonate step
Step one:
100.2g of SM1 was added to 500mL of tetrahydrofuran, and boron trifluoride diethyl etherate (212.3 g,4.0 eq) was added to the system at room temperature, followed by addition of sodium borohydride (56.8 g,4 eq) in portions. After the stirring is completed for more than 12 hours, sampling and central control are performed, after the central control is qualified, 300mL of methanol is slowly added into the system for quenching, then concentrated hydrochloric acid is dripped into the system, and the pH is adjusted to be 1-2. Concentrating until no fraction is obtained, adding dichloromethane (800 mL), dropwise adding 10% sodium hydroxide solution to adjust the pH to 9-10, separating liquid, extracting the water phase once again with dichloromethane (200 mL), combining organic phases, washing the organic phases once with 10% sodium chloride solution (500 mL), and concentrating under reduced pressure until no fraction is obtained to obtain the compound I. Dissolving the crude product without fraction by 1000mL of ethanol, adding L-tartaric acid (55.2 g, 1.0 eq), crystallizing and filtering, refluxing and pulping the filter cake by 200mL of ethanol for refining twice, cooling and filtering, adding 200mL of dichloromethane and 100mL of 25% sodium carbonate into the filter cake, stirring and layering, concentrating and drying an organic phase to obtain 23.5g of a compound of a formula II, wherein the yield is 26%, and the ee value is 99.8%;
Step two:
concentrating the mixture of the formula III after resolution in the step one until no fraction is obtained, adding 800mL of dichloromethane and 300mL of 25% sodium carbonate aqueous solution, stirring for 2h, standing for separating, and concentrating the organic phase until no fraction is obtained. Adding 500mL of dimethyl sulfoxide and 15.3g of potassium tert-butoxide, stirring overnight at 100-110 ℃ to obtain a non-target product 3- (4-bromophenyl) -1- (4- (piperidin-3-yl) -phenyl) piperidine, and adding 27% of the total yield obtained in the step one of the compound II, 99% of purity and 99.8% of ee value;
As can be seen from the data of comparative examples 1 and 3, it is necessary to protect the nitrogen atom with t-butoxycarbonyl before racemization reaction, and if not, a non-target product which is difficult to remove is produced in the subsequent racemization reaction, and racemization effect is poor and even racemization reaction does not occur.
Experiments of the embodiment 1 and the comparative examples 1-3 show that the preparation method of the nilaparib intermediate has the advantages of high product yield and purity, mild reaction, short reaction time, low cost and the like, and is suitable for industrial production.
Claims (5)
1. A preparation method of a nilaparib intermediate, which is characterized by comprising the following steps of:
(1) SM1 is used as a raw material, and reacts with boron trifluoride diethyl ether and sodium borohydride in tetrahydrofuran solvent to generate a compound I, and L-tartaric acid is used for resolution to obtain a compound shown in a formula II and a mixture shown in a formula III; the S configuration in the formula III mixture accounts for 25% -30%,
；
(2) Reacting the mixture of formula III with di-tert-butyl dicarbonate in dichloromethane and aqueous sodium carbonate to obtain a mixture of formula IV; racemizing the mixture of the formula IV and potassium tert-butoxide to obtain a mixture of the formula V, wherein the S configuration of the mixture of the formula V accounts for 45% -50%,
；
(3) Removing tert-butoxycarbonyl from the mixture of formula V under the conditions of hydrochloric acid and dichloromethane to obtain a mixture of formula VI, resolving the mixture of formula VI by using L-tartaric acid to obtain a mixture of formula II and a mixture of formula III,
；
(4) And (3) repeating the step (2) and the step (3) at least 2 times for the mixture of the formula III obtained in the step (3).
2. The process of claim 1, wherein the molar ratio of the mixture of formula IV to potassium tert-butoxide in step (2) is 1:0.5.
3. The process of claim 1, wherein the step (2) is carried out for a period of 3 hours for racemization of the mixture of formula IV with potassium tert-butoxide.
4. The method according to claim 1, wherein the reaction temperature of the racemization reaction of the mixture of formula IV and potassium tert-butoxide in step (2) is 40-45 ℃.
5. The process of claim 1, wherein the step (2) comprises racemizing the mixture of formula IV with potassium tert-butoxide in dimethyl sulfoxide solvent.
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